Stable formulations containing anti-IL-33 antibodies

Abstract

The present application relates to stable formulations containing an anti-IL-33 antibody. The present application provides pharmaceutical formulations comprising an antibody that specifically binds to human interleukin-33 (hIL-33). In addition to the anti-IL-33 antibody, the formulations may further comprise 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 considerable degree of antibody stability after storage for several months and after exposure to heat and other physical stresses.

Description

This application is a divisional application of an application filed on March 20, 2020, with application number 202080021576.X, and invention name “Stable formulation containing anti-IL-33 antibodies”. Reference to a sequence listing

[0001] This application incorporates by reference a Sequence Listing submitted in computer readable form as file 10516WO01-Sequence.txt, which was created on February 20, 2020 and contains 13,659 bytes. Technical Field

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

[0003] Interleukin-33 (IL-33) is a ligand for ST2 (a member of the Toll-like / interleukin-1 receptor superfamily) that associates with the accessory protein IL-1RAcP (for review, see, e.g., Kakkar and Lee, Nature Reviews-Drug Discovery 7(10):827-840 (2008), Schmitz et al., Immunity 23:479-490 (2005); Liew et al., Nature Reviews-Immunology 10:103-110 (2010); US2010 / 0260770; US2009 / 0041718). 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), leading to, among other things, the activation of NFκB (nuclear factor-κB). IL-33 signaling has been implicated as a factor in a variety of diseases and disorders (Liew et al., Nature Reviews—Immunology 10: 103-110 (2010)).

[0004] Therapeutic macromolecules (e.g., antibodies) must be formulated in such a way that the molecule is not only suitable for administration to patients, but also maintains its stability during storage. For example, unless the solution is properly formulated, therapeutic antibodies in liquid solutions are prone to degradation, aggregation, and / or undesirable chemical modifications. The stability of antibodies in liquid formulations depends not only on the type of excipients used in the formulation, but also on the amount and ratio of the excipients relative to each other. In addition, when preparing liquid antibody formulations, in addition to stability, other factors must also be considered. Examples of such additional considerations include the viscosity of the solution and the antibody concentration that a given formulation can accommodate. Therefore, when formulating therapeutic antibodies, great care must be taken to obtain formulations that remain stable, contain sufficient concentrations of antibodies, have a suitable viscosity, and enable formulations to be conveniently applied to patients.

[0005] Antibodies to human interleukin-33 (hIL-33) are an example of a therapeutically relevant macromolecule that requires appropriate formulation.

[0006] Although anti-hlL-33 antibodies are known in the art (see, e.g., WO 2014 / 164959), there remains a need for pharmaceutical formulations comprising anti-hlL-33 antibodies that are sufficiently stable and suitable for administration to patients. Summary of the invention

[0007] Stable liquid pharmaceutical formulations comprising an anti-IL-33 antibody and one or more excipients are provided, as well as kits comprising such formulations and uses thereof.

[0008] In one aspect, a stable liquid pharmaceutical formulation is provided, 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 cosolvent. 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 cases, the thermal stabilizer is sucrose at a concentration of 1% w / v to 10% w / v. In some cases, the organic cosolvent 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. In some cases, the antibody is present at a concentration of 15 mg / ml to 150 mg / ml.

[0009] In various embodiments of the formulation, the antibody comprises a complementarity determining region (HCDR1-HCDR2-HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a complementarity determining region (LCDR1-LCDR2-LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In some cases, the antibody comprises a HCDR1-HCDR2-HCDR3 region comprising the amino acid sequence of SEQ ID NO: 4-6-8, respectively, and a LCDR1-LCDR2-LCDR3 region comprising the amino acid sequence of SEQ ID NO: 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 isotype IgG1. In some embodiments, the heavy chain constant region is of isotype IgG4. 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.

[0010] 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 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. In some cases, the formulation has a pH of about 5 to about 5.6.

[0011] In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) about 15 mg / ml ± 1.5 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 (v) about 0.08% ± 0.016% w / v polysorbate 80. In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) about 75 mg / ml ± 5 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 (v) 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 (v) 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 (v) 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 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 (v) about 0.08% ± 0.008% 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 ± 1 mM acetate; (iii) about 70 mM ± 7 mM arginine hydrochloride; (iv) about 5% w / v ± 0.5% w / v sucrose; and (v) about 0.08% ± 0.008% w / v 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 drug formulation comprises: (i) about 15 mg / ml ± 1.5 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 (v) about 0.08% ± 0.04% w / v polysorbate 80.In some embodiments, the stable liquid pharmaceutical formulation comprises: (i) about 75 mg / ml ± 8 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 (v) about 0.08% ± 0.04% 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 (v) about 0.08% ± 0.04% w / v 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.

[0012] In some embodiments, the stable liquid drug 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, a stable liquid drug 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 some embodiments, the antibody has a human IgG heavy chain constant region. In some embodiments, the heavy chain constant region is of isotype IgG1. In some embodiments, the heavy chain constant region is of isotype IgG4.

[0013] In some embodiments, the stable liquid drug 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 drug 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.

[0014] In some embodiments, after storage for two months at 5° C., the stable liquid pharmaceutical formulation contains at least 90% of the native form of the antibody as determined by size exclusion-ultra-performance liquid chromatography (SE-UPLC). In some cases, after storage for two months at 5° C., the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage for two months at 5° C., the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC.

[0015] In some cases, after nine months of storage at -20°C, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after nine months of storage at -20°C, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after nine months of storage at -20°C, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC. In some cases, after 12 months of storage at -20°C, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after 12 months of storage at -20°C, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at -20°C for 12 months, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at -20°C for 18 months, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after storage at -20°C for 18 months, the stable liquid drug formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at -20°C for 18 months, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC.

[0016] In some cases, after nine months of storage at 2-8°C, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after nine months of storage at 2-8°C, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after nine months of storage at 2-8°C, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC. In some cases, after 12 months of storage at 2-8°C, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after 12 months of storage at 2-8°C, the stable liquid pharmaceutical formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at 2-8°C for 12 months, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at 2-8°C for 18 months, the formulation contains at least 95% of the native form of the antibody as determined by SE-UPLC. In some embodiments, after storage at 2-8°C for 18 months, the stable liquid drug formulation contains at least 97.5% of the native form of the antibody as determined by SE-UPLC. In some cases, after storage at 2-8°C for 18 months, the formulation contains at least 99% of the native form of the antibody as determined by SE-UPLC.

[0017] In some embodiments, after storage for two months at 5° C., the stable liquid pharmaceutical formulation comprises no more than 2% of high molecular weight (HMW) species as determined by SE-UPLC. In some cases, after storage for two months at 5° C., the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after storage for two months at 5° C., the formulation comprises no more than 0.6% of HMW species as determined by SE-UPLC.

[0018] In some embodiments, after nine months of storage at -20°C, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after nine months of storage at -20°C, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after nine months of storage at -20°C, the formulation comprises no more than 0.5% of HMW species as determined by SE-UPLC. In some embodiments, after 12 months of storage at -20°C, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after 12 months of storage at -20°C, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after 12 months of storage at -20°C, the formulation comprises no more than 0.5% of HMW species as determined by SE-UPLC. In some embodiments, after storage at -20°C for 18 months, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after storage at -20°C for 18 months, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after storage at -20°C for 18 months, the formulation comprises no more than 0.5% of HMW species as determined by SE-UPLC.

