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

Abstract

There is provided a pharmaceutical formulation comprising an antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4Rα). The formulation may include, in addition to the anti-IL-4Rα 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 formulation exhibits a significant degree of antibody stability in the presence of lipase, without visible particle formation that is not apparent to the naked eye, during storage and after being subjected to heat and other physical stresses.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 337,532, filed on May 2, 2022, the entire contents of which are incorporated herein by reference.

[0002] Reference to a Sequence Listing This application incorporates by reference a computer - readable sequence listing in ST.26 XML format entitled 11200WO01_Sequence, created on Apr. 24, 2023, and containing 369,229 bytes.

[0003] The present invention relates to the field of therapeutic antibody formulations. More specifically, the present invention relates to the field of pharmaceutical formulations comprising human antibodies that specifically bind to human interleukin - 4 receptor alpha.

Background Art

[0004] Interleukin - 4 (IL - 4) and interleukin - 13 (IL - 13) are important cytokines in driving allergic and T - helper cell type 2 (Th2) polarized inflammatory processes. IL - 4 and IL - 13 signaling is mediated through a heterodimeric receptor complex, and interleukin - 4 receptor alpha (IL - 4Rα) is a shared receptor subunit for both IL - 4 and IL - 13 signaling. Thus, IL - 4Rα is an attractive therapeutic target as it provides a single target for blocking both IL - 4 and IL - 13 signaling. Antibodies against hIL - 4Rα are described, for example, in U.S. Pat. Nos. 5,717,072, 7,186,809, and 7,605,237.

[0005] Therapeutic polymers (e.g., antibodies) must be formulated in a manner that not only renders the molecule suitable for administration to a patient but also maintains its stability during storage. For example, a therapeutic antibody in a liquid solution tends to undergo degradation, aggregation, and / or undesirable chemical modifications unless the solution is appropriately formulated. The stability of an antibody in a liquid formulation depends not only on the type of excipients used in the formulation but also on the amounts and ratios of the excipients relative to each other. Therapeutic formulations can also be subject to the formation of particulate matter over time during storage. The particles may be visible or invisible, and invisible particles are typically less than 150 microns or 100 microns in diameter. Formulations having a high protein concentration, e.g., a concentration of 30 mg / mL or higher, tend to aggregate and form invisible particles.

[0006] Polysorbate 20 and polysorbate 80 are commonly used in the formulation of biological polymers such as antibodies. However, polysorbates, including polysorbate 20 and polysorbate 80, can be degraded in the presence of lipase, which has been reported to result in the formation of invisible particles in the formulation over time. Without intending to be bound by theory, putative phospholipase B-like 2 (PLBL2), which is highly conserved in hamster, rat, mouse, human, and bovine, is thought to co-purify with some classes of proteins under certain processes. One solution to this problem is to employ a protein purification process that removes or reduces the activity of lipase. See, e.g., US 10,342,876. However, there remains a need for alternatives for formulating antibodies such as anti-hIL-4Rα antibodies in a manner that avoids or minimizes the formation of invisible particles while still maintaining sufficient stability and compatibility for administration to a patient. SUMMARY OF THE INVENTION

[0007] 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.

[0008] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation comprising: (i) a human antibody that specifically binds to the human interleukin-4 receptor alpha (hIL-4Rα); (ii) one or more buffers; (iii) a heat stabilizer; (iv) a viscosity reducing agent; and (v) a 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, and the formulation has a pH of 5.7 to 6.1.

[0009] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation comprising: (i) a human antibody that specifically binds to the human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region (HCVR) comprising 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 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, and the formulation has a pH of 5.7 to 6.1.

[0010] In some embodiments, the antibody comprises a heavy chain variable region (HCVR) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, each comprising the amino acid sequences of SEQ ID NOs: 3, 4, and 5, respectively, and a light chain variable region (LCVR) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, each comprising the amino acid sequences of SEQ ID NOs: 6, 7, and 8, respectively. In some embodiments, the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0011] In some embodiments, the antibody has a human IgG heavy chain constant region. Optionally, the heavy chain constant region is of isotype IgG1. Optionally, the heavy chain constant region is of isotype IgG4.

[0012] 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.

[0013] In some embodiments, the surfactant is polyethylene glycol. Optionally, the polyethylene glycol is PEG3350. In some embodiments, the surfactant is present at a concentration of from 0.0075% w / v to less than 1% w / v, from 0.0075% w / v to 0.75% w / v, from 0.01% w / v to 0.5% w / v, or from 0.01% w / v to 0.25% w / v, and in some embodiments, the surfactant is present at a concentration of from 0.01% w / v to 0.19% w / v, for example, from 0.01% w / v to 0.15% w / v or from 0.05% w / v to 0.15% w / v. In some embodiments, the surfactant is present at a concentration of 0.15% w / v or less.

[0014] In some embodiments, the surfactant is a poloxamer. Optionally, the poloxamer is poloxamer 188. In some embodiments, the surfactant is present at a concentration of from 0.0075% w / v to 0.19% w / v, or from 0.01% w / v to 0.19% w / v, for example, from 0.01% w / v to 0.15% w / v or from 0.05% w / v to 0.15% w / v. In some embodiments, the surfactant is present at a concentration of 0.15% w / v or less.

[0015] In some embodiments, the buffer comprises an acetate buffer and / or a histidine buffer. In some embodiments, the buffer comprises acetate at a concentration of 10 mM to 15 mM and / or histidine at a concentration of 15 mM to 25 mM. In some embodiments, the acetate is present at a concentration of 12.5 mM ± 1.25 mM. In some embodiments, the histidine is present at a concentration of 20 mM ± 2 mM. In some embodiments, the heat stabilizer is sucrose at a concentration of 5% w / v ± 0.5% w / v. In some embodiments, the viscosity reducing agent is arginine at a concentration of 25 mM ± 2.5 mM. In some embodiments, arginine is present at a concentration of 50 mM ± 2.5 mM. In some embodiments, arginine is present at a concentration of 75 mM ± 2.5 mM.

[0016] 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.

[0017] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of 150 mg / mL ± 10 mg / mL, the antibody specifically binds to human interleukin-4 receptor alpha (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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2. Optionally, 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.

[0018] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, the antibody specifically binds to human interleukin-4 receptor alpha (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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2. Optionally, 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.

[0019] In some embodiments, the formulation comprises a phospholipase. In some embodiments, the phospholipase protein is phospholipase B-like 2 protein.

[0020] In some embodiments, the stable liquid pharmaceutical formulations contemplated herein contain 4% or less high molecular weight (HMW) species after stirring at 25 °C for 24 hours, as determined by size exclusion ultra-performance liquid chromatography (SE-UPLC). In some embodiments, the formulation contains 4% or less 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.

[0021] In some embodiments, the formulation contains 3% or less high molecular weight (HMW) species after vortexing at room temperature for up to 120 minutes, as determined by size exclusion ultra-performance liquid chromatography (SE-UPLC). Optionally, the formulation contains 2.5% or less high molecular weight (HMW) species after vortexing at room temperature for up to 120 minutes, as determined by SE-UPLC.

[0022] In some embodiments, the formulation contains 8% or less high molecular weight (HMW) species after storage at 45 °C for 30 days, as determined by SE-UPLC. Optionally, the formulation contains 9% or less high molecular weight (HMW) species after storage at 45 °C for 40 days, as determined by SE-UPLC. Optionally, the formulation contains 11% or less high molecular weight (HMW) species after storage at 45 °C for 50 days, as determined by SE-UPLC.

[0023] In some embodiments, the formulation contains 1000 or fewer, 500 or fewer, 300 or fewer, or 150 or fewer particles having a diameter of ≧10 μm in a volume of 2.25 mL after storage at 5 °C for 6 months, as determined by microscopy, and the formulation contains a phospholipase protein.

[0024] In some embodiments, the formulation contains 1000 or fewer, 500 or fewer, 300 or fewer, or 150 or fewer particles having a diameter of ≧10 μm in a volume of 2.25 mL after storage at 5 °C for 36 months, as determined by microscopy, and the formulation contains a phospholipase protein.

