Stabilized formulations containing Anti-il-33 antibodies

Abstract

To provide pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-33, which are sufficiently stable and suitable for administration to patients.SOLUTION: The present invention provides pharmaceutical formulations which may contain, in addition to an anti-IL-33 antibody, a buffer, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months and after being subjected to thermal and other physical stresses.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing Reference This application incorporates by reference the Sequence Listing, which was filed in computer readable format as file 10516WO01-Sequence.txt, created on February 20, 2020, and contains 13,659 bytes.

[0002] The present invention relates to the field of therapeutic antibody formulations, more particularly to the field of pharmaceutical formulations comprising human antibodies that specifically bind to human interleukin-33. [Background technology]

[0003] Interleukin-33 (IL-33) is a ligand for ST2, a member of the toll-like / interleukin-1 receptor superfamily, which associates with the accessory protein IL-1RAcP (for reviews, see, e.g., Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Patent Document 1, and Patent Document 2). Upon activation of ST2 / IL-1RAcP by IL-33, a signaling cascade is triggered through downstream molecules such as MyD88 (myeloid differentiation factor 88) and TRAF6 (TNF receptor-associated factor 6), resulting in, among other things, activation of NFκB (nuclear factor-κB). IL-33 signaling has been implicated as a factor in a variety of diseases and disorders (Non-Patent Document 3).

[0004] Therapeutic macromolecules (e.g., antibodies) must be formulated in a manner that not only renders the molecules suitable for administration to patients but also maintains their stability during storage. For example, therapeutic antibodies in solution are prone to degradation, aggregation, and / or undesirable chemical modification unless the solution is properly formulated. The stability of antibodies in liquid formulations depends not only on the types of excipients used in the formulation but also on the amounts and ratios of the excipients relative to each other. Furthermore, when preparing liquid antibody formulations, other considerations besides stability must be taken into account. Examples of such additional considerations include the viscosity of the solution and the concentration of antibody that can be accommodated by a given formulation. Therefore, when formulating therapeutic antibodies, great care must be taken to arrive at a formulation that maintains stability, contains an appropriate concentration of antibody, and possesses a suitable viscosity, as well as other properties that allow the formulation to be conveniently administered to patients.

[0005] Antibodies against human interleukin-33 (hIL-33) are an example of therapeutically relevant macromolecules that require appropriate formulation.

[0006] Although anti-hIL-33 antibodies are known in the art (see, e.g., U.S. Patent No. 6,273,629), there remains a need for pharmaceutical formulations comprising anti-hIL-33 antibodies that are sufficiently stable and suitable for administration to patients. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] US2010 / 0260770 [Patent Document 2] US2009 / 0041718 [Patent Document 3] WO2014 / 164959 [Non-patent literature]

[0008] [Non-Patent Document 1] Kakkar and Lee, Nature Reviews-Drug Discovery 7(10):827-840(2008) [Non-patent document 2] Schmitz et al., Immunity 23:479-490(2005) [Non-patent document 3] Liew et al.,Nature Reviews-Immunology 10:103-110(2010) Summary of the Invention

[0009] Stable liquid pharmaceutical formulations comprising anti-IL-33 antibodies and one or more excipients are provided, as well as kits comprising such formulations and their uses.

[0010] In one aspect, a stable liquid pharmaceutical formulation is provided, comprising: (i) a human antibody that specifically binds human interleukin-33 (hIL-33); (ii) a buffer; (iii) an amino acid; (iv) a thermal stabilizer; and (v) an organic co-solvent. In some embodiments, the buffer is acetate or histidine at a concentration of 1 mM to 40 mM. In some embodiments, the buffer is acetate or histidine at a concentration of 1 mM to 20 mM. In some embodiments, the amino acid is arginine or glutamic acid at a concentration of 30 mM to 110 mM. In some embodiments, the thermal stabilizer is sucrose at a concentration of 1% w / v to 20% w / v. In some embodiments, the thermal stabilizer is sucrose at a concentration of 1% w / v to 10% w / v. In some embodiments, the organic co-solvent is a surfactant at a concentration of 0.01% w / v to 0.15% w / v. In some embodiments, the surfactant is polysorbate 80. In some embodiments, the antibody is present at a concentration of 1 mg / ml to 200 mg / ml. Optionally, the antibody is present at a concentration of 15 mg / ml to 150 mg / ml.

[0011] In various embodiments of the formulation, the antibody comprises a heavy chain variable region (HCVR) complementarity determining region (HCDR1-HCDR2-HCDR3) comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region (LCVR) complementarity determining region (LCDR1-LCDR2-LCDR3) comprising the amino acid sequence of SEQ ID NO: 10. In some cases, the antibody comprises HCDR1-HCDR2-HCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 4-6-8, respectively, and LCDR1-LCDR2-LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12-14-16, respectively. In some embodiments, the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody has a human IgG heavy chain constant region. In some embodiments, the heavy chain constant region is of the IgG1 isotype. In some embodiments, the heavy chain constant region is of the IgG4 isotype. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:18 and a light chain comprising the amino acid sequence of SEQ ID NO:20.

[0012] In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 15 mg / ml to about 150 mg / mL of a human antibody that specifically binds hIL-33, (ii) about 5 mM to about 15 mM acetate, (iii) about 60 mM to about 80 mM arginine hydrochloride, (iv) about 3% w / v to about 7% w / v sucrose, and (v) about 0.06% w / v to about 0.1% w / v polysorbate 80. In some embodiments, the formulation has a pH of about 5 to about 5.6.

[0013] In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 15 mg / ml ± 1.5 mg / ml of antibody, (ii) about 10 mM ± 2 mM of acetate, (iii) about 70 mM ± 14 mM of arginine hydrochloride, (iv) about 5% w / v ± 1% w / v of sucrose, and (iv) about 0.08% ± 0.016% w / v of polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 75 mg / ml ± 5 mg / ml of antibody, (ii) about 10 mM ± 2 mM of acetate, (iii) about 70 mM ± 14 mM of arginine hydrochloride, (iv) about 5% w / v ± 1% w / v of sucrose, and (iv) about 0.08% ± 0.016% w / v polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 150 mg / ml ± 15 mg / ml antibody, (ii) about 10 mM ± 2 mM acetate, (iii) about 70 mM ± 14 mM arginine hydrochloride, (iv) about 5% w / v ± 1% w / v sucrose, and (iv) about 0.08% ± 0.016% w / v polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 15 mg / ml ± 1.5 mg / ml antibody, (ii) about 10 mM ± 1 mM acetate, (iii) about 70 mM ± 7 mM arginine hydrochloride, (iv) about 5% w / v ± 0.5% w / v sucrose, and (iv) about 0.08% ± 0.008% w / v polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 75 mg / ml ± 5 mg / ml of antibody, (ii) about 10 mM ± 1 mM of acetate, (iii) about 70 mM ± 7 mM of arginine hydrochloride, (iv) about 5% w / v ± 0.5% w / v of sucrose, and (iv) about 0.08% ± 0.008% w / v of polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 150 mg / ml ± 15 mg / ml of antibody, (ii) about 10 mM ± 1 mM of acetate, (iii) about 70 mM ± 7 mM of arginine hydrochloride, (iv) about 5% w / v ± 0.5% w / v of sucrose, and (iv) about 0.08% ± 0.008% w / v of polysorbate 80. In some cases, the pH of the formulation is 5.2 to 5.4. In some embodiments, the pH of the formulation is about 5.3. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 15 mg / ml ± 1.5 mg / ml of antibody, (ii) about 10 mM ± 2 mM of acetate, (iii) about 70 mM ± 14 mM of arginine hydrochloride, (iv) about 5% w / v ± 1% w / v of sucrose, and (iv) about 0.08% ± 0.04% w / v of polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 75 mg / ml ± 8 mg / ml of antibody, (ii) about 10 mM ± 2 mM of acetate, (iii) about 70 mM ± 14 mM of arginine hydrochloride, (iv) about 5% w / v ± 1% w / v of sucrose, and (iv) about 0.08% ± 0.04% w / v of polysorbate 80.In some embodiments, the stable liquid pharmaceutical formulation comprises (i) about 150 mg / ml ± 15 mg / ml antibody, (ii) about 10 mM ± 2 mM acetate, (iii) about 70 mM ± 14 mM arginine hydrochloride, (iv) about 5% w / v ± 1% w / v sucrose, and (iv) about 0.08% ± 0.04% w / v polysorbate 80. In some embodiments, the pH of the formulation is 5.2 to 5.4. In some embodiments, the pH of the formulation is about 5.3.

[0014] In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, wherein the antibody comprises a HCVR comprising HCDR1, HCDR2, and HCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 4, 6, and 8, respectively, and LCDR1, LCDR2, and LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12, 14, and 16, respectively; (ii) 10 mM±2 mM acetate; (iii) 70 mM±14 mM arginine hydrochloride; (iv) 5% w / v±1% w / v sucrose; and (iv) about 0.08%±0.016% w / v polysorbate 80, wherein the formulation has a pH of 5.1 to 5.5. In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, wherein the antibody comprises a HCVR comprising HCDR1, HCDR2, and HCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 4, 6, and 8, respectively, and LCDR1, LCDR2, and LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12, 14, and 16, respectively; (ii) 10 mM±1 mM acetate; (iii) 70 mM±7 mM arginine hydrochloride; (iv) 5% w / v±0.5% w / v sucrose; and (iv) about 0.08%±0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.1 to 5.5. In some cases, the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In embodiments, the antibody has a human IgG heavy chain constant region. In some embodiments, the heavy chain constant region is of the IgG1 isotype. In some embodiments, the heavy chain constant region is of the IgG4 isotype.

[0015] In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20; (ii) 10 mM±2 mM acetate; (iii) 70 mM±14 mM arginine hydrochloride; (iv) 5% w / v±1% w / v sucrose; and (iv) about 0.08%±0.016% w / v polysorbate 80, wherein the formulation has a pH of 5.1 to 5.5. In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20; (ii) 10 mM±1 mM acetate; (iii) 70 mM±7 mM arginine hydrochloride; (iv) 5% w / v±0.5% w / v sucrose; and (iv) about 0.08%±0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.1 to 5.5.

[0016] In some embodiments, the stable liquid pharmaceutical formulation contains at least 90% of the native form of the antibody after 2 months of storage at 5° C. as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC). In some cases, the formulation contains at least 95% of the native form of the antibody after 2 months of storage at 5° C. as determined by SE-UPLC. In some cases, the formulation contains at least 99% of the native form of the antibody after 2 months of storage at 5° C. as determined by SE-UPLC.