[0019] In some embodiments, after nine months of storage at 2-8°C, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after nine months of storage at 2-8°C, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after nine months of storage at 2-8°C, the formulation comprises no more than 0.7% of HMW species as determined by SE-UPLC. In some embodiments, after 12 months of storage at 2-8°C, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after 12 months of storage at 2-8°C, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after 12 months of storage at 2-8°C, the formulation comprises no more than 0.7% of HMW species as determined by SE-UPLC. In some embodiments, after storage at 2-8° C. for 18 months, the stable liquid pharmaceutical formulation comprises no more than 2% of HMW species as determined by SE-UPLC. In some cases, after storage at 2-8° C. for 18 months, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. In some cases, after storage at 2-8° C. for 18 months, the formulation comprises no more than 0.7% of HMW species as determined by SE-UPLC.

[0020] 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.

[0021] In some embodiments, the stable liquid drug formulation is contained in a glass vial, a syringe or a large capacity device or a bolus injector. In some embodiments, the syringe includes a plunger coated with a fluorocarbon. In some embodiments, the syringe is a low tungsten syringe. In some embodiments, the syringe contains up to 2500 ppb tungsten. In some embodiments, the syringe contains about 250-750 ppb tungsten. In some embodiments, the syringe is a prefilled syringe. In some embodiments, the syringe is a prefilled staked needle syringe.

[0022] In another aspect, a pen or auto-injector delivery device is provided, comprising a stable liquid drug formulation in any embodiment discussed above or herein. In some cases, the delivery device is a disposable pen delivery device. In some cases, the delivery device is a reusable pen delivery device.

[0023] In another aspect, a container is provided comprising the stable liquid pharmaceutical formulation of any embodiment discussed above or herein.

[0024] In another aspect, a safety system delivery device is provided, comprising the stable liquid drug formulation of any embodiment discussed above or herein. In some embodiments, the safety system delivery device comprises a safety sleeve configured to be extended by manual operation. In some embodiments, the safety system delivery device comprises a safety sleeve configured to be automatically extended after injection of the stable liquid drug formulation.

[0025] In another aspect, a kit is provided, comprising (i) a container comprising a stable liquid pharmaceutical formulation as discussed above or herein, and (ii) a label for use of the pharmaceutical formulation. In some embodiments, the label indicates subcutaneous administration of the pharmaceutical formulation. In some embodiments, the label indicates intravenous administration of the pharmaceutical formulation.

[0026] In another aspect, the invention provides a unit dosage form comprising a stable liquid pharmaceutical formulation as discussed above or herein, wherein the anti-IL-33 antibody is present in an amount of 1 mg to 500 mg. In some cases, the anti-IL-33 antibody is present in an amount of about 150 mg. In some cases, 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. In some cases, the syringe is a prefilled syringe.