[0025] In some embodiments, after storage at 5° C. for 6 months as determined by microscopy, the formulation contains 500 or fewer, 300 or fewer, 250 or fewer, or 50 or fewer particles having a diameter of ≧25 μm in a volume of 2.25 mL, and the formulation contains a phospholipase protein.

[0026] In some embodiments, after storage at 5° C. for 6 months as determined by microscopy, the formulation contains 500 or fewer, 300 or fewer, 250 or fewer, or 50 or fewer particles having a diameter of ≧25 μm in a volume of 2.25 mL, and the formulation contains a phospholipase protein.

[0027] In some embodiments, the formulation does not contain an esterase inhibitor.

[0028] In some embodiments, the stable liquid pharmaceutical formulation is contained in a glass vial.

[0029] In some embodiments, the stable liquid pharmaceutical formulation is contained in a syringe. Optionally, the syringe includes a plunger coated with fluorocarbon. Optionally, the syringe is a low tungsten syringe. Optionally, the syringe is a prefilled syringe. Optionally, the syringe is a prefilled staked needle syringe.

[0030] In some embodiments, the stable liquid pharmaceutical formulation is contained in a large volume device or a bolus syringe.

[0031] In one aspect, the present disclosure provides a pen-type or auto-injector delivery device containing the stable liquid pharmaceutical formulation described above or discussed herein. Optionally, the delivery device is a disposable pen-type delivery device. Optionally, the delivery device is a reusable pen-type delivery device.

[0032] In one aspect, the present disclosure provides a container containing the stable liquid pharmaceutical formulation described above or considered herein.

[0033] In one aspect, the present disclosure provides a kit comprising (i) a container containing the stable liquid pharmaceutical formulation described above or considered herein, and (ii) labeling for use of the pharmaceutical formulation. Optionally, the labeling describes subcutaneous administration of the pharmaceutical formulation. Optionally, the labeling describes intravenous administration of the pharmaceutical formulation.

[0034] In one aspect, the present disclosure provides a unit dosage form comprising the stable liquid pharmaceutical formulation described above or considered herein, wherein the antibody is present in an amount of 1 mg to 500 mg. Optionally, the antibody is present in an amount of about 100 mg. Optionally, the antibody is present in an amount of about 200 mg. Optionally, 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. Optionally, the syringe is a pre-filled syringe. In some embodiments, the formulation of the unit dosage form is contained in a pre-filled pen. In some embodiments, the formulation of the unit dosage form is contained in an auto-injector device.

[0035] In one aspect, the present disclosure provides a safety system delivery device containing the stable liquid pharmaceutical formulation described above or considered herein. Optionally, the safety system delivery device comprises a safety sleeve configured to extend by manual operation. Optionally, the safety system delivery device comprises a safety sleeve configured to automatically extend after injection of the stable liquid pharmaceutical formulation.

[0036] In various embodiments, any of the features or components of the above or the embodiments discussed herein may be combined, and such combinations are included within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another relevant value discussed above or herein so as to enumerate a range having values representing the upper and lower limits of the range, and such ranges are included within the scope of the present disclosure. Each of the values discussed above or herein may be represented with a variation of 1%, 5%, 10%, or 20%. For example, a concentration of 10 mM may be represented as 10 mM ± 0.1 mM (1% variation), 10 mM ± 0.5 mM (5% variation), 10 mM ± 1 mM (10% variation), or 10 mM ± 2 mM (20% variation).

[0037] Other embodiments will be apparent from consideration of the specification for practicing the invention.

Brief Description of the Drawings

[0038]

Figure 1

Figure 2A

Figure 2B

Figure 3

Mode for Carrying Out the Invention

[0039] Before describing the present invention, it should be understood that since the specific methods and experimental conditions described may vary, the present invention is not limited to such methods and conditions. Since the scope of the present invention is to be limited only by the appended claims, it should also be understood that the terms used herein are used for the purpose of describing only specific embodiments and are not intended to be limiting.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in connection with a specific recited numerical value or range of values means that the value can vary by up to 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, as well as all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0041] Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, but exemplary methods and materials are described herein. All patents, applications, and non-patent publications mentioned herein are hereby incorporated by reference in their entirety.

[0042] Pharmaceutical formulation As used herein, the expression "pharmaceutical formulation" means a combination of at least one active ingredient (e.g., an anti-IL-4Rα antibody capable of exerting a biological effect in a human or non-human animal), and at least one inactive ingredient which, when combined with the active ingredient and / or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. The term "formulation" as used herein means "pharmaceutical formulation" unless otherwise indicated. 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 alpha (hIL-4Rα). More specifically, the present disclosure includes pharmaceutical formulations comprising (i) a human antibody that specifically binds to hIL-4Rα, (ii) one or more buffers, (iii) a heat stabilizer, (iv) a surfactant (e.g., an organic co-solvent), and (v) a viscosity modifier. Such additional components may be included in the formulations of the present disclosure if they do not significantly interfere with the viscosity and stability of the formulation. Specific exemplary components and formulations included in the present disclosure are described in detail below.

[0043] In certain embodiments, the pharmaceutical formulations of the present disclosure can be fluid formulations. As used herein, the expression "fluid formulation" means a mixture of at least two components that exist mainly in a fluid state at about 2°C to about 45°C. Fluid formulations include, inter alia, liquid formulations. Fluid formulations can be of low, medium, or high viscosity depending on their specific components.

[0044] An antibody that specifically binds to human IL-4 receptor alpha The pharmaceutical formulations of the present disclosure may include a human antibody or an antigen-binding fragment thereof that specifically binds to human interleukin-4 receptor alpha (IL-4Rα). References herein to IL-4R antibodies also refer to antibodies that bind to hIL-4Rα.

[0045] As used herein, the term "antibody" generally refers to an immunoglobulin molecule containing four polypeptide chains, two heavy (H) chains and two light (L) chains, and multimers thereof (e.g., IgM), the chains of which are interconnected by disulfide bonds. However, immunoglobulin molecules consisting of only heavy chains (i.e., lacking light chains) are also included within the definition of the term "antibody". Each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region includes three domains, CH1, CH2, and CH3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region includes one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs) with relatively conserved regions called framework regions (FRs) interspersed therebetween. Each VH and VL is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0046] 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, for example, in the CDRs, particularly in CDR3 (e.g., mutations are introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences from the germline of another mammalian species, such as a mouse, are grafted onto a human framework sequence. 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 above or other embodiments discussed herein, the anti-IL-4R antibody may include a human kappa light chain. In any of the above or other embodiments discussed herein, the anti-IL-4R antibody may include a human lambda light chain.

[0047] In some embodiments, the antibodies of the present disclosure may be recombinant human antibodies. As used herein, the term "recombinant human antibody" refers to all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from an animal that is transgenic for human immunoglobulin genes (e.g., a mouse) (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, 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 genetically recombinant human antibodies are subjected to in vitro mutagenesis (or, in the case of using transgenic animals for human Ig sequences, somatic mutagenesis in vivo), so that the amino acid sequences of the V H region and V L region are derived from and related to the human germline V H sequence and V L sequence, but may not naturally exist in the human antibody germline repertoire in vivo.

[0048] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" (or simply "antibody portion" or "antibody fragment") of an antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to hIL-4Rα.

[0049] As used herein, an "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to hIL-4Rα is substantially free of antibodies that specifically bind to antigens other than hIL-4Rα).

[0050] The term "specifically binds" means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding can be characterized by a dissociation constant of at least about 1×10 -6 M or greater. 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 to other antigens, such as IL-4Rα molecules from other species (orthologs). In the context of the present disclosure, a multispecific (e.g., bispecific) antibody that binds to hIL-4Rα as well as one or more additional antigens is considered to "specifically bind" to hIL-4Rα. Further, an isolated antibody may be substantially free of other cellular materials and / or chemical substances. However, in some instances, an isolated antibody may be co-purified with phospholipase expressed by the mammalian cell line (e.g., CHO cells) in which the anti-IL-4R antibody is produced.