[0017] In some embodiments, the formulation contains at least 95% of the native form of the antibody after 9 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 9 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the formulation contains at least 99% of the native form of the antibody after 9 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 12 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 12 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the formulation contains at least 99% of the native form of the antibody after 12 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains at least 95% of the native form of the antibody after 18 months of storage at −20° C. as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 18 months of storage at −20° C. as determined by SE-UPLC. In some cases, the formulation contains at least 99% of the native form of the antibody after 18 months of storage at −20° C. as determined by SE-UPLC.

[0018] In some embodiments, the stable liquid pharmaceutical formulation contains at least 95% of the native form of the antibody after 9 months of storage at 2-8° C. as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 9 months of storage at 2-8° C. as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 9 ... In some embodiments, the stable liquid pharmaceutical formulation contains at least 95% of the native form of the antibody after 12 months of storage at 2-8°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 12 months of storage at 2-8°C as determined by SE-UPLC. In some cases, the formulation contains at least 99% of the native form of the antibody after 12 months of storage at 2-8°C as determined by SE-UPLC. In some cases, the formulation contains at least 95% of the native form of the antibody after 18 months of storage at 2-8°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody after 18 months of storage at 2-8°C as determined by SE-UPLC. In some cases, the formulation contains at least 99% of the native form of the antibody after 18 months of storage at 2-8°C as determined by SE-UPLC.

[0019] In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less high molecular weight (HMW) species as determined by SE-UPLC after 2 months of storage at 5° C. In some cases, the formulation contains 1% or less HMW species as determined by SE-UPLC after 2 months of storage at 5° C. In some cases, the formulation contains 0.6% or less HMW species as determined by SE-UPLC after 2 months of storage at 5° C.

[0020] In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains 0.5% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 12 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species after 12 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains 0.5% or less HMW species after 12 months of storage at -20°C as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 18 months of storage at -20°C as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species as determined by SE-UPLC after 18 months of storage at −20° C. In some cases, the formulation contains 0.5% or less HMW species as determined by SE-UPLC after 18 months of storage at −20° C.

[0021] In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 9 months of storage at 2-8° C. as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species after 9 months of storage at 2-8° C. as determined by SE-UPLC. In some cases, the formulation contains 0.7% or less HMW species after 9 months of storage at 2-8° C. as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 12 months of storage at 2-8° C. as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species after 12 months of storage at 2-8° C. as determined by SE-UPLC. In some cases, the formulation contains 0.7% or less HMW species after 12 months of storage at 2-8° C. as determined by SE-UPLC. In some embodiments, the stable liquid pharmaceutical formulation contains 2% or less HMW species after 18 months of storage at 2-8° C. as determined by SE-UPLC. In some cases, the formulation contains 1% or less HMW species as determined by SE-UPLC after 18 months of storage at 2-8° C. In some cases, the formulation contains 0.7% or less HMW species as determined by SE-UPLC after 18 months of storage at 2-8° C.

[0022] In some embodiments, the pharmaceutical formulation exhibits a viscosity of less than about 15 cPoise, less than about 12 cPoise, or less than about 10 cPoise when measured at 20°C.

[0023] In some embodiments, the stable liquid pharmaceutical formulation is contained in a glass vial, syringe, or large volume device or bolus injector. In some embodiments, the syringe comprises a fluorocarbon-coated plunger. In some embodiments, the syringe is a low-tungsten syringe. In some embodiments, the syringe comprises up to 2500 ppb of tungsten. In some embodiments, the syringe comprises about 250-750 ppb of tungsten. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, the syringe is a pre-filled staked needle syringe.

[0024] In another aspect, in any of the embodiments above or discussed herein, a pen or auto-injector delivery device containing a stable liquid pharmaceutical formulation is provided. In some cases, the delivery device is a disposable pen delivery device. In some cases, the delivery device is a reusable pen delivery device.

[0025] In another aspect, in any of the embodiments above or discussed herein, a container containing a stable liquid pharmaceutical formulation is provided.

[0026] In another aspect, in any of the embodiments above or discussed herein, a safety system delivery device is provided that includes a stable liquid pharmaceutical formulation. In some embodiments, the safety system delivery device includes a safety sleeve configured to extend by manual operation. In some embodiments, the safety system delivery device includes a safety sleeve configured to automatically extend after injection of the stable liquid pharmaceutical formulation.

[0027] In another aspect, a kit is provided that includes (i) a container containing a stable liquid pharmaceutical formulation as discussed above or herein, and (ii) labeling for use of the pharmaceutical formulation. In some embodiments, the labeling recites subcutaneous administration of the pharmaceutical formulation. In some embodiments, the labeling recites intravenous administration of the pharmaceutical formulation.

[0028] In another aspect, the present invention provides a unit dosage form comprising a stable liquid pharmaceutical formulation as described above or herein, wherein the anti-IL-33 antibody is present in an amount of 1 mg to 500 mg. Optionally, the anti-IL-33 antibody is present in an amount of about 150 mg. Optionally, the anti-IL-33 antibody is present in an amount of about 300 mg. In some embodiments of the unit dosage form, the formulation is contained in a syringe. Optionally, the syringe is a pre-filled syringe.

[0029] In various embodiments, any of the features or components of the embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range, with the values ​​representing the upper and lower limits of the range, and such ranges are encompassed within the scope of the present disclosure. Each of the values ​​discussed above or herein may be expressed with a variance of 1%, 5%, 10%, or 20%. For example, a concentration of 10 mM may be expressed as 10 mM ± 0.1 mM (1% variance), 10 mM ± 0.5 mM (5% variance), 10 mM ± 1 mM (10% variance), or 10 mM ± 2 mM (20% variance).

[0030] Other embodiments will be apparent from a review of the detailed description. [Brief explanation of the drawings]

[0031] [Figure 1] 1 shows the pH-dependent viscosity of 150 mg / mL anti-IL-33 antibody (mAb1). [Figure 2] 1 shows the viscosity of 150 mg / mL anti-IL-33 antibody (mAb1) at different concentrations of viscosity modifier. [Figure 3] Figure 3 shows the effect of various viscosity modifiers on the stability of an anti-IL-33 antibody (mAb1) incubated for 34 days at 37°C. For clarity, the points on the far right of Figure 3 are ordered from top to bottom as follows: F13, F4, F12, F3, F2, F7, F1, F5, F8, F6, and F9. [Figure 4A] 1 shows the effect of formulation parameters on the viscosity of an anti-IL-33 antibody (mAb1). [Figure 4B] 1 shows the effect of formulation parameters on the formation of high molecular weight (HMW) variants of anti-IL-33 antibody (mAb1). DETAILED DESCRIPTION OF THE INVENTION

[0032] Before the present invention is described, it is to be understood that the present invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by those skilled in the art to which this invention belongs.As used herein, the term "about" means that when used in relation to a specific listed value, the value can vary by 1% or less from the listed value.For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (for example, 99.1, 99.2, 99.3, 99.4, etc.).

[0034] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described. All patents, applications, and non-patent publications mentioned herein are incorporated by reference in their entirety.

[0035] Pharmaceutical preparations As used herein, the term "pharmaceutical formulation" refers to a combination of at least one active ingredient (e.g., an anti-IL-33 antibody capable of exerting a biological effect in a human or non-human animal) and at least one inactive ingredient that, when combined with the active ingredient or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. As used herein, the term "formulation" refers to a "pharmaceutical formulation" unless specifically indicated otherwise. The present invention provides pharmaceutical formulations comprising at least one therapeutic polypeptide. According to certain embodiments of the present invention, the therapeutic polypeptide is an antibody that specifically binds to human interleukin-33 (hIL-33) or an antigen-binding fragment thereof. More specifically, the present invention includes formulations comprising: (i) a human antibody that specifically binds to hIL-33; (ii) a buffer; (iii) a thermal stabilizer; (iv) a surfactant (which may also be an organic cosolvent or surface stabilizer); and (v) a viscosity modifier. Additional components may be included in the formulations of the present invention, provided that such components do not significantly interfere with the viscosity and stability of the formulation. Specific exemplary components and formulations included in the present invention are described in detail below.

[0036] In certain embodiments, the pharmaceutical formulation of the present invention may be a fluid formulation. As used herein, the term "fluid formulation" refers to a mixture of at least two components that exists primarily in a fluid state at about 2°C to about 45°C. Fluid formulations include, among others, liquid formulations. Fluid formulations may be of low, medium, or high viscosity, depending on their specific components. .

[0037] An antibody that specifically binds to human IL-33 The pharmaceutical formulations of the present invention may comprise a human antibody or antigen-binding fragment thereof that specifically binds to hIL-33. As used herein, the term "hIL-33" refers to the human IL-33 protein.

[0038] As used herein, the term "antibody" is intended to refer to immunoglobulin molecules, as well as multimers thereof (e.g., IgM), generally comprising four polypeptide chains: two heavy (H) chains and two light (L) chains interconnected by disulfide bonds; however, immunoglobulin molecules consisting solely of heavy chains (i.e., lacking light chains) are also encompassed within the definition of the term "antibody." Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0039] In certain embodiments of the present invention, the anti-IL-33 antibodies of the present invention 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. Human antibodies of the present invention may include, for example, amino acid residues in the CDRs, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed 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 derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. In various embodiments, the anti-IL-33 antibodies are human IgG antibodies. In various embodiments, the anti-IL-33 antibodies are human antibodies of the isotype IgG1, IgG2, IgG3, or IgG4, or mixed isotypes. In some embodiments, the anti-IL-33 antibodies are human IgG1 antibodies. In some embodiments, the anti-IL-33 antibodies are human IgG4 antibodies. In any of the embodiments above or discussed herein, the anti-IL-33 antibody may comprise a human kappa light chain. In any of the embodiments above or discussed herein, the anti-IL-33 antibody may comprise a human lambda light chain.

[0040] The antibodies of the present invention may, in some embodiments, be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include 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 animals (e.g., mice) that are transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means, including splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be prepared by in vitro mutagenesis (or by using animals transgenic for human Ig sequences). The recombinant antibody is then subjected to in vivo somatic mutagenesis (in vivo mutagenesis), thus H and V L The amino acid sequence of the region is human germline V H and V L These are sequences that are derived from and related to sequences, but which may not naturally occur within the human antibody germline repertoire in vivo.

[0041] As used herein, the term "antigen-binding portion" of an antibody or "antibody fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to hIL-33.

[0042] 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-33 is substantially free of antibodies that specifically bind to antigens other than hIL-33).