[0027] In various embodiments, any feature or component in the feature or component of the embodiment discussed above or herein can be combined, and such combination is contained in the scope of the present disclosure.Any specific value discussed above or herein can be combined with another related value discussed above or herein to list the scope of the value of the upper and lower ends of the representation range, and such scope is contained in the scope of the present disclosure.Each of the value discussed above or herein can be represented by a change of 1%, 5%, 10% or 20%.For example, the concentration of 10mM can be expressed as 10mM ± 0.1mM (1% change), 10mM ± 0.5mM (5% change), 10mM ± 1mM (10% change) or 10mM ± 2mM (20% change). Specifically, this application provides the following: 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 cosolvent. 2. The stable liquid pharmaceutical formulation according to embodiment 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. The stable liquid pharmaceutical formulation of embodiment 1 or 2, wherein the amino acid is arginine or glutamic acid at a concentration of 30 mM to 110 mM. 4. The stable liquid pharmaceutical formulation of any one of embodiments 1-3, wherein the thermal stabilizer is sucrose at a concentration of 1% w / v to 20% w / v, or at a concentration of 1% w / v to 10% w / v. 5. The stable liquid pharmaceutical formulation of any one of embodiments 1-4, wherein the organic co-solvent is a surfactant at a concentration of 0.01% w / v to 0.15% w / v. 6. The stable liquid pharmaceutical formulation of embodiment 5, wherein the surfactant is polysorbate 80. 7. The stable liquid pharmaceutical formulation of any one of embodiments 1-6, wherein the antibody is present at a concentration of 1 mg / ml to 200 mg / ml. 8. The stable liquid pharmaceutical formulation of embodiment 7, wherein the antibody is present at a concentration of 15 mg / ml to 150 mg / ml. 9. The stable liquid drug formulation of any one of embodiments 1-8, wherein the antibody comprises complementarity determining regions (HCDR1-HCDR2-HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and complementarity determining regions (LCDR1-LCDR2-LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. 10. The stable liquid drug formulation of embodiment 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. The stable liquid drug formulation of any one of embodiments 1-10, 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. The stable liquid pharmaceutical formulation of embodiment 11, wherein the antibody has a human IgG heavy chain constant region. 13. The stable liquid pharmaceutical formulation of embodiment 12, wherein the heavy chain constant region is of isotype IgG1. 14. The stable liquid pharmaceutical formulation of embodiment 12, wherein the heavy chain constant region is of isotype IgG4. 15. The stable liquid drug formulation of embodiment 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. A stable liquid pharmaceutical formulation as described in any of embodiments 1-15, 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. The stable liquid pharmaceutical formulation of any one of embodiments 1-16, wherein the formulation has a pH of about 5 to about 5.6. 18. A stable liquid drug formulation as described in any of embodiments 1-17, 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. A stable liquid drug formulation as described in any of embodiments 1-17, 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. A stable liquid drug formulation as described in any of embodiments 1-17, 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. The stable liquid pharmaceutical formulation of any one of embodiments 1-20, wherein the pH of the formulation is 5.2 to 5.4. 22. The stable liquid pharmaceutical formulation of embodiment 21, wherein the pH of the formulation is about 5.3. 23. A stable liquid pharmaceutical formulation comprising: (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. 24. The stable liquid drug formulation of embodiment 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. The stable liquid pharmaceutical formulation of embodiment 24, wherein the antibody has a human IgG heavy chain constant region. 26. The stable liquid pharmaceutical formulation of embodiment 25, wherein the heavy chain constant region is of isotype IgG1. 27. The stable liquid pharmaceutical formulation of embodiment 25, wherein the heavy chain constant region is of isotype IgG4. 28. A stable liquid pharmaceutical formulation comprising: (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. 29. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein at least 90% of the native form of the antibody is recovered after storage at 5°C for two months as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC). 30. The stable liquid pharmaceutical formulation of embodiment 29, wherein at least 95% of the native form of the antibody is recovered after storage at 5°C for two months as determined by SE-UPLC. 31. The stable liquid pharmaceutical formulation of embodiment 30, wherein at least 99% of the native form of the antibody is recovered after storage at 5°C for two months as determined by SE-UPLC. 32. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein at least 95% of the native form of the antibody is recovered after storage at -20°C for nine months as determined by SE-UPLC. 33. The stable liquid pharmaceutical formulation of embodiment 32, wherein at least 97.5% of the native form of the antibody is recovered after storage at -20°C for nine months as determined by SE-UPLC. 34. The stable liquid pharmaceutical formulation of embodiment 33, wherein at least 99% of the native form of the antibody is recovered after storage at -20°C for nine months as determined by SE-UPLC. 35. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein at least 95% of the native form of the antibody is recovered after storage at 2-8°C for nine months as determined by SE-UPLC. 36. The stable liquid pharmaceutical formulation of embodiment 35, wherein at least 97.5% of the native form of the antibody is recovered after storage at 2-8°C for nine months as determined by SE-UPLC. 37. The stable liquid pharmaceutical formulation of embodiment 36, wherein at least 99% of the native form of the antibody is recovered after storage at 2-8°C for nine months as determined by SE-UPLC. 38. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein the formulation comprises no more than 2% of high molecular weight (HMW) species after storage at 5°C for two months as determined by SE-UPLC. 39. The stable liquid pharmaceutical formulation of embodiment 38, wherein after storage at 5°C for two months, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. 40. The stable liquid pharmaceutical formulation of embodiment 39, wherein after storage at 5°C for two months, the formulation comprises no more than 0.6% of HMW species as determined by SE-UPLC. 41. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein after storage at -20°C for nine months, the formulation comprises no more than 2% of HMW species as determined by SE-UPLC. 42. The stable liquid pharmaceutical formulation of embodiment 41, wherein after storage at -20°C for nine months, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. 43. The stable liquid pharmaceutical formulation of embodiment 42, wherein after storage at -20°C for nine months, the formulation comprises no more than 0.5% of HMW species as determined by SE-UPLC. 44. The stable liquid pharmaceutical formulation of any one of embodiments 1-28, wherein after storage for nine months at 2-8°C, the formulation comprises no more than 2% of HMW species as determined by SE-UPLC. 45. The stable liquid pharmaceutical formulation of embodiment 44, wherein after storage for nine months at 2-8°C, the formulation comprises no more than 1% of HMW species as determined by SE-UPLC. 46. ​​The stable liquid pharmaceutical formulation of embodiment 45, wherein after storage at 2-8°C for nine months, the formulation comprises no more than 0.7% of HMW species as determined by SE-UPLC. 47. The stable liquid pharmaceutical formulation of any one of embodiments 1-46, wherein the formulation exhibits a viscosity of less than about 15 centipoise. 48. The stable liquid pharmaceutical formulation of any one of embodiments 1-47 contained in a glass vial. 49. The stable liquid pharmaceutical formulation of any one of embodiments 1-47 contained in a syringe. 50. The stable liquid pharmaceutical formulation of embodiment 49, wherein the syringe comprises a fluorocarbon-coated plunger. 51. The stable liquid pharmaceutical formulation of embodiment 49, wherein the syringe is a low tungsten syringe. 52. The stable liquid pharmaceutical formulation of embodiment 49 which is a pre-filled syringe. 53. The stable liquid pharmaceutical formulation of embodiment 49 which is a pre-filled stake needle syringe. 54. The stable liquid pharmaceutical formulation of any one of embodiments 1-47 contained in a large volume device or a bolus syringe. 55. A pen or auto-injector delivery device comprising the stable liquid drug formulation of any one of embodiments 1-47. 56. The delivery device of embodiment 55, which is a disposable pen delivery device. 57. The delivery device of embodiment 55, which is a reusable pen delivery device. 58. A container comprising the stable liquid pharmaceutical formulation of any one of embodiments 1-47. 59. A kit comprising (i) a container comprising the stable liquid pharmaceutical formulation of any one of embodiments 1-47, and (ii) a label for use of the pharmaceutical formulation. 60. The kit of embodiment 59, wherein the label indicates subcutaneous administration of the pharmaceutical formulation. 61. The kit of embodiment 59, wherein the label indicates intravenous administration of the pharmaceutical formulation. 62. A unit dosage form comprising the stable liquid pharmaceutical formulation of any one of embodiments 1-47, wherein the anti-IL-33 antibody is present in an amount of 1 mg to 500 mg. 63. The unit dosage form of embodiment 62, wherein the anti-IL-33 antibody is present in an amount of about 150 mg. 64. The unit dosage form of embodiment 62, wherein the anti-IL-33 antibody is present in an amount of about 300 mg. 65. The unit dosage form of any one of embodiments 62-64, wherein said formulation is contained in a syringe. 66. The unit dosage form of embodiment 65, wherein said syringe is a prefilled syringe. 67. A safe system delivery device comprising the stable liquid drug formulation of any one of embodiments 1-47. 68. The safety system delivery device of embodiment 67, comprising a safety sleeve configured to be extended by manual operation. 69. The safety system delivery device of embodiment 67, comprising a safety sleeve configured to automatically extend following injection of the stable liquid drug formulation.

[0028] Other embodiments will become apparent upon reading the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1The pH-dependent viscosity of the anti-IL-33 antibody (mAb1) at 150 mg / mL is shown.

[0030] Figure 2 The viscosity of 150 mg / mL anti-IL-33 antibody (mAb1) with different viscosity modifier concentrations is shown.

[0031] Figure 3 The effect of various viscosity modifiers on the stability of anti-IL-33 antibody (mAb1) incubated at 37°C for 34 days is shown. For clarity, Figure 3 The rightmost points are arranged in order from top to bottom: F13, F4, F12, F3, F2, F7, F1, F5, F8, F6 and F9.

[0032] Figure 4A The effect of formulation parameters on the viscosity of anti-IL-33 antibody (mAb1) is shown.

[0033] Figure 4B Shown are the effects of formulation parameters on the formation of high molecular weight (HMW) variants of anti-IL-33 antibody (mAb1). DETAILED DESCRIPTION

[0034] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, because such methods and conditions can vary. It should also be understood that the terms used herein are only used to describe the purpose of specific embodiments, and are not intended to be restrictive, because the scope of the present invention will only be limited by the appended claims.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. As used herein, when used to refer to a specific listed value or range of values, the term "about" means that the value may differ from the listed value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0036] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described. All patents, applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety. Drug formulations

[0037] As used herein, the expression "pharmaceutical formulation" refers to a combination of at least one active ingredient (e.g., an anti-IL-33 antibody, etc., which is capable of exerting a biological effect in a human or non-human animal) and at least one inactive ingredient, which, when combined with the active ingredient and / or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. Unless otherwise specifically indicated, as used herein, the term "formulation" refers to a "pharmaceutical formulation". The present invention provides a pharmaceutical formulation comprising at least one therapeutic polypeptide. According to certain embodiments of the present invention, the therapeutic polypeptide is an antibody or antigen-binding fragment thereof that specifically binds to human interleukin-33 (hIL-33). More specifically, the present invention includes a pharmaceutical formulation comprising: (i) a human antibody that specifically binds to hIL-33; (ii) a buffer; (iii) a thermal stabilizer; (iv) a surfactant (also an organic cosolvent or an interfacial stabilizer); and (v) a viscosity modifier. Additional components may be included in the formulations of the present invention if 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.

[0038] In certain embodiments, the pharmaceutical formulations of the present invention may be fluid formulations. As used herein, the expression "fluid formulation" refers to a mixture of at least two components that exist primarily in a fluid state at about 2°C to about 45°C. Fluid formulations particularly include liquid formulations. Fluid formulations may have low, medium or high viscosity, depending on their specific ingredients. Antibodies that specifically bind to human IL-33

[0039] The pharmaceutical formulation 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 human IL-33 protein.