[0051] According to certain embodiments of the present disclosure, an anti-hIL-4R antibody, or an antigen-binding fragment thereof, comprises heavy chain complementarity determining regions HCDR1-HCDR2-HCDR3, each comprising the amino acid sequence of SEQ ID NO: 3-4-5, respectively. According to certain embodiments of the present disclosure, an anti-hIL-4R antibody, or an antigen-binding fragment thereof, comprises light chain complementarity determining regions LCDR1-LCDR2-LCDR3, each comprising the amino acid sequence of SEQ ID NO: 6-7-8, respectively. In certain embodiments, the anti-hIL-4R antibody, or an antigen-binding fragment thereof, comprises CDRs HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, each comprising the amino acid sequence of SEQ ID NO: 3-4-5-6-7-8, respectively. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment comprising 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).

[0052] In certain embodiments, the anti-hIL-4R antibody, or antigen-binding fragment thereof, each comprises heavy chain complementarity determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5, and has 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, the anti-hIL-4R antibody, or antigen-binding fragment thereof, each comprises light chain complementarity determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6-7-8, and has 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, each comprises heavy chain complementarity determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5, and has 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 each comprises light chain complementarity determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6-7-8, and has 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.

[0053] In certain embodiments, the 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, the 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, the anti-hIL-4R antibody, or antigen-binding fragment thereof, comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 1 / 2. In some embodiments, the anti-IL-4R antibody comprises, respectively, a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 1 / 2 and a human IgG1 heavy chain constant region. In some embodiments, the anti-IL-4R antibody comprises, respectively, a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 1 / 2 and a human IgG4 heavy chain constant region. In some embodiments, the anti-IL-4R antibody comprises, respectively, a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 1 / 2 and a human gG heavy chain constant region. In some embodiments, the anti-IL-4R antibody comprises, respectively, a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 1 / 2 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.

[0054] Other anti-IL-4R antibodies that can be used in the context of the methods of the present disclosure are referred to, for example, as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI 9314, antibodies known in the art, or anti-IL-4Rα antibodies described in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, U.S. Patent Application Publication No. US2021 / 0238294, or International Patent Application Publication No. WO2019 / 228405, WO2020 / 096381, WO2020 / 135471, WO2020 / 135710, or WO2020 / 239134, the contents of each of which are incorporated herein by reference.

[0055] In some embodiments, the anti-IL-4R antibody comprises one or more CDR, HCVR, and / or LCVR sequences described in Table 1 below.

[0056] The amount of the antibody or its antigen-binding fragment contained within the pharmaceutical formulation of the present disclosure can vary depending on the specific desired properties of the formulation, as well as the particular circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation can contain from about 1 mg / mL to about 500 mg / mL of the antibody, from about 5 mg / mL to about 250 mg / mL of the antibody, from about 5 mg / mL to about 200 mg / mL of the antibody, from about 15 mg / mL to about 200 mg / mL, from about 25 mg / mL to about 200 mg / mL of the antibody, from about 50 mg / mL to about 200 mg / mL of the antibody, from about 100 mg / mL to about 200 mg / mL, from about 125 mg / mL to about 175 mg / mL, or from about 150 mg / mL to about 200 mg / mL of the antibody. For example, the formulation of the present disclosure can be a liquid formulation containing from 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 an antibody or its antigen-binding fragment that specifically binds to hIL-4Rα. In certain embodiments, the pharmaceutical formulation can be a liquid formulation containing from 5 ± 0.5 mg / mL to 200 ± 20 mg / mL of the antibody, from 15 ± 1.5 mg / mL to 200 ± 20 mg / mL of the antibody, from 25 ± 2.5 mg / mL to 200 ± 20 mg / mL of the antibody, from 50 ± 5 mg / mL to 200 ± 20 mg / mL of the antibody, from 100 ± 10 mg / mL to 200 ± 20 mg / mL of the antibody, 150 ± 10 mg / mL of the antibody, or 175 ± 10 mg / mL.In some embodiments, the pharmaceutical formulation contains an anti-IL-4R antibody at 140±5 mg / mL to 160±5 mg / mL. Optionally, the pharmaceutical formulation contains an anti-IL-4R antibody at 165 mg / mL±5 mg / mL to 185 mg / mL±5 mg / mL. Optionally, the pharmaceutical formulation contains an anti-IL-4R antibody at 150 mg / mL±5 mg / mL. Optionally, the pharmaceutical formulation contains an anti-IL-4R antibody at 175 mg / mL±5 mg / mL.

[0057] Biological equivalents The present disclosure includes antibodies having an amino acid sequence that is different from those of the exemplary molecules disclosed herein but retains the ability to bind to hIL-4R. Such variant molecules may contain one or more additions, deletions, or substitutions of amino acids compared to the parent sequence, but exhibit a biological activity that is essentially equivalent to the biological activity of the antibodies discussed herein.

[0058] The present disclosure includes antigen-binding molecules that are biologically equivalent to any of the exemplary antibodies described herein. In some embodiments, the antigen-binding molecule is a biological equivalent of dupilumab. Two antibodies are considered to be biologically equivalent if, for example, under similar experimental conditions, at the same molar dose, when administered either as a single dose or multiple doses, they do not show a significant difference in the rate and extent of absorption, and are pharmaceutical equivalents or pharmaceutical alternatives. For some antibodies, the absorption range is equivalent, but the absorption rate is not equivalent. However, if the difference in absorption rate is intentional, reflected in the labeling, and, for example, not essential for obtaining the effective body drug concentration in chronic use and is considered not medically important for the specific pharmaceutical tested, then those antibodies can be considered biologically equivalent and are considered equivalents or pharmaceutical alternatives.

[0059] In one embodiment, two antibodies are biologically equivalent if there are no clinically significant differences in their safety, purity, and efficacy.

[0060] In one embodiment, two antibodies are biologically equivalent if a patient can be switched one or more times between a reference product and a biological product, and there is no expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity or a decrease in efficacy, compared to continuous therapy without such switching.

[0061] Biological equivalence can be demonstrated by in vivo and in vitro methods. Biological equivalence assays include, for example, (a) in vivo tests in humans or other mammals in which the concentration of an antibody or its metabolite is measured as a function of time in blood, plasma, serum, or other biological fluids, (b) in vitro tests that correlate with and reasonably predict human in vivo bioavailability data, (c) in vivo tests in humans or other mammals in which an appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time, and (d) appropriately controlled clinical trials that demonstrate the safety, efficacy, or bioavailability or biological equivalence of the antigen-binding protein.

[0062] Formulation Excipients and pH The pharmaceutical formulations of the present disclosure include one or more excipients. As used herein, the term "excipient" means any non-therapeutic agent added to a formulation to provide the desired consistency, viscosity, or stabilizing effect.

[0063] The pharmaceutical formulations of the present disclosure may also contain a buffer or buffer system that serves to maintain a stable pH and assist in the stabilization of the anti-IL-4R antibody. In some embodiments, the buffer or buffer system comprises at least one buffer having a buffering range that 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 some embodiments, the formulation has a pH of 5.9 ± 0.3. In some embodiments, the formulation has a pH of 5.9 ± 0.2. In some embodiments, the formulation has a pH of 5.9 ± 0.1. In certain embodiments, the buffer comprises a histidine buffer. In certain embodiments, the buffer comprises 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 comprises a histidine buffer at a concentration of 15 mM to 25 mM. In some embodiments, the buffer comprises a histidine buffer at a concentration of 20 mM ± 2 mM. Optionally, the histidine buffer is present at a concentration of 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, or 25 mM. In some embodiments, the buffer comprises an acetate buffer at a concentration of 10 mM to 15 mM. In some embodiments, the buffer comprises an acetate buffer at a concentration of 12.5 mM ± 1.25 mM. Optionally, the acetate buffer is present at a concentration of 10 mM, 10.5 mM, 11 mM, 11.5 mM, 12 mM, 12.5 mM, 13 mM, 13.5 mM, 14 mM, 14.5 mM, or 15 mM. In some embodiments, the formulations of the present disclosure contain both histidine and acetate buffers at any of the concentrations discussed above. Optionally, the formulation contains a histidine buffer at a concentration of 15 mM to 25 mM and an acetate buffer at a concentration of 10 mM to 15 mM. Optionally, the formulation contains a histidine buffer at a concentration of 20 mM ± 2 mM and an acetate buffer at a concentration of 12.5 mM ± 1.25 mM.