[0043] "Specifically binds" or similar terms means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding is at least about 1 x 10 -6 The specific binding of an antibody to hIL-33 may be characterized by a dissociation constant of 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-33 may have cross-reactivity to other antigens, such as IL-33 molecules from other species (orthologs). In the context of the present invention, multispecific (e.g., bispecific) antibodies that bind to hIL-33, as well as one or more additional antigens, are considered to "specifically bind" to hIL-33. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0044] Exemplary anti-hIL-33 antibodies that can be included in the pharmaceutical formulations of the present invention are set forth in WO2014 / 164959, the disclosure of which is incorporated by reference in its entirety.

[0045] According to certain embodiments of the present invention, an anti-hIL-33 antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 4-6-8, respectively. According to certain embodiments of the present invention, an anti-hIL-33 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 12-14-16, respectively.

[0046] In certain embodiments, the anti-hIL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-hIL-33 antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the anti-hIL-33 antibody or antigen-binding fragment thereof comprises an HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10. In some embodiments, the anti-IL-33 antibody comprises an HCVR / LCVR comprising the amino acid sequences of SEQ ID NOs: 2 / 10, respectively, and a human IgG1 heavy chain constant region. In some embodiments, the anti-IL-33 antibody comprises an HCVR / LCVR comprising the amino acid sequences of SEQ ID NOs: 2 / 10, respectively, and a human IgG4 heavy chain constant region. In some embodiments, the anti-IL-33 antibody comprises an HCVR / LCVR comprising the amino acid sequences of SEQ ID NOs: 2 / 10, respectively, and a human IgG4 heavy chain constant region. In some embodiments, an anti-IL-33 antibody comprises a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 2 / 10, respectively, and a human IgG1 or IgG4 heavy chain constant region. In some embodiments, an anti-IL-33 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain comprising the amino acid sequence of SEQ ID NO: 20. An anti-IL-33 antibody having a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10 is referred to herein as mAb1. This antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain comprising the amino acid sequence of SEQ ID NO:20.

[0047] The amount of antibody or antigen-binding fragment thereof contained in the pharmaceutical formulation of the present invention can vary depending on the desired specific properties of the formulation, as well as the particular situation and purpose for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation can contain about 1 mg / mL to about 500 mg / mL of antibody, about 5 mg / mL to about 400 mg / mL of antibody, about 5 mg / mL to about 200 mg / mL of antibody, about 15 mg / mL to about 150 mg / mL, about 25 mg / mL to about 180 mg / mL of antibody, about 25 mg / mL to about 150 mg / mL of antibody, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 150 mg / mL, or about 140 mg / mL to about 160 mg / mL of antibody. For example, the formulations of the present invention may contain a medicament containing a medicament containing 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, or about 120 mg / mL that specifically binds to hIL-33. The liquid formulation may comprise about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 131 mg / mL, about 132 mg / mL, about 133 mg / mL, about 134 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 the antibody or antigen-binding fragment thereof.In certain embodiments, the pharmaceutical formulation comprises an antibody having a concentration of 5±0.75 mg / mL to 150±22.5 mg / mL, an antibody having a concentration of 7.5±1.125 mg / mL to 140±21 mg / mL, an antibody having a concentration of 10±1.5 mg / mL to 130±19.5 mg / mL, an antibody having a concentration of 12.5±1.875 mg / mL to 120±18 mg / mL, an antibody having a concentration of 15±2.25 mg / mL to 110±16.5 mg / mL, an antibody having a concentration of 17.5±2.625 mg / mL to 100±15 mg / mL, an antibody having a concentration of 18.5±2.625 mg / mL to 120±15 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 130±19.5 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 130±19.5 mg / mL, an antibody having a concentration of 18.5±2.625 mg / mL to 120±15 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 130±15 mg / mL, an antibody having a concentration of 18.5±2.625 mg / mL to 130±15 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 120±15 mg / mL, an antibody having a concentration of 18.5±2.625 mg / mL to 130±15 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 130±15 mg / mL, an antibody having a concentration of 19.5±2.625 mg / mL to 130 The liquid formulation may contain 20±3 mg / mL to 90±13.5 mg / mL of antibody, 22.5±3.375 mg / mL to 80±12 mg / mL of antibody, 25±3.75 mg / mL to 70±10.5 mg / mL of antibody, 27.5±4.125 mg / mL to 60±9 mg / mL of antibody, 30±4.5 mg / mL to 50±7.5 mg / mL of antibody, 25±3.75 mg / mL of antibody, or 50±7.5 mg / mL. In some embodiments, the pharmaceutical formulation contains 15±0.15 mg / mL to 150±1.5 mg / mL of anti-IL-33 antibody. In some cases, the pharmaceutical formulation contains 75 mg / mL±3.75 mg / mL of anti-IL-33 antibody. In some cases, the pharmaceutical formulation contains 150 mg / mL ± 7.5 mg / mL of the anti-IL-33 antibody.

[0048] biological equivalent The present invention encompasses antibodies having amino acid sequences that differ from those of the exemplary molecules disclosed herein but that retain the ability to bind to hIL-33. Such variant molecules may contain one or more additions, deletions, or substitutions of amino acids when compared to the parent sequence, but may exhibit biological activity that is essentially equivalent to that of the antibodies discussed herein.

[0049] The present invention includes antigen-binding molecules that are biologically equivalent to any of the exemplary antibodies defined herein.For example, when administered at the same molar dose under similar experimental conditions, either in a single dose or multiple doses, two antibodies are considered to be biologically equivalent if they are pharmaceutical equivalents or pharmaceutical substitutes that do not show significant differences in the rate and extent of absorption.Some antibodies will be considered to be equivalents or pharmaceutical substitutes if they are equivalent in the degree of absorption but not in the rate of absorption, but such differences in the rate of absorption are intentional and reflected in the labeling, for example, for chronic use. They may be considered bioequivalents because they are not essential to achieving effective body drug concentrations during use and are not considered medically significant for the particular drug studied.

[0050] In one embodiment, two antibodies are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0051] In one embodiment, two antibodies are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without a clinically significant change in immunogenicity or an expected increase in risk of adverse effects, including attenuation of efficacy, compared to maintenance therapy without such switching.

[0052] Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence measurements include, for example, (a) in vivo studies in humans or other mammals in which the concentration of an antibody or its metabolites is measured as a function of time in blood, plasma, serum, or other biological fluids, (b) in vitro studies that correlate with and reasonably predict human in vivo bioavailability data, (c) in vivo studies in humans or other mammals in which the relevant acute pharmacological effects of the antibody (or its target) are measured as a function of time, and (d) well-controlled clinical studies that establish the safety, efficacy, or bioavailability or bioequivalence of the antigen-binding protein.

[0053] Formulation excipients and pH The pharmaceutical formulations of the present invention include one or more excipients. As used herein, the term "excipient" refers to any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity, or stabilizing effect.

[0054] In certain embodiments, the pharmaceutical formulations of the present invention comprise at least one amino acid (e.g., arginine, histidine, or glutamic acid). In some embodiments, the amino acid is arginine. In some embodiments, the arginine is provided in the form of arginine hydrochloride. In some embodiments, the amino acid is a combination of arginine and glutamic acid. In some cases, the amino acid (e.g., arginine) functions as a viscosity modifier for the anti-IL-33 antibody formulation.

[0055] The amount of amino acids contained in the pharmaceutical formulations of the present invention can vary depending on the specific desired properties of the formulation, as well as the particular situation and purpose for which the formulation is intended to be used. In certain embodiments, the formulation can contain 1 mM to about 200 mM amino acids, about 5 mM to about 150 mM, about 25 mM to about 125 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, about 60 mM to about 80 mM, or about 65 mM to about 75 mM amino acids. For example, pharmaceutical formulations of the present invention may contain about 1 mM, 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, about 100 mM, about 105 mM, about 110 mM, about 115 mM, about 120 mM, or about 125 mM of amino acids (e.g., arginine). In some embodiments, the formulation contains about 70 mM of amino acids (e.g., arginine).

[0056] The pharmaceutical formulations of the present invention may also contain one or more carbohydrates, such as one or more sugars. The sugars may be reducing or non-reducing sugars. "Reducing sugars" include, for example, sugars with a ketone or aldehyde group, and contain a reactive hemiacetal group that allows the sugar to function as a reducing agent. Specific examples of reducing sugars include fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose, and erythritol. and maltose. Non-reducing sugars are acetals and may contain an anomeric carbon that does not substantially react with amino acids or polypeptides to initiate the Maillard reaction. Specific examples of non-reducing sugars include sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose. Sugar acids include, for example, saccharinic acid, gluconate, and other polyhydroxy sugars and their salts. In some embodiments, the sugar is sucrose. In some cases, the sugar (e.g., sucrose) functions as a thermal stabilizer for the anti-IL-33 antibody.

[0057] The amount of sugar (e.g., sucrose) contained in the pharmaceutical formulations of the present invention will vary depending on the specific context and intended purpose of the formulation. In certain embodiments, the formulation may contain 0.1% to about 20% sugar, about 0.5% to about 20% sugar, about 1% to about 20% sugar, about 2% to about 15% sugar, about 3% to about 10% sugar, about 3% to about 7% sugar, or about 4% to about 6% sugar. For example, the pharmaceutical formulations of the present invention may contain about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 15%, or about 20% sugar (e.g., sucrose). In some embodiments, the formulation contains about 5% sugar (e.g., sucrose).

[0058] The pharmaceutical formulations of the present invention may also be protected from rough handling or, for example, orbital shaking. The formulation may contain one or more organic co-solvents (or surface stabilizers) of a type and amount that stabilizes the anti-IL-33 antibody under conditions of agitation, such as shaking. In some embodiments, the organic co-solvent is a surfactant. As used herein, the term "surfactant" refers to 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. Surfactants can be ionic or non-ionic. Exemplary non-ionic surfactants that can be included in the formulations of the present invention include, for example, alkyl poly(ethylene oxide), alkyl polyglucosides (e.g., octyl glucoside and decyl maltoside), fatty alcohols such as cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA, and cocamide TEA. Specific nonionic surfactants that can be included in the formulations of the invention include, for example, polysorbates such as polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85; poloxamers such as poloxamer 188 (also known as Pluronic F68) and poloxamer 407; polyethylene-polypropylene glycol; or polyethylene glycol (PEG). Polysorbate 20 is also known as TWEEN 20, sorbitan monolaurate, and polyoxyethylene sorbitan monolaurate. In some embodiments, the surfactant is polysorbate 80.