[0040] As used herein, the term "antibody" is generally intended to refer to immunoglobulin molecules comprising four polypeptide chains interconnected by disulfide bonds, i.e., two heavy (H) chains and two light (L) chains, as well as multimers thereof (e.g., IgM); however, immunoglobulin molecules consisting only of heavy chains (i.e., lacking light chains) are also encompassed within the definition of the term "antibody". Each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region includes three domains, CH1, CH2, and CH3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region includes one domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with more conservative regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0041] 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 regions and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo), for example in CDRs, particularly in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from germlines of other mammalian species (such as mice) have been transplanted onto human framework sequences. In various embodiments, the anti-IL-33 antibody is a human IgG antibody. In various embodiments, the anti-IL-33 antibody is a human antibody of isotype IgG1, IgG2, IgG3 or IgG4 or a mixed isotype. In some embodiments, the anti-IL-33 antibody is a human IgG1 antibody. In some embodiments, the anti-IL-33 antibody is a human IgG4 antibody. In any embodiment discussed above or herein, the anti-IL-33 antibody may include a human κ light chain. In any of the embodiments discussed above or herein, the anti-IL-33 antibody may comprise a human lambda light chain.

[0001] In some embodiments, the antibodies of the present invention may be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells, antibodies separated from recombinant combinatorial human antibody libraries, antibodies separated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, produced or isolated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic for human Ig sequences, somatic mutagenesis in the receptor), and thus the V H Area and V L The amino acid sequence of the region is as follows: H Sequence and V L Sequences are not naturally present in vivo in the human antibody germline repertoire.

[0042] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or similarly "antibody portion" or "antibody fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to hIL-33.

[0043] As used herein, "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds hIL-33 is substantially free of antibodies that specifically bind antigens other than hIL-33).

[0044] The term "specific binding" and the like refers to the formation of a relatively stable complex between an antibody or its antigen-binding fragment and an antigen under physiological conditions. Specific binding can be achieved by at least about 1x10 -6 M or greater dissociation constant. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. However, an isolated antibody that specifically binds to IL-33 may have cross-reactivity with other antigens, such as IL-IL-33 molecules from other species (orthologs). In the context of the present invention, a multispecific (e.g., bispecific) antibody that binds hIL-33 and one or more additional antigens is considered to "specifically bind" hIL-33. In addition, the isolated antibody may be substantially free of other cellular material and / or chemicals.

[0045] Exemplary anti-hIL-33 antibodies that may be included in the pharmaceutical formulations of the invention are described in WO 2014 / 164959, the disclosure of which is incorporated by reference in its entirety.

[0046] According to certain embodiments of the present invention, the anti-hIL-33 antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region HCDR1-HCDR2-HCDR3 comprising the amino acid sequence of SEQ ID NO: 4-6-8, respectively. According to certain embodiments of the present invention, the anti-hIL-33 antibody or antigen-binding fragment thereof comprises a light chain complementary determining region LCDR1-LCDR2-LCDR3 comprising the amino acid sequence of SEQ ID NO: 12-14-16, respectively.

[0047] 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 a HCVR / LCVR amino acid sequence pair comprising the amino acid sequence of SEQ ID NO: 2 / 10. In some embodiments, the anti-IL-33 antibody comprises a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 2 / 10, respectively, and a human IgG1 heavy chain constant region. In some embodiments, the anti-IL-33 antibody comprises a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 2 / 10, respectively, and a human IgG4 heavy chain constant region. In some embodiments, the anti-IL-33 antibody comprises a HCVR / LCVR comprising the amino acid sequence of SEQ ID NO: 2 / 10, respectively, and a human IgG heavy chain constant region. In some embodiments, the 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, the 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 has 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.

[0048] The amount of the antibody or antigen-binding fragment thereof contained in the pharmaceutical formulation of the present invention may vary depending on the specific desired properties of the formulation and the specific circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation may 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 of antibody; or about 140 mg / mL to about 160 mg / mL of antibody. For example, the formulation of the present invention can be a liquid formulation comprising 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 11 or about 200 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds to hIL-33.In certain embodiments, the pharmaceutical formulation is a liquid formulation that may include 5±0.75 mg / mL to 150±22.5 mg / mL antibody; 7.5±1.125 mg / mL to 140±21 mg / mL antibody; 10±1.5 mg / mL to 130±19.5 mg / mL antibody; 12.5±1.875 mg / mL to 120±18 mg / mL antibody; 15±2.25 mg / mL to 110±16.5 mg / mL antibody; 17.5±2.625 mg / mL / mL to 100±15mg / mL antibody; 20±3mg / mL to 90±13.5mg / mL antibody; 22.5±3.375mg / mL to 80±12mg / mL antibody; 25±3.75mg / mL to 70±10.5mg / mL antibody; 27.5±4.125mg / mL to 60±9mg / mL antibody; 30±4.5mg / mL to 50±7.5mg / mL antibody; 25±3.75mg / mL antibody; or 50±7.5mg / mL. In some embodiments, the pharmaceutical formulation comprises 15±0.15mg / ml to 150±1.5mg / ml of anti-IL-33 antibody. In some cases, the pharmaceutical formulation comprises 75mg / mL±3.75mg / mL of anti-IL-33 antibody. In some cases, the pharmaceutical formulation comprises 150 mg / mL ± 7.5 mg / mL of an anti-IL-33 antibody. Bioequivalent

[0049] The present invention encompasses antibodies having amino acid sequences that differ from those of the exemplary molecules disclosed herein, but retain the ability to bind hIL-33. Such variant molecules may include one or more additions, deletions or substitutions of amino acids when compared to the parent sequence, but exhibit biological activity substantially equivalent to that of the antibodies discussed herein.

[0050] The present invention includes antigen binding molecules that are bioequivalent to any of the exemplary antibodies listed herein. If, for example, two antibodies are drug equivalents or drug substitutes that do not show significant differences in absorption rate and degree when administered (single dose or multiple doses) with the same molar dose under similar experimental conditions, then the two antibodies are considered to be bioequivalent. If some antibodies are equivalent in their absorption degree but not equivalent in their absorption rate, then the antibodies will be considered to be equivalents or drug substitutes, and the antibodies can be considered to be bioequivalent, because the differences in such absorption rates that are intended and reflected on the label are not necessary for reaching effective body drug concentrations when, for example, used for a long time and are considered to be medically insignificant for the specific drug product under study.

[0051] In one embodiment, two antibodies are bioequivalent if there are no clinically meaningful differences in safety, purity, and potency.

[0052] In one embodiment, two antibodies are bioequivalent if a patient can switch between the reference product and the biological product one or more times without an expected increased risk of adverse effects, including clinically significant changes in immunogenicity or reduction in effectiveness, compared to continued treatment without such switching.

[0053] Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence measurements include, for example, (a) in vivo tests in humans or other mammals, where the concentration of the antibody or its metabolites is measured over time in blood, plasma, serum or other biological fluids; (b) in vitro tests that are correlated with and reasonably predictive of human in vivo bioavailability data; (c) in vivo tests in humans or other mammals, where the appropriate acute pharmacological effects of the antibody (or its target) are measured over time; and (d) in well-controlled clinical trials to establish the safety, efficacy or bioavailability or bioequivalence of the antigen binding protein. Formulation excipients and pH

[0054] The pharmaceutical formulations of the present invention comprise one or more excipients. As used herein, the term "excipient" means any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity or stabilizing effect.