[0064] The pharmaceutical formulations of the present disclosure may also contain one or more carbohydrates, such as one or more sugars. The sugar can be a reducing sugar or a non-reducing sugar. A "reducing sugar" includes, for example, a sugar having a ketone group or an aldehyde group and contains a reactive hemiacetal group that enables 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. A non-reducing sugar is an acetal and can contain anomeric carbon that is substantially non-reactive with an amino acid or polypeptide to initiate the Maillard reaction. Specific examples of non-reducing sugars include sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose. Sugar acids include, for example, saccharic acid, gluconic acid, and other polyhydroxy sugars, and salts thereof. In some embodiments, the sugar is sucrose. In some cases, the sugar (e.g., sucrose) acts as a heat stabilizer for the anti-IL-4R antibody.

[0065] The amount of sugar (e.g., sucrose) contained within the pharmaceutical formulations of the present disclosure will vary depending on the specific circumstances in which the formulation is used and the intended purpose. In certain embodiments, the formulation can contain from about 0.1% to about 20% sugar, from about 0.5% to about 20% sugar, from about 1% to about 20% sugar, from about 2% to about 15% sugar, from about 3% to about 8% sugar, or from about 4% to about 6% sugar. For example, the pharmaceutical formulations of the present disclosure can 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 of the above percentages corresponds to weight / volume (w / v) percent.

[0066] The pharmaceutical formulations of the present disclosure may also contain one or more organic co-solvents in a type and amount that stabilizes the anti-IL-4R antibody under conditions of rough handling or agitation, such as orbital shaking. In some embodiments, the organic co-solvent is a surfactant. As used herein, the term "surfactant" means a substance that reduces the surface tension of the fluid in which it is dissolved and / or reduces the interfacial tension between oil and water. The surfactant can be ionic or non-ionic. Specific non-ionic surfactants that can be included in the formulations of the present disclosure include, for example, poloxamers such as poloxamer 188, and polyethylene glycol (PEG) such as PEG3350.

[0067] The amount of surfactant contained within the pharmaceutical formulations of the present disclosure can vary depending on the desired specific properties of the formulation, as well as the particular circumstances and the purpose for which the formulation is intended to be used. In certain embodiments, the formulation can contain at least about 0.0075% surfactant. In certain embodiments, the formulation can contain at least about 0.01% surfactant. In certain embodiments, the formulation can contain from about 0.0075% to about 0.5% surfactant. In certain embodiments, the formulation can contain less than 0.2% surfactant. In certain embodiments, the formulation can 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 0.09% surfactant, or from about 0.01% to about 0.09% surfactant. For example, the formulations of the present disclosure can 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% surfactant (e.g., poloxamer 188 or PEG 3350). In some embodiments, the formulation contains less than 0.2% poloxamer (e.g., poloxamer 188). In some embodiments, the formulation contains from about 0.0075% to 0.19% poloxamer 188. In some embodiments, the formulation contains from about 0.01% to 0.19% poloxamer 188. In some embodiments, the formulation contains less than 1% polyethylene glycol (e.g., PEG 3350). In some embodiments, the formulation contains from about 0.0075% to about 0.5% PEG 3350. In some embodiments, the formulation contains from about 0.01% to 0.19% PEG 3350.Each of the above ratios corresponds to a weight / volume (w / v) percent.

[0068] In certain embodiments, the pharmaceutical formulations of the present disclosure contain 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. Optionally, the amino acid (e.g., arginine) acts as a viscosity modifier for the anti-IL-4R antibody formulation.

[0069] The amount of amino acid contained within the pharmaceutical formulations of the present disclosure can vary depending on the desired specific properties of the formulation, as well as the particular circumstances and the intended purpose for which the formulation is to be used. In certain embodiments, the formulation can contain from about 1 mM to about 200 mM of amino acid, from about 5 mM to about 150 mM, from about 10 mM to about 100 mM of amino acid, from about 20 mM to about 80 mM of amino acid, from about 20 mM to about 30 mM of amino acid, from about 45 mM to about 55 mM of amino acid, or from about 70 mM to about 80 mM of amino acid. For example, the pharmaceutical formulations of the present disclosure can contain about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, or about 100 mM of amino acid (e.g., arginine). In some embodiments, the formulation contains about 25 mM of amino acid (e.g., arginine). In some embodiments, the formulation contains about 50 mM of amino acid (e.g., arginine). In some embodiments, the formulation contains about 75 mM of amino acid (e.g., arginine).

[0070] Exemplary formulations 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 of the sequences disclosed in Table 1 below), (ii) acetate, (iii) histidine, (iv) sucrose, (v) arginine, and (v) a surfactant comprising polyethylene glycol or poloxamer.

[0071] In some cases, a 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 comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0072] In some cases, a 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 comprising polyethylene glycol 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), and the formulation has a pH of 5.7 to 6.1.

[0073] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, 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 comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0074] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, 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, and the formulation has a pH of 5.7 to 6.1.

[0075] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, 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 comprising PEG3350 at a concentration of 0.01% w / v to 0.19% w / v or at a concentration of 0.01% w / v to 0.5% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0076] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0077] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, 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 comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0078] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, 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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0079] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, the antibody specifically binding to human IL-4Rα and comprising a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising PEG3350 at a concentration of 0.01% w / v to 0.19% w / v or 0.01% w / v to 0.5% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0080]

[0081] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, the antibody specifically binding to human IL-4Rα and comprising a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, and 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 150 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0083] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 containing PEG3350 at a concentration of 0.01% w / v to 0.19% w / v or 0.01% w / v to 0.5% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0084] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 containing poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0085] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, 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 comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0086] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, 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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.7 to 6.1.

[0087] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising PEG3350 at a concentration of 0.01% w / v to 0.19% w / v or 0.01% w / v to 0.5% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0088] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or 5.9 ± 0.2.

[0089] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0090] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0091] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, the antibody specifically binding to human IL-4Rα and comprising 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 comprising PEG3350 at a concentration of 0.01% w / v to 0.19% w / v or 0.01% w / v to 0.5% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0092] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, the antibody specifically binding to human IL-4Rα and comprising 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 comprising poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, and the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0093] In any of the various embodiments of the pharmaceutical formulations described above or discussed herein, the human IL-4R antibody may comprise a human IgG1 heavy chain constant region.

[0094] In any of the various embodiments of the pharmaceutical formulations described above or discussed herein, the human IL-4R antibody may comprise a human IgG4 heavy chain constant region.

[0095] 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.

[0096] Additional non-limiting examples of pharmaceutical formulations encompassed by the present disclosure are described elsewhere in this specification, including the examples presented below.

[0097] Stability of Pharmaceutical Formulations The pharmaceutical formulations of the present disclosure exhibit a high level of stability. As used herein in the context of pharmaceutical formulations, the term "stable" means that the antibody within the pharmaceutical formulation retains an acceptable degree of structure and / or function and / or biological activity after storage over a defined period of time. A formulation can be stable even if the antibody contained therein does not maintain 100% of its structure and / or function and / or biological activity after storage over a defined period of time. Under certain circumstances, maintenance of about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of the structure and / or function and / or biological activity of the antibody after storage over a defined period of time may be considered "stable".