[0059] The amount of surfactant contained within the pharmaceutical formulations of the present invention can vary depending on the specific desired properties of the formulation, as well as the particular situation and purpose for which the formulation is intended to be used. In certain embodiments, the formulation may contain 0.05% to about 5% surfactant, about 0.05% to about 0.15% surfactant, about 0.04% to about 0.12%, about 0.05% to about 0.11%, about 0.06% to about 0.1% surfactant, or about 0.07% to about 0.09% surfactant. For example, a formulation of the present invention may contain about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, or about 0.30% surfactant (e.g., polysorbate 80). In some embodiments, a formulation contains about 0.08% surfactant (e.g., polysorbate 80). Each of the above percentages corresponds to a weight / volume (w / v) percent.

[0060] The pharmaceutical formulations of the present invention may also include a buffer or buffer system that helps maintain a stable pH and stabilize the anti-IL-33 antibody. In some embodiments, the buffer or buffer system includes at least one buffer with a buffer range that completely or partially overlaps the pH range of 4.9 to 5.7. In certain embodiments, the buffer includes a histidine buffer. In certain embodiments, the buffer is an acetate buffer. In certain embodiments, the buffer (e.g., acetate) is present at a concentration of about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 1 mM to about 20 mM, about 3 mM to about 18 mM, about 5 mM to about 15 mM, or about 8 mM to about 12 mM. In some embodiments, the buffer (e.g., acetate) is present at a concentration of 5.3 mM ± 0.3 mM, 5.3 mM ± 0.2 mM, or 5.3 mM ± 0.1 mM. In some embodiments, the buffer is present at a concentration of about 4.6 mM, about 4.7 mM, about 4.8 mM, about 4.9 mM, about 5.0 mM, about 5.1 mM, about 5.2 mM, about 5.3 mM, about 5.4 mM, about 5.5 mM, about 5.6 mM, about 5.7 mM, about 5.8 mM, about 5.9 mM, or about 6.0 mM.

[0061] Exemplary Formulations According to one embodiment of the present invention, a pharmaceutical formulation comprises (i) a human antibody (e.g., mAb1) that specifically binds to hIL-33, (ii) a buffer (e.g., acetate), (iii) an amino acid (e.g., arginine), (iv) a heat stabilizer (e.g., sucrose), and (v) an organic co-solvent (e.g., polysorbate 80).

[0062] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33 (e.g., mAb1) at a concentration of about 1 mg / ml to about 200 mg / ml; (ii) a buffer (e.g., acetate) at a concentration of about 1 mM to about 20 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 30 mM to about 110 mM; (iv) a heat stabilizer (e.g., sucrose) at a concentration of about 1% w / v to about 10% w / v; and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.01% w / v to about 0.15% w / v.

[0063] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33 (e.g., mAb1) at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) a buffer (e.g., acetate) at a concentration of about 5 mM to about 15 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 50 mM to about 90 mM; (iv) a heat stabilizer (e.g., sucrose) at a concentration of about 3% w / v to about 7% w / v; and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.05% w / v to about 0.11% w / v.

[0064] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) a buffer (e.g., acetate) at a concentration of about 5 mM to about 15 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 50 mM to about 90 mM; (iv) a heat stabilizer (e.g., sucrose) at a concentration of about 3% w / v to about 7% w / v; and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.05% w / v to about 0.11% w / v.

[0065] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml, the human antibody having a heavy chain constant region of isotype IgG1; (ii) a buffer (e.g., acetate) at a concentration of about 5 mM to about 15 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 50 mM to about 90 mM; and (iv) an amino acid (e.g., arginine) at a concentration of about 3% w / v to about 7% w / v. a heat stabilizer (e.g., sucrose), and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.05% w / v to about 0.11% w / v.

[0066] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml, wherein the antibody has a heavy chain constant region of the IgG4 isotype; (ii) a buffer (e.g., acetate) at a concentration of about 5 mM to about 15 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 50 mM to about 90 mM; (iv) a heat stabilizer (e.g., sucrose) at a concentration of about 3% w / v to about 7% w / v; and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.05% w / v to about 0.11% w / v.

[0067] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) a buffer (e.g., acetate) at a concentration of about 5 mM to about 15 mM; (iii) an amino acid (e.g., arginine) at a concentration of about 50 mM to about 90 mM; (iv) a heat stabilizer (e.g., sucrose) at a concentration of about 3% w / v to about 7% w / v; and (v) an organic co-solvent (e.g., polysorbate 80) at a concentration of about 0.05% w / v to about 0.11% w / v.

[0068] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 5 mM to about 15 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 50 mM to about 90 mM; (iv) sucrose at a concentration of about 3% w / v to about 7% w / v; and (v) polysorbate 80 at a concentration of about 0.05% w / v to about 0.11% w / v.

[0069] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody, at a concentration of about 15 mg / ml to about 150 mg / ml, that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody has a heavy chain constant region of the IgG1 isotype; (ii) acetate at a concentration of about 5 mM to about 15 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 50 mM to about 90 mM; (iv) sucrose at a concentration of about 3% w / v to about 7% w / v; and (v) polysorbate 80 at a concentration of about 0.05% w / v to about 0.11% w / v.

[0070] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody, at a concentration of about 15 mg / ml to about 150 mg / ml, that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody has a heavy chain constant region of the IgG4 isotype; (ii) acetate at a concentration of about 5 mM to about 15 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 50 mM to about 90 mM; (iv) sucrose at a concentration of about 3% w / v to about 7% w / v; and (v) polysorbate 80 at a concentration of about 0.05% w / v to about 0.11% w / v.

[0071] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 5 mM to about 15 mM; and (iii) arginine at a concentration of about 50 mM to about 90 mM. (e.g., arginine hydrochloride), (iv) sucrose at a concentration of about 3% w / v to about 7% w / v, and (v) polysorbate 80 at a concentration of about 0.05% w / v to about 0.11% w / v.

[0072] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 8 mM to about 12 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 65 mM to about 75 mM; (iv) sucrose at a concentration of about 4% w / v to about 6% w / v; and (v) polysorbate 80 at a concentration of about 0.07% w / v to about 0.09% w / v.

[0073] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody, at a concentration of about 15 mg / ml to about 150 mg / ml, that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody has a heavy chain constant region of the IgG1 isotype; (ii) acetate at a concentration of about 8 mM to about 12 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 65 mM to about 75 mM; (iv) sucrose at a concentration of about 4% w / v to about 6% w / v; and (v) polysorbate 80 at a concentration of about 0.07% w / v to about 0.09% w / v.

[0074] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, at a concentration of about 15 mg / ml to about 150 mg / ml, and that comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody has a heavy chain constant region of the IgG4 isotype; (ii) acetate at a concentration of about 8 mM to about 12 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 65 mM to about 75 mM; (iv) sucrose at a concentration of about 4% w / v to about 6% w / v; and (v) polysorbate 80 at a concentration of about 0.07% w / v to about 0.09% w / v.

[0075] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 8 mM to about 12 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 65 mM to about 75 mM; (iv) sucrose at a concentration of about 4% w / v to about 6% w / v; and (v) polysorbate 80 at a concentration of about 0.07% w / v to about 0.09% w / v.

[0076] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 10 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 70 mM; (iv) sucrose at a concentration of about 5% w / v; and (v) polysorbate 80 at a concentration of about 0.08% w / v.

[0077] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml, wherein the antibody has a heavy chain constant region of the IgG1 isotype; (ii) acetate at a concentration of about 10 mM; and (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 70 mM. (iv) sucrose at a concentration of about 5% w / v; and (v) polysorbate 80 at a concentration of about 0.08% w / v.

[0078] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33 and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml, wherein the antibody has a heavy chain constant region of the IgG4 isotype; (ii) acetate at a concentration of about 10 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 70 mM; (iv) sucrose at a concentration of about 5% w / v; and (v) polysorbate 80 at a concentration of about 0.08% w / v.

[0079] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) acetate at a concentration of about 10 mM; (iii) arginine (e.g., arginine hydrochloride) at a concentration of about 70 mM; (iv) sucrose at a concentration of about 5% w / v; and (v) polysorbate 80 at a concentration of about 0.08% w / v.

[0080] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0081] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, at a concentration of about 15 mg / ml ± 1.5 mg / ml, and comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0082] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 75 mg / ml ± 5 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0083] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10, at a concentration of about 150 mg / ml ± 15 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0084] In some cases, the stable liquid pharmaceutical formulation comprises (i) a human antibody that specifically binds to hIL-33, the human antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2, an LCVR comprising the amino acid sequence of SEQ ID NO: 10, and a human IgG4 heavy chain constant region, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) about 10 mM ± 1 mM acetate; and (iii) about 70 mM ± 7 mM acetate. (iv) arginine hydrochloride, (iv) 5% w / v±0.5% w / v sucrose, and (iv) about 0.08%±0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3±0.1.

[0085] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2, a LCVR comprising the amino acid sequence of SEQ ID NO: 10, and a human IgG4 heavy chain constant region, at a concentration of about 15 mg / ml ± 1.5 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0086] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2, a LCVR comprising the amino acid sequence of SEQ ID NO: 10, and a human IgG4 heavy chain constant region, at a concentration of about 75 mg / ml ± 5 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0087] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, and comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2, a LCVR comprising the amino acid sequence of SEQ ID NO: 10, and a human IgG4 heavy chain constant region, at a concentration of about 150 mg / ml ± 15 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0088] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml to about 150 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0089] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 15 mg / ml ± 1.5 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0090] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 75 mg / ml ± 5 mg / ml; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0091] In some cases, the stable liquid pharmaceutical formulation has a concentration of (i) about 150 mg / ml ± 15 mg / ml and a human antibody that specifically binds to hIL-33, the human antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, at a concentration of about 1000 mM; (ii) about 10 mM ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) 5% w / v ± 0.5% w / v sucrose; and (iv) about 0.08% ± 0.008% w / v polysorbate 80, wherein the formulation has a pH of 5.3 ± 0.1.

[0092] Additional non-limiting examples of pharmaceutical formulations encompassed by the present invention are set forth elsewhere herein, including in the Examples provided below.

[0093] Stability and viscosity of pharmaceutical formulations The pharmaceutical formulations of the present invention exhibit a high level of stability. As used herein with respect to pharmaceutical formulations, the term "stable" means that the antibody in the pharmaceutical formulation retains an acceptable degree of structure and / or function and / or biological activity after storage for a defined amount 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 for a defined amount 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 for a defined amount of time can be considered "stable".