[0055] 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, 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) acts as a viscosity modifier for the anti-IL-33 antibody formulation.

[0056] The amount of amino acids included in the pharmaceutical formulations of the present invention may vary depending on the specific desired properties of the formulation and the specific circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the formulation may include about 1 mM to about 200 mM of amino acids; about 5 mM to about 150 mM; about 25 mM to about 125 mM of amino acids; about 50 mM to about 100 mM of amino acids; about 50 mM to about 90 mM of amino acids; about 60 mM to about 80 mM of amino acids; or about 65 mM to about 75 mM of amino acids. For example, the pharmaceutical formulations of the present invention may include 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 an amino acid (e.g., arginine). In some embodiments, the formulation includes about 70 mM of an amino acid (e.g., arginine).

[0057] The pharmaceutical formulations of the present invention may also include one or more carbohydrates, such as one or more sugars. Sugars may be reducing sugars or non-reducing sugars. "Reducing sugars" include, for example, sugars having ketone or aldehyde groups and containing reactive hemiacetal groups, which allow the sugar to act as a reducing agent. Specific examples of reducing sugars include fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose, and maltose. Non-reducing sugars may include anomeric carbon, which is an acetal and does not substantially react with amino acids or polypeptides to induce a Maillard reaction. Specific examples of non-reducing sugars include sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose. Sugar acids include, for example, saccharic acid, gluconate, and other polyhydroxy sugars and salts thereof. In some embodiments, the sugar is sucrose. In some cases, sugars (e.g., sucrose) act as a thermal stabilizer for anti-IL-33 antibodies.

[0058] The amount of sugar (e.g., sucrose) included in the pharmaceutical formulations of the present invention will vary depending on the specific circumstances and intended purpose of the formulation. In certain embodiments, the formulation may contain about 0.1% to about 20% sugar; about 0.5% to about 20% sugar; about 1% to about 20% sugar; about 2% to about 15% sugar; about 3% to about 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).

[0059] The pharmaceutical formulations of the present invention may also include one or more organic cosolvents (or interfacial stabilizers), the type and amount of which stabilize the anti-IL-33 antibody under conditions of rough handling or agitation (e.g., orbital oscillation). In some embodiments, the organic cosolvent is a surfactant. As used herein, the term "surfactant" 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. The surfactant may be ionic or nonionic. Exemplary nonionic surfactants that may 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 present 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), 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.

[0060] The amount of surfactant included in the pharmaceutical formulation of the present invention may vary depending on the specific desired properties of the formulation and the specific circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the formulation may include about 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% surfactant; about 0.06% to about 0.1% surfactant; or about 0.07% to about 0.09% surfactant. For example, the formulations of the invention may comprise 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% of a surfactant (e.g., polysorbate 80). In some embodiments, the formulation comprises about 0.08% of a surfactant (e.g., polysorbate 80). Each percentage indicated above corresponds to a weight / volume percentage (w / v).

[0061] The pharmaceutical formulations of the present invention may also include a buffer or a buffer system for maintaining a stable pH and helping to stabilize the anti-IL-33 antibody. In some embodiments, the buffer or buffer system includes at least one buffer having a buffer range that completely or partially overlaps with the range of pH 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 1mM to about 40mM, about 1mM to about 30mM, about 1mM to about 20mM; about 3mM to about 18mM; about 5mM to about 15mM; or about 8mM to about 12mM. In some embodiments, the buffer (e.g., acetate) is present at a concentration of 5.3mΜ ± 0.3mM, 5.3mM ± 0.2mM, or 5.3mM ± 0.1mM. 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. Exemplary Formulations

[0062] According to one aspect of the present invention, the 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 thermal stabilizer (e.g., sucrose); and (v) an organic cosolvent (e.g., polysorbate 80).

[0063] In some cases, the stable liquid drug 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 thermal 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.

[0064] In some cases, the stable liquid drug 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 thermal 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 drug 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; (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 thermal 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.

[0066] In some cases, the stable liquid drug 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 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; (iv) a thermal 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 drug 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 isotype IgG4; (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 thermal 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 drug 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 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) 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 thermal 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.

[0069] In some cases, the stable liquid drug 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; (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 drug 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 isotype IgG1; (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 drug 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 isotype IgG4; (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.

[0072] In some cases, the stable liquid drug 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 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) 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.

[0073] In some cases, the stable liquid drug 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.

[0074] In some cases, the stable liquid drug 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 isotype IgG1; (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 drug 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 isotype IgG4; (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 drug 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 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) 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.

[0077] In some cases, the stable liquid drug 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; (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.

[0078] In some cases, the stable liquid drug 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 isotype IgG1; (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 drug 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 isotype IgG4; (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 drug 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 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) 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.

[0081] In some cases, the stable liquid drug 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0082] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 15 mg / ml±1.5 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0083] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 75 mg / ml±5 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0084] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 150 mg / ml±15 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0085] In some cases, the stable liquid drug 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, a LCVR comprising the amino acid sequence of SEQ ID NO:10, and a human IgG4 heavy chain constant region; (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, wherein the formulation has a pH of 5.3±0.1.

[0086] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 15 mg / ml±1.5 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0087] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 75 mg / ml±5 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0088] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 150 mg / ml±15 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0089] In some cases, the stable liquid drug 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 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) 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, wherein the formulation has a pH of 5.3 ± 0.1.

[0090] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 15 mg / ml±1.5 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0091] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 75 mg / ml±5 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0092] In some cases, the stable liquid drug formulation comprises (i) a human antibody at a concentration of about 150 mg / ml±15 mg / ml 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; (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, wherein the formulation has a pH of 5.3±0.1.

[0093] Additional non-limiting examples of pharmaceutical formulations encompassed by the invention are described elsewhere herein, including the working examples given below. Stability and viscosity of drug formulations

[0094] Pharmaceutical formulations of the present invention show a high level of stability. As used herein with respect to pharmaceutical formulations, the term "stable" refers to the structure and / or function and / or biological activity of the antibody in the pharmaceutical formulation after a defined amount of storage time. Even if the antibody contained therein does not maintain 100% of its structure and / or function and / or biological activity after a defined amount of storage time, the formulation can also be stable. In some cases, after a defined amount of storage time, the maintenance of the structure and / or function and / or biological activity of about 90%, about 95%, about 96%, about 97%, about 98% or about 99% of the antibody can be considered as "stable".

[0095] Stability can be measured in particular by determining the percentage of native antibodies retained in the formulation after a defined amount of storage time at a given temperature. The percentage of native antibodies can be determined in particular by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). "Acceptable degree of stability", as the phrase is used herein, means that at least 90% of the native form of the antibody can be detected in the formulation after a defined amount of storage time at a given temperature. In certain embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the native form of the antibody can be detected in the formulation after a defined amount of storage time at a given temperature. The defined amount of time after which stability is measured can be at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer. When evaluating stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, stored at about -80°C, about -30°C, about -20°C, about 0°C, about 4-8°C, about 5°C, about 25°C, about 35°C, about 37°C, or about 45°C. For example, if greater than about 90%, 95%, 96%, or 97% of native antibodies are detected by SE-HPLC after storage at 5°C for 3 months, the pharmaceutical formulation can be considered stable. The pharmaceutical formulation may also be considered stable if greater than about 90%, 95%, 96%, or 97% of native antibodies are detected by SE-HPLC after 6 months storage at 5° C. The 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 native antibodies are detected by SE-HPLC after 9 months storage at 5° C. The 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 native antibodies are detected by SE-HPLC after 3 months storage at 25° C. The 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 native antibodies are detected by SE-HPLC after 6 months storage at 25° C. The 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 native antibodies are detected by SE-HPLC after 9 months storage at 25° C.