[0098] Stability can be measured, inter alia, by determining the proportion of antibody that forms aggregates within the formulation after storage for a specified amount of time at a specified temperature or after stress conditions (e.g., agitation), and stability is inversely proportional to the proportion of aggregates formed. The proportion of aggregated antibody can be determined, inter alia, 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, "acceptable level of stability" means that after storage for a specified time at a given temperature or under specific stress conditions, at most about 15%, 10%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, or 0.1% of the antibody is detected as aggregates in the formulation. The specified amount of time after which 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. The temperature at which a pharmaceutical formulation can be stored when evaluating stability can be any temperature from about -80°C to about 45°C, for example, storage at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C to 8°C, about 5°C, about 25°C, about 35°C, about 37°C, or about 45°C. The "stress conditions" to which a formulated antibody can be subjected can be agitation stress (e.g., vortexing) for a period of 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 more. For example, a pharmaceutical formulation containing an anti-IL-4R antibody can be considered stable if, after storage at 5°C for nine months, 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 the aggregated form. A pharmaceutical formulation can also be considered stable if, after storage at 45°C for 56 days, less than about 12% of the antibody is detected in the aggregated form.The pharmaceutical preparation can also be considered stable if less than about 10% or less than about 9% of the antibody is detected in the aggregated form after storage at 45°C for 42 days. The pharmaceutical preparation can also be considered stable if less than about 8% or less than about 7.5% or less than about 7% of the antibody is detected in the aggregated form after storage at 45°C for 28 days. The pharmaceutical preparation can also be considered stable if less than about 6% of the antibody is detected in the aggregated form after storage at 45°C for 14 days. Even 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 the aggregated form after storage at -20°C, -30°C, or -80°C for three months, the pharmaceutical preparation can be considered stable. The pharmaceutical preparation can also be considered stable if less than 3% or less than 2.5% of the antibody is detected in the aggregated form after stirring at room temperature for 120 minutes (e.g., via vortex). In some cases, the pharmaceutical preparation can be considered stable if it contains 4% or less high molecular weight (HMW) species after stirring at 25°C for 24 hours as determined by SE-UPLC. In some cases, the formulation can be considered stable if it contains 4% or less 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.

[0099] Stability can be measured, inter alia, by determining particulate formulations in the preparation after storage at a specified temperature for a specified time. Particle formation can be determined, for example, by microscopic techniques or microflow imaging techniques.

[0100] Mammalian cell lines routinely used to produce recombinant antibodies are known to co-purify with antibodies and may contain enzymes that can be present in pharmaceutical formulations of the antibodies. In some cases, such enzymes can degrade excipients of the pharmaceutical formulation over time, thereby resulting in the formation of invisible particles (e.g., on the order of 10 to 25 μm or greater). For example, phospholipase is a lipase that hydrolyzes phospholipids into fatty acids and other products. Phospholipases are classified into four broad categories: phospholipase A (including phospholipase A1 and phospholipase A2), phospholipase B, and phospholipase C and phospholipase D which are phosphodiesterases. In addition to standard phospholipases, phospholipase B-like enzymes present in the lysosomal lumen are thought to be involved in lipid catalysis. For example, phospholipase B-like 2 (PLBL2) is presumed to have esterase activity based on sequence homology and intracellular localization (Jensen et al., Biochem. J. 402:449-458 (2007)). PLBL2 is highly conserved in hamster, rat, mouse, human, and bovine and can co-purify with some classes of target proteins (e.g., therapeutic antibodies such as anti-IL-4R antibodies) produced in mammalian cell lines under certain processes. It is possible to remove such enzymes via purification or to include inhibitors (e.g., esterase inhibitors) to counteract the activity of the enzymes (e.g., as disclosed in U.S. Patent No. 10,342,876), but the selection of excipients that prevent particle formation while stabilizing the antibody in the pharmaceutical formulation is also an object. Thus, in some embodiments, the formulations of the present disclosure contain a detectable amount of phospholipase (e.g., PLBL2). Methods for detecting and quantifying the presence and activity of phospholipases are known in the art. In some embodiments, phospholipase is detected by immunoassay (e.g., ELISA). In some embodiments, phospholipase is detected by liquid chromatography-mass spectrometry (LC-MS).

[0101] Thus, a pharmaceutical preparation (containing phospholipase) can be considered stable if, after storage at a defined temperature (e.g., 5 °C) for a defined period (e.g., 6, 12, 18, 24, or 36 months or more), the number of particles is below a specified number (e.g., 3000 particles, 1000 particles, 500 particles, 250 particles, 100 particles, or 50 particles per container of ≥ 10 microns) identified within a volume of 2.25 mL. For example, a pharmaceutical preparation can be considered stable if, after storage at 5 °C for 24 months, 1000 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 24 months, 500 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 24 months, 250 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 24 months, 150 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 1000 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 500 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 250 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 150 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 100 or fewer particles are identified within a volume of 2.25 mL via microscopy. A pharmaceutical preparation can also be considered stable if, after storage at 5 °C for 36 months, 50 or fewer particles are identified within a volume of 2.25 mL via microscopy.

[0102] Stability can also be measured, inter alia, by determining the proportion of native antibody remaining in the formulation after storage for a defined amount of time at a given temperature. The proportion of native antibody can be determined, inter alia, by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). "Acceptable level of stability", as the term is used herein, means that at least 90% of the native form of the antibody can be detected in the formulation after storage for a defined amount of time at a given temperature. In certain embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the native form of the antibody can be detected in the formulation after storage for a defined amount of time at a given temperature. The defined amount of time after which stability is measured 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 more. The temperature at which the pharmaceutical formulation can be stored when assessing stability can be any temperature from about -80°C to about 45°C, for example, storage at about -80°C, about -30°C, about -20°C, about 0°C, about 2°C to 8°C, 4°C to 8°C, about 5°C, about 25°C, about 35°C, about 37°C, or about 45°C.

[0103] Stability can also be measured, in particular, by determining the proportion of antibodies (acidic forms) that migrate into more acidic fractions during ion exchange rather than in the major antibody fraction (major charge form), and stability is inversely proportional to the fraction of acidic form antibodies. Without wishing to be bound by theory, deamidation of an antibody can make the antibody more negatively charged and thus more acidic compared to the non-deamidated antibody (see, e.g., Robinson, N., Protein Deamidation, PNAS, April 16, 2002, 99(8):5283-5288). The proportion of "acidic" antibodies can be determined, in particular, by ion exchange chromatography (e.g., cation exchange ultra performance liquid chromatography [CEX-UPLC] or cation exchange ultra high performance liquid chromatography [CEX-UPLC]). As used herein, "acceptable level of stability" means that after storage for a defined period of time at a given temperature, up to 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in the aggregated form in the formulation. The defined amount of time after which 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. The temperature at which the pharmaceutical formulation can be stored when evaluating stability can be any temperature from about -80°C to about 45°C, for example, storage at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C to 8°C, about 5°C, about 25°C, or about 45°C.

[0104] Measuring the binding affinity of an antibody to its target can also be used to evaluate stability. For example, the formulations of the present disclosure, after storage for a specified 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., 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 before such storage, it can be considered stable. The binding affinity can be determined by any method such as ELISA or surface plasmon resonance. The 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 it with the activity of the IL-4R system in the absence of the antibody.

[0105] References to the stability of a pharmaceutical formulation "after" a specified period are intended to mean that the measurement of stability parameters (e.g., native%, HMW species%, or acidic type%) is made at or near the end of the specified period, and are not intended to mean that the pharmaceutical formulation necessarily maintains the same degree of stability for the parameters measured thereafter. For example, a reference to a particular stability after 12 months means that the measurement of stability is made 12 months or approximately 12 months after the start of the test. Additional methods for evaluating the stability of an antibody in a formulation are demonstrated in the examples presented below.

[0106] As described in the examples below, the present disclosure is based, in part, on the discovery that combinations of the claimed excipients and anti-IL-4R antibodies produce formulations that are stable over long periods of storage (e.g., 36 months).

[0107] Containers and Administration Methods The pharmaceutical formulations of the present disclosure may be contained within any container suitable for the storage of pharmaceuticals and other therapeutic compositions. For example, the pharmaceutical formulations may be contained within a sealed and sterilized plastic or glass container having a predetermined volume, such as a vial, ampoule, syringe, cartridge, bottle, or IV bag. Different types of vials, such as transparent or opaque (e.g., amber-colored) glass or plastic vials, may be used to contain the formulations of the present disclosure. Similarly, any type of syringe may be used to contain and / or administer the pharmaceutical formulations of the present disclosure. In some embodiments, the pharmaceutical formulations are contained within a pre-filled syringe. In some embodiments, the pharmaceutical formulations are contained within a pre-filled fixed-needle syringe.