[0094] Stability can be measured, inter alia, by determining the percentage of native antibody remaining in the formulation after storage at a given temperature for a defined amount of time. The percentage of native antibody can be determined, inter alia, by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). As used herein, "acceptable degree of stability" means that at least 90% of the native form of the antibody can be detected in the formulation after storage at a given temperature for a defined amount of time. 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 at a given temperature for a defined amount of time. 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 between about -80°C and about 45°C, such as 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. For example, a pharmaceutical formulation can be considered stable if greater than about 90%, 95%, 96%, or 97% of the native antibody is detected by SE-HPLC after 3 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, or 97% of the native antibody is detected by SE-HPLC after 6 months of storage at 5° C. A pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5% of the native antibody is detected by SE-HPLC after 9 months of storage at 5° C.A pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5% of the native antibody is detected by SE-HPLC after 3 months of storage at 25° C. A pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5% of the native antibody is detected by SE-HPLC after 6 months of storage at 25° C. A pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5% of the native antibody is detected by SE-HPLC after 9 months of storage at 25° C. A drug formulation may also be considered to be stable.

[0095] Other methods, such as differential scanning calorimetry (DSC) to determine thermal stability, controlled stirring to determine mechanical stability, and absorbance at about 350 nm or about 405 nm to determine solution turbidity, can be used to assess the stability of the formulations of the invention. For example, the OD of a formulation after storage at about 5°C to about 25°C for 6 months or more can be measured. 405 The change in OD of the formulation at t=0 405 to less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01, or less), the formulations of the present invention can be considered stable.

[0096] Measuring the binding affinity of an antibody to a target can also be used to assess stability. For example, after storage of a formulation of the present invention for a defined amount of time (e.g., 14 days to 9 months) at, e.g., -80°C, -30°C, -20°C, 5°C, 25°C, 37°C, 45°C, etc., the anti-IL-33 antibody contained within the formulation binds to hIL-33 with an affinity that is at least 80%, 85%, 90%, 95%, or more of the binding affinity of the antibody prior to storage. Binding affinity can be determined by any method, e.g., ELISA or plasmon resonance. Biological activity can be determined by an IL-33 activity assay, such as by contacting IL-33-expressing cells with a formulation containing an anti-IL-33 antibody. Binding of the antibody to such cells can be measured directly, e.g., via FACS analysis. Alternatively, downstream activity of the IL-33 system can be measured in the presence of the antibody and compared to the activity of the IL-33 system in the absence of the antibody.

[0097] Stability can be measured, inter alia, by determining the percentage of antibody that forms aggregates within a formulation after storage at a defined temperature for a defined amount of time, with stability being inversely proportional to the percent aggregates formed. The percentage 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 performance liquid chromatography [SE-UPLC]). "Acceptable degree of stability," as that phrase is used herein, means that up to 6% of the antibody is in a detectable aggregated form in the formulation after storage at a given temperature for a defined amount of time. In certain embodiments, acceptable degree of stability means that up to about 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in aggregates in the formulation after storage at a given temperature for a defined amount of time. 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 assessing stability can be any temperature between about -80°C and about 45°C, for example, 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. For example, a pharmaceutical formulation may be considered stable if less than about 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% of the antibody is detected in aggregated form after 9 months of storage at 5° C. A pharmaceutical formulation may also be considered stable if less than about 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% of the antibody is detected in aggregated form after 6 months of storage at 25° C.A pharmaceutical formulation may also be considered stable if less than about 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, or 0.1% of the antibody is detected in aggregated form after 28 days of storage at 45° C. A pharmaceutical formulation may also be considered stable if less than about 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1%, 0.5%, or 0.1% of the antibody is detected in aggregated form after 3 months of storage at −20° C., −30° C., or −80° C.

[0098] Stability can be measured, inter alia, by determining the percentage of antibody that migrates in the acidic fraction ("acidic form") during ion exchange rather than the main fraction ("mainly charged form") of the antibody, with stability being inversely proportional to the fraction of antibody in acidic form. Without wishing to be bound by theory, deamidation of an antibody can make the antibody more negatively charged and therefore more acidic relative to non-deamidated antibody (e.g., Robinson, N., Protein Deamidation, PNAS, April 16, 2002, 99(8):5283-5288). The percentage of "acidified" antibody can be determined by ion exchange chromatography (e.g., cation exchange high-performance liquid chromatography [CEX-HPLC] or cation exchange ultra-performance liquid chromatography [CEX-UPLC]). "Acceptable degree of stability," as that phrase is used herein, means that up to 52% of the antibody is in the more acidic form detected in the formulation after storage at a defined temperature for a defined amount of time. In certain embodiments, an acceptable degree of stability means that up to about 52%, 50%, 45%, 40%, 35%, 30%, 29%, 28%, 27%, 26%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in acidic form in the formulation after storage at a given temperature for a defined amount of time. 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 may be stored when assessing stability may be any temperature between about -80°C and about 45°C, for example, 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.For example, a pharmaceutical formulation is considered stable if less than about 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 3 months of storage at -80°C, -30°C, or -20°C. A pharmaceutical formulation is also considered stable if less than about 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 9 months of storage at 5°C. A pharmaceutical formulation is also considered stable if less than about 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 28 days of storage at 25°C. A pharmaceutical formulation is also considered stable if less than about 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 28 days of storage at 37°C. A pharmaceutical formulation is also considered stable if less than about 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in the more acidic form after 28 days of storage at 45°C.

[0099] In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 2%, no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than 1.6%, or no more than 1.5% HMW species as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 24 months of storage at -80°C, -30°C, or -20°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, or no more than 0.5% HMW species as measured by SE-UPLC after 9 months of storage at -80°C, -30°C, or -20°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, or no more than 0.6% HMW species as measured by SE-UPLC after 2 months of storage at 5°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 2%, no more than 1.8%, no more than 1.6%, no more than 1.4%, no more than 1.2%, or no more than 1.0% HMW species as measured by SE-UPLC after two months of storage at 25°C and 60% relative humidity. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 6%, no more than 5.5%, no more than 5.4%, no more than 5.3%, no more than 5.2%, or no more than 5.1% HMW species as measured by SE-UPLC after two months of storage at 40°C and 75% relative humidity. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 1%, no more than 0.9%, no more than 0.8%, or no more than 0.7% HMW species as measured by SE-UPLC after nine months of storage at 2-8°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 3%, no more than 2.8%, no more than 2.6%, no more than 2.4%, no more than 2.2%, or no more than 2.0% HMW species as measured by SE-UPLC after 24 months of storage at 2-8° C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 2%, no more than 1.8%, no more than 1.6%, no more than 1.5%, no more than 1.4%, or no more than 1.3% HMW species as measured by SE-UPLC after 6 months of storage at 25° C. and 60% relative humidity.In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 1%, no more than 0.9%, no more than 0.8%, or no more than 0.7% HMW species as measured by SE-UPLC after 6 months of storage at 2-8° C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention contains no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, or no more than 0.5% HMW species as measured by SE-UPLC after 3 months of storage at 2-8° C.

[0100] In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 97.5%, or at least 97.9% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 24 months of storage at -80°C, -30°C, or -20°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 9 months of storage at -80°C, -30°C, or -20°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 2 months of storage at 5°C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, or at least 98.8% of the native form of the antibody as measured by size-exclusion ultra performance liquid chromatography (SE-UPLC) after 2 months of storage at 25° C. and 60% relative humidity. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, or at least 98.8% of the native form of the antibody as measured by size-exclusion ultra performance liquid chromatography (SE-UPLC) after 2 months of storage at 40° C. and 75% relative humidity. The "stable" pharmaceutical compositions or formulations of the invention comprise at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 94.1% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 9 months of storage at 2-8° C. In certain embodiments, the "stable" pharmaceutical compositions or formulations of the invention comprise at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 24 months of storage at 2-8° C. In certain embodiments, the "stable" pharmaceutical compositions or formulations of the invention comprise at least 95%, at least 96%, at least 97%, at least 97.5%, or at least 97.6% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 24 months of storage at 2-8° C. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 98.4% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 6 months of storage at 25° C. and 60% relative humidity. In certain embodiments, a "stable" pharmaceutical composition or formulation of the invention comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the native form of the antibody as measured by size-exclusion ultra-performance liquid chromatography (SE-UPLC) after 3 months or 6 months of storage at 2-8° C.

[0101] Reference to the stability of a pharmaceutical formulation "after" a particular period of time is intended to mean that measurements of the stability parameters (e.g., % native form, % HMW species, or % acidic form) were made at or around the end of the particular period of time, and is not intended to mean that the pharmaceutical formulation will necessarily maintain the same degree of stability for the parameter measured thereafter. For example, a reference to a particular stability after 9 months means that the stability measurements were made at the beginning of the study or after about 9 months. Additional methods for assessing the stability of an antibody in a formulation are demonstrated in the Examples provided below.

[0102] In fluid form, the pharmaceutical formulations of the present invention may, in certain embodiments, exhibit low to moderate levels of viscosity. As used herein, "viscosity" can be "kinematic viscosity" or "absolute viscosity." "Kinematic viscosity" is a measure of the resistive flow of a fluid under the influence of gravity. When two fluids of equal volume are placed in the same capillary viscometer and allowed to flow by gravity, a viscous fluid will take longer to flow through the capillary than a less viscous fluid. For example, if one fluid takes 200 seconds to complete its flow and another takes 400 seconds, the second fluid is twice as viscous as the first on the kinematic viscosity scale. "Absolute viscosity," sometimes referred to as dynamic or simple viscosity, is the product of kinematic viscosity and fluid density (absolute viscosity = kinematic viscosity × density). The dimension of kinematic viscosity is L 2 / T, where L is length and T is time. Kinematic viscosity is generally expressed in centistokes (cSt). The SI unit of kinematic viscosity is mm 2 / s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is millipascal-second (mPa-s), with 1 cP = 1 mPa-s.

[0103] As used herein, with respect to the fluid formulations of the present invention, a low level of viscosity would refer to an absolute viscosity of less than about 20 cPoise (cP) at 20°C. For example, a fluid formulation of the present invention would be considered to have a "low viscosity" if the formulation exhibits an absolute viscosity of about 19 cP, about 18 cP, about 17 cP, about 16 cP, about 15 cP, about 14 cP, about 13 cP, about 12 cP, about 11 cP, about 10 cP, about 9 cP, about 8 cP, about 7 cP, about 6 cP, about 5 cP, about 4 cP, or less, when measured using standard viscosity measurement techniques. As used herein, with respect to the fluid formulations of the present invention, a moderate level of viscosity would refer to an absolute viscosity of about 30 cP to about 20 cP. For example, when measured using standard viscosity measurement techniques, A fluid formulation of the present invention will be considered to have a "medium viscosity" if the formulation exhibits an absolute viscosity of about 30 cP, about 29 cP, about 28 cP, about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP, or about 20 cP. Each of these values ​​refers to measurements made at 20°C.