[0096] Other methods can be used to assess the stability of the formulations of the invention, for example, thermal stability using differential scanning calorimetry (DSC), mechanical stability using controlled stirring, and solution turbidity using absorbance at about 350 nm or about 405 nm. For example, if the OD of the formulation at t=0 is greater than that at about 5°C to about 25°C after storage for 6 months or more, the OD of the formulation at t=0 is greater than that at about 5°C to about 25°C. 405 Compared with the OD 405 If the change in ρ is less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01 or less), the formulation of the invention can be considered stable.

[0097] Measuring the binding affinity of an antibody to its target can also be used to assess stability. For example, if after storage 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 said storage, then the formulation of the invention can be considered stable. 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 cells expressing IL-33 with a formulation comprising an anti-IL-33 antibody. Binding of the antibody to such cells can be measured directly, such as by 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.

[0098] Stability can be measured in particular by determining the percentage of antibodies that form aggregates in a formulation after a defined amount of time stored at a defined temperature, wherein stability is inversely proportional to the percentage of aggregates formed. The percentage of aggregated antibodies can be determined in particular by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC] or size exclusion ultra-high performance liquid chromatography [SE-UPLC]). "Acceptable degree of stability", when the phrase is used herein, refers to the detection of up to 6% of antibodies in aggregated form in a formulation after a defined amount of time stored at a given temperature. In certain embodiments, an acceptable degree of stability refers to the detection of up to about 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% of antibodies in aggregate form in a formulation after a defined amount of time stored at a given temperature. 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. When assessing stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, stored at about -80°C, about -30°C, about -20°C, about 0°C, about 4°-8°C, about 5°C, about 25°C, about 35°C, about 37°C, or about 45°C. For example, 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 nine months of storage at 5° C., the 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 six months of storage at 25° C., the 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., the pharmaceutical formulation may also be considered stable. The pharmaceutical formulation may also be considered stable if less than about 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1%, 0.5% or 0.1% of the antibody is detected in aggregated form after storage at -20°C, -30°C or -80°C for three months.

[0099] Stability can be measured, inter alia, by determining the percentage of antibody that migrates in a more acidic fraction ("acidic form") than the main fraction of the antibody ("mainly charged form") during ion exchange, wherein stability is inversely proportional to the proportion of antibody in the acidic form. Without being bound by theory, deamidation of an antibody may cause the antibody to become more negatively charged and thus more acidic relative to a non-deamidated antibody (see, e.g., Robinson, N., Protein Deamidation, PNAS, April 16, 2002, 99(8):5283-5288). The percentage of "acidified" antibody can be determined by ion exchange chromatography (e.g., cation exchange high performance liquid chromatography [CEX-HPLC] or cation exchange ultra high performance liquid chromatography [CEX-UPLC]). "Acceptable degree of stability", as the phrase is used herein, means that up to 52% of the antibody is detected in the formulation in the more acidic form 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 is detected in the more acidic form in the formulation after storage for a defined amount of time at a given temperature. The defined amount of time after which stability is measured can be at least 2 weeks, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or more. When evaluating stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, at about -80°C, about -30°C, about -20°C, about 0°C, about 4-8°C, about 5°C, about 25°C, or about 45°C. For example, 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 storage at -80°C, -30°C, or -20°C for three months, the pharmaceutical formulation can be considered stable.The pharmaceutical formulation may also be 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 storage at 5°C for nine months. The pharmaceutical formulation may also be 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 storage at 25°C for 28 days. The pharmaceutical formulation may also be 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 storage at 37°C for 28 days. The pharmaceutical formulation may also be 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 storage at 45°C for 28 days.

[0100] In certain embodiments, a "stable" pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species after storage for 24 months at -80°C, -30°C, or -20°C, as measured by size exclusion ultra performance liquid chromatography (SE-UPLC). In certain embodiments, a "stable" pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species after storage for nine months at -80°C, -30°C, or -20°C, as measured by SE-UPLC. In certain embodiments, after storage for two months at 5° C., a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species as measured by SE-UPLC. In certain embodiments, after storage for two months at 25° C. and 60% relative humidity, a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species as measured by SE-UPLC. In certain embodiments, after storage for two months at 40° C. and 75% relative humidity, a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species as measured by SE-UPLC. In certain embodiments, after nine months of storage at 2-8° C., a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises no more than 1%, no more than 0.9%, no more than 0.8%, or no more than 0.7% of HMW species as measured by SE-UPLC. In certain embodiments, after 24 months of storage at 2-8° C., a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species as measured by SE-UPLC. In certain embodiments, after six months of storage at 25° C. and 60% relative humidity, a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species as measured by SE-UPLC.In certain embodiments, a "stable" pharmaceutical composition or pharmaceutical formulation of the invention comprises no more than 1%, no more than 0.9%, no more than 0.8%, or no more than 0.7% of HMW species after storage for six months at 2-8° C., as measured by SE-UPLC. In certain embodiments, a "stable" pharmaceutical composition or pharmaceutical formulation of the invention comprises 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% of HMW species after storage for three months at 2-8° C., as measured by SE-UPLC.

[0101] In certain embodiments, after storage at -80°C, -30°C or -20°C for 24 months, a "stable" pharmaceutical composition or pharmaceutical 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). In certain embodiments, after storage at -80°C, -30°C or -20°C for nine months, a "stable" pharmaceutical composition or pharmaceutical 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). In certain embodiments, after storage for two months at 5° C., a “stable” pharmaceutical composition or pharmaceutical 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). In certain embodiments, after storage for two months at 25° C. and 60% relative humidity, a “stable” pharmaceutical composition or pharmaceutical 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). In certain embodiments, after storage for two months at 40° C. and 75% relative humidity, a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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). In certain embodiments, after storage for nine months at 2-8° C., a “stable” pharmaceutical composition or pharmaceutical 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). In certain embodiments, after storage at 2-8° C. for 24 months, a “stable” pharmaceutical composition or pharmaceutical formulation of the invention comprises 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). In certain embodiments, after storage at 25° C. and 60% relative humidity for six months, a “stable” pharmaceutical composition or pharmaceutical 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).In certain embodiments, a "stable" pharmaceutical composition or pharmaceutical 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 after storage at 2-8°C for three or six months as measured by size exclusion ultra performance liquid chromatography (SE-UPLC).

[0102] Reference to the stability of a pharmaceutical formulation "after" a specified period of time is intended to indicate that the measurement of a stability parameter (e.g., % native form, % HMW species, or % acidic form) is performed at or about the end of the specified period of time, and is not intended to indicate that the pharmaceutical formulation must maintain the same degree of stability for the measured parameter thereafter. For example, reference to a specific stability after 9 months means that the stability is measured 9 months after the start of the study or about 9 months after the start of the study. Additional methods for assessing antibody stability in a formulation are shown in the Examples given below.