[0108] The pharmaceutical formulations of the present disclosure may be contained within a "normal tungsten" syringe, or a "low tungsten" syringe. As will be appreciated by those skilled in the art, the process of making a glass syringe generally involves the use of a hot tungsten rod that functions to create a hole in the glass, thereby creating a hole through which liquid can be drawn and expelled from the syringe. This process results in the deposition of trace amounts of tungsten on the inner surface of the syringe. Subsequent washing and other processing steps can be used to reduce the amount of tungsten in the syringe. As used herein, the term "normal tungsten" means that the syringe contains more than 500 parts per billion (ppb) of tungsten. The term "low tungsten" means that the syringe contains 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.

[0109] The rubber plunger used in a syringe and the rubber stopper used to close the opening of a vial can be coated to prevent contamination of the pharmaceutical contents of the syringe or vial and / or to maintain its stability. Thus, according to certain embodiments, the pharmaceutical formulations of the present disclosure may be contained within a syringe containing a coated plunger or within a vial sealed with a coated rubber stopper. For example, the plunger or stopper can be coated with a fluorocarbon film. Examples of coated stoppers or plungers suitable for use in vials and syringes containing the pharmaceutical formulations of the present disclosure are referred to, for example, in U.S. Pat. Nos. 4,997,423, 5,908,686, 6,286,699, 6,645,635, and 7,226,554, the contents of which are hereby incorporated by reference in their entirety. Certain exemplary coated rubber stoppers and plungers that can be used in the context of the present disclosure are commercially available under the trade name “FluroTec®” from West Pharmaceutical Services, Inc. (Exton, Pa.). According to certain embodiments of the present disclosure, the pharmaceutical formulation may be contained within a low tungsten syringe containing a fluorocarbon-coated plunger. In some embodiments, the container is a syringe such as an Ompi EZ-Fill™ syringe or a BD Neopak™ syringe. In some cases, the syringe is a 1 mL long glass syringe having a 1 mL iWest piston, a 27G thin wall 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 10 mL syringe (e.g., a glass syringe).

[0110] The pharmaceutical preparation can be administered to a patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.), or by transdermal, mucosal, nasal, pulmonary, and / or oral administration. The pharmaceutical preparation of the present disclosure can be subcutaneously delivered using a number of reusable pen-type delivery devices / or autoinjector delivery devices. By way of example, and without limitation, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany) may be mentioned. Examples of disposable pens and / or autoinjector delivery devices having use in subcutaneous delivery of the pharmaceutical composition of the present disclosure include, by way of several examples, SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA™ Pen (Abbott Labs, Abbott Park IL), but are not limited thereto. In some cases, the pharmaceutical preparation is contained in a syringe specifically adapted for use with an autoinjector.Subcutaneous injection can be administered using a 20 - 30 gauge needle, or a 25 - 30 gauge needle. In some cases, subcutaneous injection can be administered using a 25 gauge needle. In some cases, subcutaneous injection can be administered using a 27 gauge needle. In some cases, subcutaneous injection can be administered using a 29 gauge needle.

[0111] Another type of delivery device can include a safety system. Such devices can be relatively inexpensive and, upon completion of injection, can operate to extend a safety sleeve manually or automatically over the needle. Examples of safety systems can include the ERIS device by West Pharmaceutical, or the UltraSafe device by Becton Dickinson. Additionally, the use of a large volume device (“LVD”) or a bolus syringe for delivering the pharmaceutical formulations of the present disclosure is also contemplated herein. In some cases, the LVD or bolus syringe can be configured to inject a drug into a patient. For example, the LVD or bolus syringe can be configured to deliver a “large” volume of drug (typically about 2 mL to about 10 mL).

[0112] 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 ISO11608 - 1:2014(E). As described in ISO11608 - 1:2014(E), needle - based injection systems can be broadly distinguished into multiple - dose container systems and single - dose (with partial or complete discharge) container systems. The container can be an exchangeable container or an integral non - exchangeable container.

[0113] As further described in ISO 11608-1:2014(E), a multi-dose container system can be associated with a needle-based injection device having an exchangeable container. In such a system, each container holds a multi-dose and its size may be fixed or variable (pre-set by the user). Another multi-dose container system can be associated with a needle-based injection device having an integral non-exchangeable container. In such a system, each container holds a multi-dose and its size may be fixed or variable (pre-set by the user).

[0114] As further described in ISO 11608-1:2014(E), a single-dose container system can be associated with a needle-based injection device having an exchangeable container. In one example of such a system, each container holds a single-dose and the entire volume deliverable thereby is discharged (complete discharge). In a further example, each container holds a single-dose and a portion of the volume deliverable thereby is discharged (partial discharge). As also described in ISO 11608-1:2014(E), a single-dose container system can be associated with a needle-based injection device having an integral exchangeable container. In one example of such a system, each container holds a single-dose and the entire volume deliverable thereby is discharged (complete discharge). In a further example, each container holds a single-dose and a portion of the volume deliverable thereby is discharged (partial discharge).

[0115] An exemplary sleeve-triggered auto-injector with manual needle insertion is described in International Publication No. WO2015 / 004052. Exemplary audible administration end feedback mechanisms are described in International Publication Nos. WO2016 / 193346 and WO2016 / 193348. Exemplary needle safety mechanisms after using an auto-injector are described in International Publication No. WO2016 / 193352. An exemplary needle sheath removal mechanism for a syringe auto-injector is described in International Publication No. WO2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication No. WO2016 / 193355.

[0116] The pharmaceutical formulations of the present disclosure can also be contained in unit dosage forms. As used herein, the term "unit dosage form" refers to physically discrete units suitable as a single dosage for a patient to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier, diluent, or excipient. In various embodiments, the unit dosage form is contained within a container as discussed herein. The actual dosage level of the active ingredient (e.g., anti-IL-4R antibody) in the formulations of the present disclosure can be varied to obtain the amount of the 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 being used, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the duration of the treatment, other drugs, the compounds and / or materials being used in combination with the particular composition being used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, as well as similar factors well known in the medical arts. As used herein, the term "diluent" refers to a solution suitable for modifying or achieving one or more of the exemplary or appropriate concentrations described herein.

[0117] In various embodiments, the unit dosage form contains an amount of an active ingredient (e.g., an anti-IL-4R antibody) intended for single use. In various embodiments, the amount of the active ingredient in the unit dosage form is from about 0.1 mg to about 5000 mg, from about 100 mg to about 1000 mg, and from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 200 mg, from about 250 mg to about 350 mg, from about 125 mg to about 175 mg, from about 275 mg to about 325 mg, or a range or interval thereof. For example, ranges of values using any combination of the values listed above (or values included within the ranges listed above) as upper and / or lower limits are intended to be included. In certain embodiments, the formulation is often supplied as a liquid in unit dosage form. In some embodiments, the unit dosage form contains about 100 mg of the 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.

[0118] The present disclosure also includes a method of preparing a unit dosage form. In an exemplary embodiment, a method for preparing a pharmaceutical unit dosage form includes combining a formulation of any of the foregoing embodiments within a suitable container (e.g., a container discussed herein).

[0119] Therapeutic use of pharmaceutical formulations The pharmaceutical formulations of the present disclosure are useful, inter alia, for the treatment, prevention, and / or amelioration of any disease or disorder associated with IL-4R activity.

[0120] The treatment methods of the present disclosure include administering to a subject any formulation comprising an anti-hIL-4R antibody disclosed herein. The subject to which the pharmaceutical formulation is administered can be, for example, any human or non-human animal in need of such treatment, prevention, and / or amelioration, or otherwise would benefit from inhibition or attenuation of IL-4R and / or IL-IL-4R-mediated activity. The present disclosure includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for the treatment, prevention, and / or amelioration of any disease or disorder associated with IL-4R activity.

[0121] In some embodiments, the disease or disorder associated with IL-4R activity is an inflammatory condition, an allergic condition, a lung / respiratory disorder, a gastrointestinal disorder, or a skin disease. In some embodiments, the disease or disorder is a type 2 inflammatory disease. 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), allergic reactions, allergic bronchopulmonary aspergillosis, alopecia areata, asthma (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 inducible urticaria, cold-induced urticaria, contact dermatitis (e.g., allergic contact dermatitis), COPD, eosinophilic esophagitis, eosinophilic duodenitis, eosinophilic gastroenteritis, Graves' disease, herpes, hypertrophic scar, inflammatory bowel disease, Kawasaki disease, nasal polyps, nephrotic syndrome, Netherton syndrome, preeclampsia, prurigo nodularis, pruritus (e.g., chronic pruritus of unknown origin), rhinitis (e.g., allergic rhinitis), sinusitis (e.g., allergic fungal rhinosinusitis, chronic sinusitis with or without nasal polyps), scleroderma, sickle cell disease, Sjogren's syndrome, tuberculosis, ulcerative colitis, and Whipple's disease.