[0104] As demonstrated in the Examples below, the present invention is based, in part, on the discovery that the combination of the claimed excipients with an anti-IL-33 antibody produces a formulation that is stable and has a desirable viscosity.

[0105] Container and method of administration The pharmaceutical formulations of the present invention can be contained in any suitable container for storing pharmaceuticals and other therapeutic compositions.For example, the pharmaceutical formulations can be contained in a sealed and sterilized plastic or glass container with a defined volume, such as a vial, an ampoule, a syringe, a cartridge, a bottle, or an IV bag.For example, different types of vials, including transparent and opaque (e.g., amber) glass or plastic vials, can be used to contain the formulations of the present invention.Similarly, any type of syringe can be used to contain and / or administer the pharmaceutical formulations of the present invention.In some embodiments, the pharmaceutical formulations are contained in a pre-filled syringe.In some embodiments, the pharmaceutical formulations are contained in a pre-filled fixed-needle syringe.

[0106] The pharmaceutical formulations of the present invention can be contained in "normal tungsten" syringes or "low tungsten" syringes. As will be understood by those skilled in the art, the process of making glass syringes generally involves the use of a hot tungsten rod, which functions to puncture 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 interior surface of the syringe. Subsequent cleaning 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, a low tungsten syringe according to the present invention can 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, or even less ppb of tungsten.

[0107] 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 maintain their stability.Therefore, according to certain embodiments, the pharmaceutical formulation of the present invention can be contained in a syringe with a coated plunger or in 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 and / or plungers suitable for use with vials and syringes containing the pharmaceutical formulations of the present disclosure are mentioned in, for example, U.S. Patent Nos. 4,997,423, 5,908,686, 6,286,699, 6,645,635, and 7,226,554, the contents of which are incorporated herein by reference in their entirety. Certain exemplary coated rubber stoppers and plungers that may be used in the present invention are commercially available under the trade name "FluroTec®" available from West Pharmaceutical Services, Inc. (Lionville, PA). According to certain embodiments of the present invention, the pharmaceutical formulation may be contained within a low-tungsten syringe that includes a fluorocarbon-coated plunger. In some embodiments, the container is Ompi E The syringe is a syringe such as a Z-Fill™ syringe or a BD Neopak™ syringe. In some cases, the syringe is a 1 mL long glass syringe with a 1 mL iWest piston, a 27G thin-walled needle, and an FM30 or BD260 needle shield. In some cases, the syringe is a 2.25 mL glass syringe with a West NovaPure™ 1-3 mL piston, a 27G thin-walled needle, and an FM30 or BD260 needle shield. 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).

[0108] The pharmaceutical formulations may be administered to a subject by injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or by oral routes, such as transdermal, mucosal, nasal, pulmonary, and / or oral administration. Many reusable pen and / or autoinjector delivery devices can be used to deliver the pharmaceutical formulations of the present invention subcutaneously. Examples include AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, 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 Examples of disposable pen and / or autoinjector delivery devices that are suitable for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the SOLOSTAR pen (sanofi-aventis), FLEXPEN (Novo Nordisk), and KWIKPEN (Eli Lilly), the SURECLICK autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA pen (Abbott Labs, Abbott Park, IL), to name just a few. In some cases, the pharmaceutical formulation is contained in a syringe specifically adapted for use with an autoinjector.Subcutaneous injections may be administered using a 20-30 gauge needle or a 25-30 gauge needle. In some cases, subcutaneous injections may be administered using a 25 gauge needle. In some cases, subcutaneous injections may be administered using a 27 gauge needle. In some cases, subcutaneous injections may be administered using a 29 gauge needle.

[0109] Another type of delivery device can include a safety system. Such devices are relatively inexpensive and operate to manually or automatically extend a safety sleeve over the needle once the injection is complete. Examples of safety systems include the ERIS device by West Pharmaceutical or the UltraSafe device by Becton Dickinson. In addition, the use of a large volume device ("LVD") or bolus injector to deliver the pharmaceutical formulations of the present invention is also contemplated herein. In some cases, the LVD or bolus injector can be configured to inject the medication into the patient. For example, an LVD or A bolus injector may be configured to deliver a "large volume" of medication (typically about 2 ml to about 10 ml).

[0110] The pharmaceutical formulations of the present invention may also be contained in unit dosage forms. As used herein, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for a patient to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect in association with 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., an anti-IL-33 antibody) in the formulations of the present invention may be varied to obtain an amount of active ingredient that is effective to achieve a 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 various pharmacokinetic factors, including the activity of the particular composition of the present invention used, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical field. As used herein, the term "diluent" refers to a solution suitable for modifying or achieving the exemplary or suitable concentrations described herein.

[0111] In various embodiments, the unit dosage form contains an amount of active ingredient (e.g., an anti-IL-33 antibody) intended for a single use. In various embodiments, the amount of active ingredient in the unit dosage form is about 0.1 mg to about 5000 mg, about 100 mg to about 1000 mg, and about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 250 mg to about 350 mg, about 125 mg to about 175 mg, about 275 mg to about 325 mg, or a range or interval thereof. Ranges intermediate to the above-listed amounts, e.g., about 135 mg to about 165 mg or 285 mg to 315 mg, are also intended to be part of the present invention. For example, ranges of values ​​using any combination of the above-listed values ​​(or values ​​included within the above-listed ranges) as upper and / or lower limits are intended to be included. In certain embodiments, formulations are often supplied as liquid unit dosage forms. In some embodiments, the unit dosage form contains about 150 mg. In some embodiments, the unit dosage form contains about 300 mg. In some embodiments, the unit dosage form according to the present invention is suitable for subcutaneous administration to a patient.

[0112] The present invention also includes methods of preparing unit dosage forms. In exemplary embodiments, the method for preparing a pharmaceutical unit dosage form includes combining the formulations of any of the foregoing embodiments in a suitable container (e.g., those containers discussed herein).

[0113] Therapeutic Uses of Pharmaceutical Preparations The pharmaceutical formulations of the present invention are useful, inter alia, for the treatment, prevention, and / or amelioration of any disease or disorder associated with IL-33 activity. In particular, the pharmaceutical formulations of the present invention are useful for the treatment, prevention, and / or amelioration of any disease or disorder associated with or mediated by IL-33 expression, signaling, or activity, or treatable by blocking the interaction between IL-33 and an IL-33 ligand (e.g., ST2) or otherwise inhibiting IL-33 activity and / or signaling.

[0114] Therapeutic methods of the present invention include administering to a subject any formulation comprising an anti-hIL-33 antibody as disclosed herein. The subject to whom the pharmaceutical formulation is administered can be, for example, any human or animal in need of such treatment, prevention, and / or amelioration, or who would otherwise benefit from inhibition or attenuation of IL-33 and / or IL-33-mediated activity. or a non-human animal. For example, the subject may be an individual diagnosed with or considered at risk for any of the aforementioned diseases or disorders. The present invention further 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-33 activity, including any of the above exemplary diseases, disorders, and conditions.

[0115] In some embodiments, the present invention provides kits that include a pharmaceutical formulation (e.g., a container having a formulation or unit dosage form) as discussed herein and packaging or labeling (e.g., a package insert) with instructions for using the pharmaceutical formulation for the treatment of a disease or disorder as discussed above. In some cases, the instructions provide for the use of the unit dosage form for the treatment of a disease or disorder as discussed herein.

[0116] The sequences discussed herein and shown in the accompanying sequence listing correspond to mAb1, a fully human antibody with an IgG4 heavy chain constant region, used throughout the following examples. The SEQ ID NOs are shown below. [Table 1]

[0117] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as the invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation 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.

[0118] Example 1: Effect of buffer and pH on the stability of anti-IL-33 antibodies The effects of buffer and pH on the thermal stability of mAb1 were investigated in liquid formulations by incubating 5 mg / mL mAb1 at 45°C for 28 days in a series of buffer systems across a varying pH range. The following pH and buffer systems were studied: acetate (pH 4.5-5.5), L-histidine (pH 5.5-6.5), and phosphate (pH 6.0-7.0). Based on the results from SE-UPLC analysis, the greatest protein stability was observed when mAb1 was formulated in L-histidine buffer at pH 6.0-6.5. Based on the results from CEX-UPLC analysis, the greatest protein stability was observed when mAb1 was formulated in L-histidine or acetate buffer at pH 5.0-6.0. These analyses also revealed that the formation of HMW species and charge variants was the primary degradation pathway. The results are shown in Table 1.

[0119] [Table 2]

[0120] The effects of pH and buffer on the thermal stability of mAb1 were investigated in liquid formulations by incubating 150 mg / mL of mAb1 for 28 days at 37°C in a series of L-histidine and acetate buffers ranging from pH 4.5, 5.0, and 6.0 in the presence of 5% sucrose as a thermal stabilizer. Based on the results of SE-UPLC analysis for molecular weight species and CEX-UPLC analysis for charge variants, aggregation (i.e., formation of HMW species) and formation of charge variants were the major degradation pathways. mAb1 stability at pH 5.0 and 6.0 in L-histidine buffers and at pH 5.0 in acetate buffer is comparable, as shown in Table 2.

[0121] [Table 3]

[0122] Example 2: Effect of surfactants and thermal stabilizers on the stability of anti-IL-33 antibodies The effect of two surfactants, 0.1% polysorbate 20 and 0.1% polysorbate 80, on the thermal stability of 5 mg / mL mAb1 was first investigated in a liquid formulation using a research lot of material. The results of the thermal stability study are summarized in Table 3. When incubated at 45°C, the addition of either polysorbate 20 or polysorbate 80 had a detrimental effect on the thermal stability of mAb1 relative to a control formulation lacking any surfactant. An increase in high molecular weight species and charge variants was observed. The addition of 0.1% polysorbate 80 caused a relative increase in HMW species and less formation of charge variant forms compared to the addition of 0.1% polysorbate 20.