[0103] In certain embodiments, the pharmaceutical formulations of the present invention in fluid form may exhibit low to moderate levels of viscosity. As used herein, "viscosity" may be "kinematic viscosity" or "absolute viscosity." "Kinematic viscosity" is a measure of the resistance of a fluid to flow under the influence of gravity. When equal volumes of two fluids are placed in the same capillary viscometer and allowed to flow under gravity, the viscous fluid takes longer to flow through the capillary than the less viscous fluid. For example, if one fluid takes 200 seconds to complete its flow and another fluid takes 400 seconds, then on the kinematic viscosity scale, the viscosity of the second fluid is twice that of the first fluid. "Absolute viscosity" is sometimes called dynamic viscosity or simple viscosity, which is the product of kinematic viscosity and fluid density (absolute viscosity = kinematic viscosity x density). The dimension of kinematic viscosity is L 2 / T, where L is the length and T is the time. Usually, kinematic viscosity is expressed in centistokes (cSt). The SI unit for kinematic viscosity is mm 2 / s, which is 1 cSt. Absolute viscosity is expressed in centipoise (cP). The SI unit of absolute viscosity is milliPascal second (mPa-s), where 1 cP = 1 mPa-s.

[0104] As used herein, a low viscosity level for a fluid formulation of the present invention will exhibit an absolute viscosity of less than about 20 centipoise (cP) at 20° C. For example, a fluid formulation of the present invention will 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, a medium viscosity level for a fluid formulation of the present invention will exhibit an absolute viscosity between about 30 cP and about 20 cP. For example, a fluid formulation of the present invention would 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 when measured using standard viscosity measurement techniques. Each of these values ​​refers to measurements obtained at 20°C.

[0105] As shown in the following examples, the present invention is based in part on the discovery that the combination of the claimed excipients and an anti-IL-33 antibody results in a formulation that is stable and has a desired viscosity. Container and method of application

[0106] The pharmaceutical formulations of the present invention can be contained in any container suitable for storing drugs and other therapeutic compositions. For example, the pharmaceutical formulations can be contained in sealed and sterilized plastic or glass containers with a defined volume, such as vials, ampoules, syringes, cartridges, bottles, or IV bags. Different types of vials can be used to contain the formulations of the present invention, including, for example, transparent and opaque (e.g., amber) glass or plastic vials. 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 pre-filled syringes. In some embodiments, the pharmaceutical formulations are contained in pre-filled stake needle syringes.

[0107] The pharmaceutical formulations of the present invention may be contained in a "normal tungsten" syringe or a "low tungsten" syringe. As will be appreciated by those of ordinary skill in the art, the process of manufacturing a glass syringe typically involves the use of a hot tungsten rod that is used to pierce the glass, thereby forming a hole from which liquid can be drawn and expelled from the syringe. This process results in trace amounts of tungsten being deposited on the inner surface of the syringe. Subsequent washing and other processing steps may be used to reduce the tungsten content in the syringe. As used herein, the term "normal tungsten" means that the syringe contains greater than 500 parts per billion (ppb) of tungsten. The term "low tungsten" means that the syringe contains less than 500 ppb of tungsten. For example, according to the present invention, a low tungsten syringe may contain less than about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 ppb or less of tungsten.

[0108] The rubber plungers used in syringes and the rubber stoppers used to close the openings of vials can be coated to prevent contamination of the drug contents of the syringe or vial and / or to maintain its stability. Therefore, according to certain embodiments, the pharmaceutical formulation of the present invention can be contained in a syringe including 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 or plungers suitable for use with vials and syringes containing the pharmaceutical formulations of the present invention are mentioned in, for example, U.S. Patents 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. Specific exemplary coated rubber stoppers and plungers that can be used in the context of the present invention can be found under the trade names Commercially available, it can be obtained from West Pharmaceutical Services, Inc. (Lionville, PA). According to certain embodiments of the present invention, the drug formulation can be contained in a low tungsten syringe including a fluorocarbon-coated plunger. In some embodiments, the container is a syringe, such as the Ompi EZ-Fill TM Syringe or BD Neopak TM Syringe. In some cases, the syringe is a 1 mL long glass syringe with a 1 mL iWest plunger, a 27G thin-walled needle, and an FM30 needle shield or a BD260 needle shield. In some cases, the syringe is a West NovaPure TM2.25mL glass syringe with 1-3mL plunger, 27G thin wall needle and FM30 needle shield 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 a 10 mL syringe (e.g., a glass syringe).

[0109] The pharmaceutical formulation can be administered to the patient by parenteral routes, such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or transdermal, mucosal, nasal, pulmonary and / or oral administration. A variety of reusable pens and / or automatic syringe delivery devices can be used for subcutaneous delivery of the pharmaceutical formulations of the present invention. Examples include, but are not limited to, AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM PEN (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM PEN (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM 、OPTIPENPRO TM 、OPTIPEN STARLET TM OPTICLIK TM(sanofi-aventis, Frankfurt, Germany), to name a few. Examples of disposable pen and / or auto-injector delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR TM Pen (Sanofi), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TM In some cases, the drug formulation is contained in a syringe that is particularly suitable for use with an autoinjector. Subcutaneous injections can be administered using a 20-30 gauge needle or a 25-30 gauge needle. In some cases, subcutaneous injections can be administered using a 25 gauge needle. In some cases, subcutaneous injections can be administered using a 27 gauge needle. In some cases, subcutaneous injections can be administered using a 29 gauge needle.

[0110] Another type of delivery device can include a safety system. Such devices can be relatively cheap and operate immediately after the injection is completed to manually or automatically extend a safety sleeve on the needle. The example of a safety system can include the ERIS device of West Pharmaceutical or the UltraSafe device of BD (Becton Dickinson). In addition, it is also contemplated herein to use a large volume device ("LVD") or a bolus syringe to deliver the drug formulation of the present invention. In some cases, the LVD or bolus syringe can be configured to inject the drug into the patient. For example, the LVD or bolus syringe can be configured to deliver a "large" volume of drug (usually about 2ml to about 10ml).

[0111] 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 for use as unit doses for patients to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect and the required pharmaceutical carrier, diluent or excipient. In various embodiments, the unit dosage form is contained in a container as discussed herein. The actual dosage level of the active ingredient (e.g., anti-IL-33 antibody) in the formulations of the present invention may vary so as to obtain an amount of active ingredient that is effective for achieving the desired therapeutic response for a particular patient, composition, and mode of administration without adversely affecting the patient. The selected dosage level will depend on a variety of pharmacokinetic factors, including the activity of the particular composition of the present invention employed, the route of administration, the time of administration, the excretion rate of the particular compound employed, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and past 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 changing or achieving one or more exemplary or appropriate concentrations as described herein.

[0112] 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 amounts, for example, 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, it is intended to include a range of values ​​using any of the above listed values ​​(or values ​​included in the above listed ranges) as an upper and / or lower limit. In a specific embodiment, the formulation is typically provided in a liquid form in a unit dosage form. 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.