[0122] In some embodiments, the present disclosure provides a kit comprising a pharmaceutical formulation (e.g., a container containing a formulation or unit dosage form) discussed herein, and a package or labeling (e.g., an insert) including instructions for using the pharmaceutical formulation for the treatment of a disease or disorder discussed above. Optionally, the instructions provide for the use of the unit dosage form discussed herein for the treatment of a disease or disorder.

[0123] A summary of the sequences and corresponding SEQ ID NOs referred to herein is shown in Table 1 below.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Example

[0124] The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure the accuracy of the numbers (e.g., amounts, temperatures, etc.) used, but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0125] Example 1: Prevention of particle formation in lipase-containing formulations containing PEG3350 or poloxamer 188 Although not intended to be bound by theory, putative phospholipase B-like 2 (PLBL2), which is highly conserved in hamster, rat, mouse, human, and bovine, co-purifies with some classes of target proteins produced in certain cell lines under certain processes and is thought to have esterase activity involved in the hydrolysis of polysorbates 20 and 80. As an alternative to removing lipase via a purification method (e.g., as described in U.S. Patent No. 10,342,876), formulations of the IL-4R antibody were prepared using alternative surfactants and particle formation was measured over time. Anti-IL-4R antibodies containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 at a concentration of 150 mg / mL of mAb1 were formulated at pH 5.9 with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and either various concentrations of PEG3350 or poloxamer 188. The formulations were stored in syringes at 5°C for up to 36 months while making periodic measurements of the number of particles (≥10 μm and ≥25 μm) present in the formulation as determined by microscopy.

[0126] As shown in Figure 1, few particles ≥10 μm or ≥25 μm were identified in the formulation over the 36-month observation period. Furthermore, no significant differences or changes in the number of invisible particles were observed over the storage period among the different PEG3350-containing or poloxamer 188-containing formulations. This experiment shows that low concentrations of PEG3350 or poloxamer 188 can prevent particle formation over a long period of time.

[0127] Example 2: Stirring Stress Stability of Formulations Containing PEG3350 or Poloxamer 188 The stirring stress stability of an IL-4R antibody formulation containing surfactants PEG3350 or poloxamer 188 at different concentrations was tested. An anti-IL-4R antibody containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 at a concentration of 150 mg / mL was formulated at pH 5.9 with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and various concentrations of PEG3350 or poloxamer 188. The formulation was stored in glass vials and stirred by vortexing (speed setting = 4) for 30 minutes, 60 minutes, or 120 minutes. Subsequently, the proportion of high molecular weight (HMW) species was determined by size exclusion ultra-high performance liquid chromatography (SE-UPLC).

[0128] As shown in Figure 2A, formulations of the antibody with at least 0.01% (w / v) PEG3350 prevented an observable increase in HMW species (quantified by SE-UHPLC) due to stirring. Small amounts of PEG3350 (0.001% or 0.005%) were insufficient to prevent HMW formation. Similarly, as shown in Figure 2B, formulations of the antibody with at least 0.01% (w / v) poloxamer 188 prevented an observable increase in HMW species, although HMW species were observed with lower amounts of poloxamer 188 (0.001% or 0.005%).

[0129] Example 3: Thermal stress stability of formulations containing PEG3350 or poloxamer 188 The thermal stress stability of an IL-4R antibody formulation containing PEG3350 or poloxamer 188 was tested and compared with various IL-4R antibody formulations containing polysorbate. An anti-IL-4R antibody containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 at a concentration of 150 mg / mL was formulated at pH 5.9 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. These formulations were subjected to thermal stress (45 °C) for up to 56 days, and the percentage of high molecular weight (HMW) species was determined by size exclusion ultra-high performance liquid chromatography (SE-UPLC) at 7, 14, 28, 42, and 56 days.

[0130] As shown in Figure 3, antibody formulations containing PEG3350 or poloxamer 188 at concentrations of 0.01% or 0.02% showed similar thermal stability to antibody formulations containing less polysorbate (up to 0.1% w / v). By 28 days, PEG3350- or poloxamer 188-containing formulations showed a lower percentage of HMW species than the control formulation containing 0.2% polysorbate 20.

[0131] Example 4: Thermal Stress Stability of Formulations Containing Various Concentrations of Poloxamer 188 or PEG3350 The thermal stress stability of IL-4R antibody formulations containing different concentrations of poloxamer 188 or PEG3350 was tested under thermal stress conditions (45 °C) for up to 3 months. An anti-IL-4R antibody containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 at a concentration of 150 mg / mL was formulated at pH 5.9 with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and a surfactant [0.2% w / v polysorbate 80, 0.01%, 0.1%, or 0.5% w / v poloxamer 188, or 0.01%, 0.1%, or 0.5% w / v PEG3350]. These formulations were stored in glass vials at 45 °C for 1, 2, or 3 months. The percentage of recovered drug (antibody) was determined by reverse-phase ultra-high performance liquid chromatography (RP-UPLC). The percentage of high molecular weight (HMW) species was determined by size exclusion ultra-high performance liquid chromatography (SE-UPLC). The formation of charge variant species was measured by cation exchange ultra-high performance liquid chromatography (CEX-UPLC). Microflow imaging (MFI) was used to measure invisible particles.

[0132] Table 2 shows the stability data of the formulations containing 0.2% (w / v) polysorbate 80 at 0, 1, and 3 months. Tables 3, 4, and 5 show the stability data of the formulations containing 0.01%, 0.1%, and 0.5% poloxamer 188, respectively. Tables 6, 7, and 8 show the stability data of the formulations containing 0.01%, 0.1%, and 0.5% PEG3350, respectively. As shown in Tables 3 and 6, even the lowest concentrations of poloxamer 188 and PEG3350 tested (0.01%) provided protection to a similar extent as 0.2% polysorbate 80. The 0.01% poloxamer 188 formulation showed stability characteristics similar to those of 0.1% and 0.5% poloxamer 188 (see Tables 3-5). The 0.01% PEG3350 formulation showed stability characteristics similar to those of 0.1% and 0.5% PEG3350 (see Tables 6-8).

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

[0133] Example 5: Stability Data of Formulations Containing Poloxamer 188 or PEG3350 at Various Concentrations under Storage and Stress Conditions The stability of IL-4R antibody formulations with various concentrations of Poloxamer 188 or PEG3350 was tested under storage conditions at 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 containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 at a concentration of 150 mg / mL were formulated at pH 5.9 with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, and 5% w / v sucrose, either in the absence of surfactant or in the presence of 0.02%, 0.04%, or 0.1% w / v of Poloxamer 188 or PEG3350. 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. The number of particles in the container was measured using membrane microscopy and / or MFI.

[0134] Tables 9 to 11 show the data of the formulations without surfactants. Tables 12 to 14, 15 to 17, and 18 to 20 show the stability data of the formulations containing 0.02%, 0.04%, and 0.1% (w / v) of poloxamer 188, respectively. Tables 21 to 23, 24 to 26, and 27 to 29 show the stability data of the formulations containing 0.02%, 0.04%, and 0.1% of PEG3350, respectively. As shown in Tables 12, 15, and 18, the formulations containing 0.02%, 0.04%, or 0.1% (w / v) of poloxamer had significantly fewer particles after long-term storage at 5°C (up to 18 months). Similarly, as shown in Tables 21, 24, and 27, the formulations containing 0.02%, 0.04%, or 0.1% of PEG3350 had significantly fewer particles after long-term storage at 5°C (up to 18 months). Under accelerated conditions at 25°C or thermal stress conditions at 45°C, the formulations containing 0.02%, 0.04%, or 0.1% (w / v) of poloxamer 188 or PEG3350 had significantly fewer invisible particles than the formulations without surfactants (see Tables 10, 13, 16, 19, 22, 25, and 28).