[0123] Additional studies were conducted to investigate polysorbate 80 concentration using a representative study lot of material at a 50 mg / mL mAb1 concentration. Polysorbate 80 concentrations included in the study were 0%, 0.01%, 0.02%, 0.04%, 0.06%, 0.08%, and 0.1%. Results are summarized in Tables 4 and 5. When stirred for 60 minutes, a 0.8% increase in the relative percentage of HMW was observed for samples containing no polysorbate 80 (Table 4). Examination of the SE-UPLC chromatograms indicated that this increase was due to the formation of a higher-order aggregate peak that was not present in the starting material. Addition of 0.02% or more polysorbate 80 prevented the formation of this aggregate species after 60 minutes of stirring. When incubated at 45°C for 28 days, the thermal stability of mAb1 was not affected by the polysorbate concentrations studied (Table 5).

[0124] mAb1 at 5 mg / mL in a liquid formulation showed improved stability when formulated with 5% sucrose and incubated under accelerated conditions, as shown in Table 3. After 28 days of incubation at 45°C, the relative amount of HMW species was 100% higher than that of the control without sucrose. There was a 0.7% increase in the formulation containing 5% sucrose compared to a 1.2% increase in the formulation containing 5% sucrose.

[0125] [Table 4]

[0126] [Table 5]

[0127] [Table 6]

[0128] Example 3: Effect of viscosity modifiers on the stability of anti-IL-33 antibodies The mAb1 is contained in a pre-filled syringe (PFS) and delivered through a delivery device such as an auto-injector. The viscosity is determined by the ease of injection through the pre-filled syringe (PFS). Maintaining a reasonably low viscosity is advantageous for the development of delivery devices such as auto-injectors.

[0129] The effect of pH on the viscosity of 150 mg / mL mAb1 in 10 mM L-histidine buffer was investigated. As shown in Figure 1, mAb1 viscosity is highly dependent on pH over the pH range of 4.8 to 6.7. The lower the pH, the lower the mAb1 viscosity. The effect of excipients on formulation viscosity was also investigated in mAb1 liquid formulations with the following potential viscosity modifiers: sodium acetate, L-arginine hydrochloride, monosodium L-glutamate, and magnesium chloride up to 200 mM. The base formulation contained 150 mg / mL mAb1, 27 mM acetate, and 5% sucrose at pH 5.3. The results are shown in Figure 2. All of these additives at 25 to 150 mM reduced the viscosity of 150 mg / mL mAb1 at pH 5.3 by 2 to 5 cP.

[0130] The effect of viscosity modifiers on the stability of 150 mg / mL mAb1 was also investigated by incubating the formulations at 37°C for 34 days. The formation of HMW species was the primary degradation pathway, and the results are shown in Figure 3. Compared to the control formulation without any viscosity modifier, the addition of magnesium chloride or sodium acetate promoted the formation of HMW after incubation at 37°C. Meanwhile, L-arginine hydrochloride and monosodium L-glutamate had no adverse effect on mAb1 stability. Instead, 75 mM L-arginine hydrochloride improved mAb1 stability against HMW formation.

[0131] Based on its viscosity-lowering effect and impact on thermal stability, L-arginine hydrochloride was selected as the viscosity modifier for mAb1 formulations.

[0132] Example 4: Effect of formulation parameters on viscosity and stability A custom experimental design was applied to understand the effect of each formulation component, as well as pH, and the interaction of these parameters on the stability and viscosity of mAb1. Formulation parameters in this study include protein concentration (135-165 mg / mL), sucrose concentration (5-9%), L-arginine hydrochloride concentration (0-75 mM), and pH. For all formulations in this study, surfactant remained constant at 0.1%.

[0133] The viscosity of the formulation remained unchanged before and after 28 days of incubation at 40°C / 75% RH.

[0134] The viscosity versus key formulation parameters was analyzed by fitting models using JMP12 with standard least squares personality and effect leverage emphasis. The main factors affecting formulation viscosity are mAb1 concentration, pH, and L-arginine hydrochloride concentration, as shown in Figure 4A.

[0135] The stability of the formulations after 28 days of incubation at 40°C / 75% RH was also investigated. No significant differences in color and appearance, turbidity, pH change, protein recovery, or charge variant changes were observed for the 14 formulations after 28 days of incubation at 40°C / 75% RH. The primary stability attribute was the formation of HMW species.

[0136] The HMW formation rate versus key formulation parameters was analyzed by fitting models using JMP12 with standard least squares regression and effect leverage emphasis. The main factors affecting HMW formation were pH, L-arginine hydrochloride concentration, and sucrose concentration, as shown in Figure 4B.

[0137] The formulation composition selection is based on the JMP12 desirability function. The study was based on minimizing formulation viscosity and HMW formation rate using a ion. Using multiparametric analysis, a composition containing 5% sucrose and 70 mM L-arginine hydrochloride at pH 5.3 with an antibody (mAb1) concentration of 150 mg / ml was generated. This formulation minimized formulation viscosity as well as HMW formation, while reducing the sensitivity of viscosity and stability variations to variations in excipient composition.

[0138] Example 5: Effect of detergent concentration on the stability of anti-IL-33 antibodies Polysorbate 80 was identified as a stabilizing surfactant in the study discussed in Example 2 above. The base formulation for this study was 150 mg / mL mAb1, 10 mM acetate buffer, 5% (w / v) sucrose, and 70 mM L-arginine hydrochloride. Polysorbate 80 concentrations in the initial evaluation were 0.01%, 0.02%, 0.04%, 0.05%, 0.06%, 0.08%, and 0.1%. Results are summarized in Table 6. After 48 hours of orbital shaking at 250 rpm, an increase in the relative percentage of HMW was observed for samples containing low levels of polysorbate 80. Polysorbate 80 at 0.055% or higher prevented the formation of this aggregated species after 48 hours of orbital shaking.

[0139] [Table 7]

[0140] The tolerance range of polysorbate 80 in a 150 mg / mL mAb1 formulation was further investigated by studying its agitation stability as well as its thermal stability. Using the same base formulation, the polysorbate 80 concentrations in this range study were 0.02%, 0.05%, 0.08%, and 0.12%. The formulations were subjected to 48 hours of orbital shaking at 250 rpm and one month of heat stress at 40°C / 75% RH. The orbital shaking results confirmed that concentrations of 0.05% or higher of polysorbate 80 prevented the formation of this aggregated species after 48 hours of orbital shaking (see Table 7). The thermal stability of mAb1 was not affected by the polysorbate concentrations studied (see Table 7). These results indicate that concentrations of 0.05-0.12% polysorbate 80 were stable under agitation stress without adverse effects on the formulation stability. It was shown that polysorbate 80 provides sufficient stabilization to prevent the formation of aggregates under stress. Based on these results, a target concentration of 0.08% of polysorbate 80 was selected for the 150 mg / mL mAb1 formulation.

[0141] [Table 8]

[0142] Example 6: Stability of liquid-formulated anti-IL-33 antibody drug substance Ongoing long-term storage stability studies are being conducted on formulations of mAb1 to evaluate their stability over 36 months of storage at -80°C, -30°C, and -20°C. As shown in Tables 9-10, compositions containing 150 mg / ml mAb1 were physically and chemically stable when stored at -80°C, -30°C, and -20°C for 24 months. No appreciable changes in physical or chemical stability were detected in any of the monitored attributes. Furthermore, compositions containing 150 mg / ml mAb1 have been shown to be stable when stored at -80°C, -30°C, and -20°C for at least 9 months (see Tables 11-13). Finally, compositions containing 15 mg / ml mAb1 have been shown to be stable when stored at -80°C, -30°C, and -20°C for at least 9 months (see Tables 16-18). All results collected to date are shown in Tables 8-20 below.

[0143] [Table 9]

[0144] [Table 10]

[0145] [Table 11]

[0146] [Table 12]

[0147] [Table 13]

[0148] [Table 14]

[0149] [Table 15]

[0150] [Table 16]

[0151] [Table 17]

[0152] [Table 18]

[0153] [Table 19]

[0154] [Table 20]

[0155] [Table 21]

[0156] Example 7: Stability of liquid-formulated anti-IL-33 antibody drug Nine-month study stability data are available to date for 15 mg / mL and 150 mg / mL drug products of mAb1 in glass vials. Both antibody concentrations were physically and chemically stable when stored at 2-8°C for 9 months (see Tables 21 and 22). An additional stability study of the 150 mg / mL drug product of mAb1 was observed to be physically and chemically stable when stored at 2-8°C for 24 months (see Table 23). No appreciable changes in physical or chemical stability were detected in any of the attributes monitored.

[0157] Results from the analysis of mAb1 drug formulations at 15 mg / mL and 150 mg / mL after incubation under accelerated and stress conditions are provided in Tables 24 and 25, respectively. mAb1 drug formulations showed significant growth when stirred (orbital at 250 rpm at ambient temperature) for 48 hours. The mAb1 drug formulation was physically and chemically stable under conditions of 40°C / 75% RH (shaking). No discernible change in physical or chemical stability was detected in any of the monitored attributes. For both the 15 mg / mL and 150 mg / mL drug formulations, no discernible change in HMW and LMW species was observed when incubated at 25°C for 1 month, indicating that the mAb1 drug formulation can be exposed to room temperature for short periods of time. After incubation at 40°C / 75% RH for 2 months, discernible formation of HMW species and charge variants (increase in the relative proportion of acidic species) was detected. Results from this accelerated condition demonstrated that the increase in HMW species and the formation of charge variants are the major degradation pathways for the drug formulation.

[0158] Additionally, 6-month study stability data is available to date for the 150 mg / mL drug formulation in prefilled syringes (PFS). Stability has been tested in five PFS. Stability data is provided in Tables 26-34. 3-month study stability data is available for the 75 mg / mL drug formulation in glass vials (see Table 36).

[0159] [Table 22]

[0160] Table 23

[0161] Table 24

[0162] Table 25

[0163] Table 26

[0164] Table 27

[0165] Table 28

[0166] Table 29

[0167] Table 30

[0168] Table 31

[0169] Table 32

[0170] [Table 33]

[0171] [Table 34]

[0172] [Table 35]

[0173] [Table 36]

[0174] [Table 37]

[0175] Results from long-term storage, accelerated, and stress stability studies indicate that the mAb1 formulation is stable during manufacturing (formulation, fill / finish, and labeling operations) and can withstand brief exposure to room temperature without compromising physical or chemical stability.

[0176] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. A stable liquid pharmaceutical formulation comprising: (i) a human antibody that specifically binds to human interleukin-33 (hIL-33); (ii) a buffer; (iii) an amino acid; (iv) a thermal stabilizer; and (v) an organic co-solvent.

2. 2. The stable liquid pharmaceutical formulation of claim 1, wherein the buffer is acetate or histidine at a concentration of 1 mM to 40 mM, or at a concentration of 1 mM to 20 mM.