[0135] The formulations were subjected to a stirring stress of 24 hours at 25°C and then stored as follows: for 6, 12, or 18 months at 5°C, for 6 months at 25°C, or for 1 or 2 months at 45°C. The formulations containing 0.02%, 0.04%, or 0.1% (w / v) of poloxamer 188 or PEG3350 had significantly less formation of HMW species after stirring for 24 hours at 25°C compared to the formulations lacking surfactants. Furthermore, the formulations containing 0.02%, 0.04%, or 0.1% (w / v) of poloxamer 188 or PEG3350 showed a lower percentage of HMW species and an improvement in stability after 24 hours of stirring followed by long-term storage at 5°C or 25°C conditions. See Tables 11, 14, 17, 20, 23, 26, and 29.

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

[0136] The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the present invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims.

Table 30

Claims

1. A stable liquid pharmaceutical preparation, (i) Human antibodies that specifically bind to human interleukin-4 receptor alpha (hIL-4Rα), (ii) One or more buffers, (iii) Heat stabilizer, (iv) Viscosity modifiers, and (v) A surfactant comprising polyethylene glycol or poloxamer in a concentration of 0.01% w / v to 0.19% w / v, The aforementioned formulation is a stable liquid pharmaceutical formulation having a pH of 5.7 to 6.

1.

2. (a) The antibody comprises a heavy chain variable region (HCVR) comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3, respectively, comprising the amino acid sequences of SEQ ID NOs: 3, 4, and 5, and a light chain variable region (LCVR) comprising complementarity-determining regions LCDR1, LCDR2, and LCDR3, respectively, comprising the amino acid sequences of SEQ ID NOs: 6, 7, and 8, and optionally, the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO:

2. (b) The antibody has a human IgG heavy chain constant region, and in some cases the heavy chain constant region is isotype IgG1 or isotype IgG4, (c) The stable liquid pharmaceutical formulation according to claim 1, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

3. The aforementioned surfactant, (a) Polyethylene glycol, in some cases PEG3350, or (b) Poloxamer, and in some cases, poloxamer 188 The stable liquid pharmaceutical formulation according to claim 1.

4. The buffer comprises an acetate buffer and / or a histidine buffer. In some cases, (a) The buffer solution contains an acetate at a concentration of 10 mM to 15 mM or 12.5 mM ± 1.25 mM, or (b) The stable liquid pharmaceutical formulation according to claim 1, wherein the buffer solution contains histidine at a concentration of 15 mM to 25 mM or 20 mM ± 2 mM.

5. The heat stabilizer is sucrose at a concentration of 2.5% w / v to 7.5% w / v, and in some cases, the sucrose is present at a concentration of 5% w / v ± 0.5% w / v. (b) The viscosity modifier is arginine at a concentration of (i) 20 mM to 80 mM, (ii) 25 mM ± 2.5 mM, (iii) 50 mM ± 2.5 mM, or (iv) 75 mM ± 2.5 mM, and / or (c) The stable liquid pharmaceutical formulation according to claim 1, wherein the antibody is present at concentrations of (i) up to 200 mg / mL, (ii) 100 mg / mL to 200 mg / mL, (iii) 150 mg / mL ± 15 mg / mL, or (iv) 175 mg / mL ± 15 mg / mL.

6. A stable liquid pharmaceutical preparation, (i) A human antibody having a concentration of 150 mg / mL ± 10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, The formulation has a pH of 5.9 ± 0.

2. In some cases, the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10, in a stable liquid pharmaceutical formulation.

7. A stable liquid pharmaceutical preparation, (i) A human antibody having a concentration of 175 mg / mL ± 10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing 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 comprising PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, The formulation has a pH of 5.9 ± 0.

2. In some cases, the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10, in a stable liquid pharmaceutical formulation.

8. The stable liquid pharmaceutical formulation according to claim 1, wherein the formulation contains a phospholipase protein.

9. The aforementioned formulation, (a) After vortexing for up to 120 minutes at room temperature, as determined by size exclusion ultrahigh performance liquid chromatography (SE-UPLC), the molecular weight (H) is 3% or less. It contains MW species, and in some cases, after vortex stirring at room temperature for up to 120 minutes as determined by SE-UPLC, it contains 2.5% or less high molecular weight (HMW) species. (b) After storage at 45°C for 30 days, as determined by SE-UPLC, containing 8% or less high molecular weight (HMW) species, (c) As determined by SE-UPLC, after storage at 45°C for 40 days, it contains 9% or less high molecular weight (HMW) species, or (d) The stable liquid pharmaceutical formulation according to claim 1, comprising 11% or less high molecular weight (HMW) species after storage at 45°C for 50 days, as determined by SE-UPLC.

10. The aforementioned formulation, (a) A formulation containing 1000 or fewer, 500 or fewer, or 150 or fewer particles having a diameter of ≥10 μm in a volume of 2.25 mL, as determined by microscopy, after storage at 5°C for 6 months, wherein the formulation contains a phospholipase protein, and in some cases the phospholipase protein is a phospholipase B-like 2 protein. (b) A formulation containing 1000 or fewer, 500 or fewer, or 150 or fewer particles having a diameter of ≥10 μm in a volume of 2.25 mL, as determined by microscopy, after storage at 5°C for 36 months, wherein the formulation contains a phospholipase protein, and optionally the phospholipase protein is a phospholipase B-like 2 protein. (c) A formulation containing 500 or fewer, 250 or fewer, or 50 or fewer particles having a diameter of ≥25 μm in a volume of 2.25 mL, as determined by microscopy, after storage at 5°C for 6 months, wherein the formulation contains a phospholipase protein, and in some cases the phospholipase protein is a phospholipase B-like protein 2, or (d) A stable liquid pharmaceutical formulation according to claim 1, wherein, after storage at 5°C for 6 months as determined by microscopy, the formulation contains 500 or fewer, 250 or fewer, or 50 or fewer particles having a diameter of ≥25 μm in a volume of 2.25 mL, the formulation contains a phospholipase protein, and optionally the phospholipase protein is a phospholipase B-like 2 protein.

11. The aforementioned formulation, (a) After stirring at 25°C for 24 hours, as determined by SE-UPLC, the mixture contains 4% or less high molecular weight (HMW) species, or (b) A stable liquid pharmaceutical formulation according to claim 1, comprising 4% or less high molecular weight (HMW) species after stirring at 25°C for 24 hours and storage at (i) 5°C for 6, 12, or 18 months, or (ii) 25°C for 6 months, as determined by SE-UPLC.

12. A stable liquid pharmaceutical preparation according to any one of claims 1 to 11, contained in a glass vial, a large-capacity device, or a bolus syringe.

13. A stable liquid pharmaceutical preparation contained in a syringe, according to any one of claims 1 to 11, In some cases, (a) The syringe comprises a plunger coated with fluorocarbon or a low-tungsten syringe, and / or (b) A stable liquid pharmaceutical preparation in which the syringe is a pre-filled syringe, or in some cases, a pre-filled stakeneedle syringe.

14. A pen-type or auto-injector delivery device containing a stable liquid pharmaceutical preparation according to any one of claims 1 to 11, In some cases, (a) The delivery device is a disposable pen-type delivery device, or (b) A pen-type or auto-injector delivery device in which the delivery device is a reusable pen-type delivery device.

15. A container containing a stable liquid pharmaceutical preparation according to any one of claims 1 to 11.

16. A unit dosage form comprising a stable liquid pharmaceutical preparation according to any one of claims 1 to 11, wherein the antibody is present in an amount of 1 mg to 500 mg, In some cases, (a) The antibody is present in an amount of (i) about 300 mg, (ii) about 200 mg, or (iii) about 100 mg, (b) A unit dosage form in which the preparation is contained in a syringe, and in some cases the syringe is a pre-filled syringe.

17. A safety system delivery device containing a stable liquid pharmaceutical preparation according to any one of claims 1 to 11, In some cases, (a) including a safety sleeve configured to be extended by manual operation, or (b) A safety system delivery device including a safety sleeve configured to automatically extend after the injection of the stable liquid pharmaceutical formulation.

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