3. 3. The stable liquid pharmaceutical formulation according to claim 1, wherein the amino acid is arginine or glutamic acid at a concentration of 30 mM to 110 mM.

4. 4. The stable liquid pharmaceutical formulation according to any one of claims 1 to 3, wherein the heat stabilizer is sucrose at a concentration of 1% to 20% w / v, or at a concentration of 1% to 10% w / v.

5. 5. The stable liquid pharmaceutical formulation according to any one of claims 1 to 4, wherein the organic co-solvent is a surfactant at a concentration of 0.01% w / v to 0.15% w / v.

6. 6. The stable liquid pharmaceutical formulation of claim 5, wherein the surfactant is polysorbate 80.

7. 7. The stable liquid pharmaceutical formulation of any one of claims 1 to 6, wherein the antibody is present at a concentration of 1 mg / ml to 200 mg / ml.

8. 8. The stable liquid pharmaceutical formulation of claim 7, wherein the antibody is present at a concentration of 15 mg / ml to 150 mg / ml.

9. The stable liquid pharmaceutical formulation of any one of claims 1 to 8, wherein the antibody comprises a heavy chain variable region (HCVR) complementarity determining region (HCDR1-HCDR2-HCDR3) comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region (LCVR) complementarity determining region (LCDR1-LCDR2-LCDR3) comprising the amino acid sequence of SEQ ID NO:

10.

10. 10. The stable liquid pharmaceutical formulation of claim 9, wherein the antibody comprises HCDR1-HCDR2-HCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 4-6-8, respectively, and LCDR1-LCDR2-LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12-14-16, respectively.

11. 11. The stable liquid pharmaceutical formulation of any one of claims 1 to 10, wherein the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

12. 12. The stable liquid pharmaceutical formulation of claim 11, wherein the antibody has a human IgG heavy chain constant region.

13. 13. The stable liquid pharmaceutical formulation of claim 12, wherein the heavy chain constant region is of the isotype IgG1.

14. 13. The stable liquid pharmaceutical formulation of claim 12, wherein the heavy chain constant region is of the isotype IgG4.

15. 12. The stable liquid pharmaceutical formulation of claim 11, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO:

20.

16. 16. The stable liquid pharmaceutical formulation of any one of claims 1 to 15, comprising: (i) about 15 mg / ml to about 150 mg / mL of the human antibody that specifically binds to hIL-33; (ii) about 5 mM to about 15 mM acetate; (iii) about 60 mM to about 80 mM arginine hydrochloride; (iv) about 3% w / v to about 7% w / v sucrose; and (v) about 0.06% w / v to about 0.1% w / v polysorbate 80.

17. 17. The stable liquid pharmaceutical formulation of any one of claims 1 to 16, wherein the formulation has a pH of about 5 to about 5.

6.

18. 18. The stable liquid pharmaceutical formulation of any one of claims 1 to 17, comprising: (i) about 15 mg / ml ± 1.5 mg / ml of the antibody; (ii) about 10 mM ± 2 mM acetate; (iii) about 70 mM ± 14 mM arginine hydrochloride; (iv) about 5% w / v ± 1% w / v sucrose; and (iv) about 0.08% ± 0.016% w / v polysorbate 80.

19. 18. The stable liquid pharmaceutical formulation of any one of claims 1 to 17, comprising: (i) about 75 mg / ml ± 5 mg / ml of the antibody; (ii) about 10 mM ± 2 mM acetate; (iii) about 70 mM ± 14 mM arginine hydrochloride; (iv) about 5% w / v ± 1% w / v sucrose; and (iv) about 0.08% ± 0.016% w / v polysorbate 80.

20. 18. The stable liquid pharmaceutical formulation of any one of claims 1 to 17, comprising: (i) about 150 mg / ml ± 15 mg / ml of the antibody; (ii) about 10 mM ± 2 mM acetate; (iii) about 70 mM ± 14 mM arginine hydrochloride; (iv) about 5% w / v ± 1% w / v sucrose; and (iv) about 0.08% ± 0.016% w / v polysorbate 80.

21. 21. The stable liquid pharmaceutical formulation according to any one of claims 1 to 20, wherein the pH of the formulation is 5.2 to 5.

4.

22. 22. The stable liquid pharmaceutical formulation of claim 21, wherein the pH of the formulation is about 5.

3.

23. (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, said antibody comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 4, 6, and 8, respectively, and LCDR1, LCDR2, and LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12, 14, and 16, respectively; (ii) 10 mM ± 2 mM acetate; (iii) 70 mM ± 14 mM arginine hydrochloride; (iv) 5% w / v ± 1% w / v sucrose; (iv) about 0.08%±0.016% w / v polysorbate 80, A stable liquid pharmaceutical formulation, wherein the formulation has a pH of 5.1 to 5.

5.

24. 24. The stable liquid pharmaceutical formulation of claim 23, wherein the antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

25. 25. The stable liquid pharmaceutical composition of claim 24, wherein the antibody has a human IgG heavy chain constant region. Agent.

26. 26. The stable liquid pharmaceutical formulation of claim 25, wherein the heavy chain constant region is of the isotype IgG1.

27. 26. The stable liquid pharmaceutical formulation of claim 25, wherein the heavy chain constant region is of the isotype IgG4.

28. (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg / ml to 150±15 mg / ml, the antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20; (ii) 10 mM ± 2 mM acetate; (iii) 70 mM ± 14 mM arginine hydrochloride; (iv) 5% w / v ± 1% w / v sucrose; (iv) about 0.08%±0.016% w / v polysorbate 80, A stable liquid pharmaceutical formulation, wherein the formulation has a pH of 5.1 to 5.

5.

29. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein at least 90% of the native form of the antibody is recovered after 2 months of storage at 5°C as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC).

30. 30. The stable liquid pharmaceutical formulation of claim 29, wherein at least 95% of the native form of the antibody is recovered after 2 months of storage at 5°C as determined by SE-UPLC.

31. 31. The stable liquid pharmaceutical formulation of claim 30, wherein at least 99% of the native form of the antibody is recovered after 2 months of storage at 5°C as determined by SE-UPLC.

32. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein at least 95% of the native form of the antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC.

33. 33. The stable liquid pharmaceutical formulation of claim 32, wherein at least 97.5% of the native form of the antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC.

34. 34. The stable liquid pharmaceutical formulation of claim 33, wherein at least 99% of the native form of the antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC.

35. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein at least 95% of the native form of the antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC.

36. 36. The stable liquid pharmaceutical formulation of claim 35, wherein at least 97.5% of the native form of the antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC.

37. 37. The stable liquid pharmaceutical formulation of claim 36, wherein at least 99% of the native form of the antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC.

38. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein the formulation contains no more than 2% high molecular weight (HMW) species after 2 months of storage at 5°C as determined by SE-UPLC.

39. 39. The stable liquid pharmaceutical formulation of claim 38, wherein the formulation contains 1% or less HMW species after 2 months of storage at 5°C as determined by SE-UPLC.

40. 40. The stable liquid pharmaceutical formulation of claim 39, wherein the formulation contains 0.6% or less HMW species after 2 months of storage at 5°C as determined by SE-UPLC.

41. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein the formulation contains 2% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC.

42. 42. The stable liquid pharmaceutical formulation of claim 41, wherein the formulation contains 1% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC.

43. 43. The stable liquid pharmaceutical formulation of claim 42, wherein the formulation contains 0.5% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC.

44. 29. The stable liquid pharmaceutical formulation of any one of claims 1 to 28, wherein the formulation contains no more than 2% HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC.

45. 45. The stable liquid pharmaceutical formulation of claim 44, wherein the formulation contains 1% or less HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC.

46. 46. ​​The stable liquid pharmaceutical formulation of claim 45, wherein the formulation contains less than or equal to 0.7% HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC.

47. 47. The stable liquid pharmaceutical formulation of any one of claims 1 to 46, wherein the formulation exhibits a viscosity of less than about 15 cPoise.

48. 48. The stable liquid pharmaceutical formulation of any one of claims 1 to 47, contained in a glass vial.

49. 48. The stable liquid pharmaceutical formulation of any one of claims 1 to 47, contained in a syringe.

50. 50. The stable liquid pharmaceutical formulation of claim 49, wherein the syringe comprises a fluorocarbon coated plunger.

51. 50. The stable liquid pharmaceutical formulation of claim 49, wherein the syringe is a low-tungsten syringe.

52. 50. The stable liquid pharmaceutical formulation of claim 49, which is a pre-filled syringe.

53. 50. The method of claim 49, which is a pre-filled staked needle syringe. A stable liquid pharmaceutical formulation as described above.

54. 48. The stable liquid pharmaceutical formulation of any one of claims 1 to 47, contained in a large volume device or bolus syringe.

55. A pen or auto-injector delivery device comprising a stable liquid pharmaceutical formulation according to any one of claims 1 to 47.

56. 56. The delivery device of claim 55, which is a disposable pen delivery device.

57. 56. The delivery device of claim 55, which is a reusable pen delivery device.

58. A container comprising the stable liquid pharmaceutical formulation of any one of claims 1 to 47.

59. 48. A kit comprising: (i) a container containing the stable liquid pharmaceutical formulation of any one of claims 1 to 47; and (ii) labeling for use of said pharmaceutical formulation.

60. 60. The kit of claim 59, wherein the labeling recites subcutaneous administration of the pharmaceutical formulation.

61. 60. The kit of claim 59, wherein the labeling recites intravenous administration of the pharmaceutical formulation.

62. 48. A unit dosage form comprising the stable liquid pharmaceutical formulation of any one of claims 1 to 47, wherein the anti-IL-33 antibody is present in an amount of 1 mg to 500 mg.

63. 63. The unit dosage form of claim 62, wherein the anti-IL-33 antibody is present in an amount of about 150 mg.

64. 63. The unit dosage form of claim 62, wherein the anti-IL-33 antibody is present in an amount of about 300 mg.

65. 65. The unit dosage form of any one of claims 62 to 64, wherein the formulation is contained in a syringe.

66. 66. The unit dosage form of claim 65, wherein the syringe is a pre-filled syringe.

67. A safety system delivery device comprising the stable liquid pharmaceutical formulation of any one of claims 1 to 47.

68. 68. The safety system delivery device of claim 67, including a safety sleeve configured to be manually extended.

69. 68. The safety system delivery device of claim 67, comprising a safety sleeve configured to automatically extend after injection of the stable liquid pharmaceutical formulation.

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