[0113] The invention also includes methods of preparing unit dosage forms.In an exemplary embodiment, a method for preparing a pharmaceutical unit dosage form comprises combining the formulation of any of the preceding embodiments in a suitable container (eg, those discussed herein). Therapeutic uses of pharmaceutical formulations

[0114] The pharmaceutical formulations of the present invention are particularly useful for treating, preventing and / or ameliorating any disease or condition associated with IL-33 activity. Specifically, the pharmaceutical formulations of the present invention are particularly useful for treating, preventing and / or ameliorating any disease or condition associated with IL-33 expression, signaling or activity or mediated by it, or by blocking the interaction between IL-33 and IL-33 ligands (eg, ST2), or otherwise inhibiting IL-33 activity and / or signaling.

[0115] The treatment 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 may be, for example, any person or non-human animal who is in need of such treatment, prevention and / or improvement, or who would otherwise benefit from inhibition or reduction of IL-33 and / or IL-33-mediated activity. For example, the subject may be an individual diagnosed with any of the above-mentioned diseases or conditions or considered to be at risk. The present invention also includes the use of any pharmaceutical formulation disclosed herein in the manufacture of a medicament for treating, preventing and / or ameliorating any disease or condition associated with IL-33 activity, including any of the exemplary diseases, conditions and pathologies mentioned above.

[0116] In some embodiments, the invention provides a kit comprising a pharmaceutical formulation as discussed herein (e.g., a container having a formulation or a unit dosage form), and packaging or labeling (e.g., a package insert) having instructions for using the pharmaceutical formulation to treat a disease or condition as discussed above. In some cases, the instructions provide the use of a unit dosage form as discussed herein for treating a disease or condition.

[0117] The sequences discussed herein and shown in the accompanying sequence listing correspond to mAbl, a fully human antibody with an IgG4 heavy chain constant region, which was used in all of the following examples. The sequence identities are shown below. Sequence Table (SEQ ID NO) Example

[0118] The following examples are presented to provide a complete disclosure and description of how to prepare and use the methods and compositions of the present invention to those of ordinary skill in the art, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numerals used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is or is close to atmospheric pressure. Example 1: Effects of buffer and pH on the stability of anti-IL-33 antibodies

[0119] The effects of buffer and pH on the thermal stability of mAb1 were examined in liquid formulations by incubating 5 mg / mL mAb1 at 45 ° C in a series of buffer systems with different pH ranges for 28 days. The following pH and buffer systems were studied: acetate (pH 4.5 to 5.5), L-histidine (pH 5.5 to 6.5), and phosphate (pH 6.0 to 7.0). Based on the results of SE-UPLC analysis, when mAb1 was formulated in L-histidine buffer between pH 6.0 and pH 6.5, maximum protein stability was observed. Based on the results of CEX-UPLC analysis, when mAb1 was formulated in L-histidine or acetate buffer between pH 5.0 and pH 6.0, maximum protein stability was observed. These analyses also show that the formation of HMW species and charge variants is the main degradation pathway. The results are shown in Table 1. Table 1: Effect of buffer and pH on the stability of 5 mg / mL mAb1 incubated at 45°C for 28 days a % total protein recovery was defined as: total peak area determined by SE-UPLC on day 28 / total peak area determined by SE-UPLC on day 0*100%. b Reported as change in purity relative to the starting material. In all formulations, the starting material (unincubated) contained ≥97.2% of the native peak (obtained by SE-UPLC) and ≥56.5% of the main peak (obtained by CEX-UPLC).

[0120] The effects of pH and buffer on the thermal stability of mAb1 were examined in liquid formulations by incubating 150 mg / mL mAb1 in the presence of 5% sucrose as a thermal stabilizer at 37°C in a series of L-histidine and acetate buffers ranging from pH 4.5, 5.0, and 6.0 for 28 days. 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 are the main degradation pathways. The stability of mAb1 in L-histidine buffers at pH 5.0 and 6.0 is comparable to that in acetate buffer at pH 5.0, as shown in Table 2. Table 2: Effect of pH and buffer on the stability of 150 mg / mL mAb1 incubated at 37°C for 28 days a% total protein recovery was defined as: total peak area determined by SE-UPLC on day 28 / total peak area determined by SE-UPLC on day 0*100%. b Reported as change in purity relative to the starting material. In all formulations, the starting material (unincubated) contained ≥89.1% of the native peak (obtained by SE-UPLC) and ≥64.8% of the main peak (obtained by CEX-UPLC). Example 2: Effects of surfactants and thermal stabilizers on the stability of anti-IL-33 antibodies

[0121] Using the material of the research batch, the effect of two surfactants, i.e. 0.1% polysorbate 20 and 0.1% polysorbate 80, on the thermal stability of 5mg / mL mAb1 was first examined in the liquid formulation. The results of the thermal stability study are summarized in Table 3. When incubated at 45°C, the addition of polysorbate 20 or polysorbate 80 had an adverse effect on the thermal stability of mAb1 relative to the control formulation without any surfactant. An increase in high molecular weight species and charge variants was observed. Compared with the addition of 0.1% polysorbate 20, the addition of 0.1% polysorbate 80 resulted in a relative increase in HMW species and less formation of charge variant forms.

[0122] Another study was conducted at a mAb1 concentration of 50 mg / mL using a representative research batch of material to explore the concentration of polysorbate 80. The concentrations of polysorbate 80 included in the study were 0%, 0.01%, 0.02%, 0.04%, 0.06%, 0.08% and 0.1%. The results are summarized in Tables 4 and 5. When stirred for 60 minutes, for samples without polysorbate 80, an increase of 0.8% in the relative percentage of HMW was observed (Table 4). Inspection of the SE-UPLC chromatograms showed that this increase was due to the formation of higher-order aggregate peaks that were not present in the starting material. The addition of ≥0.02% polysorbate 80 prevented the formation of this aggregate species after stirring for 60 minutes. When incubated at 45°C for 28 days, the thermal stability of mAb1 was not affected by the polysorbate concentration studied (Table 5).

[0123] When formulated with 5% sucrose and incubated under accelerated conditions, 5 mg / mL mAb1 in liquid formulations showed improved stability, as shown in Table 3. After 28 days of incubation at 45°C, the relative amount of HMW species in the formulation containing 5% sucrose increased by 0.7% compared to a 1.2% increase in the control formulation without sucrose. Table 3: Effect of surfactant on the stability of 5 mg / mL mAb1 incubated at 45°C for 28 days a Reported as change in purity relative to the starting material. In all four formulations, the starting material (unincubated) contained ≥97.2% of the native peak (obtained by SE-UPLC) and ≥57.6% of the main peak (obtained by CEX-UPLC). b Data were analyzed at the 14-day time point of this study because CEX chromatograms for formulations containing polysorbate 20 and polysorbate 80 could not be integrated at the 28-day time point due to severe degradation of each sample. Table 4: Effect of polysorbate 80 concentration on the stability of 50 mg / mL mAb1 after stirring (vortexing for 120 minutes) a Reported as change in purity relative to the starting material. In all six formulations, the starting material (unincubated) contained 97.9% of the native peak (obtained by SE-UPLC) and > 68.7% of the main peak (obtained by CEX-UPLC). Table 5: Effect of polysorbate 80 concentration on the stability of 50 mg / mL mAb1 incubated at 45°C for 28 days a Reported as change in purity relative to the starting material. In all six formulations, the starting material (unincubated) contained 97.9% of the native peak (obtained by SE-UPLC) and > 68.7% of the main peak (obtained by CEX-UPLC). Example 3: Effect of viscosity modifier on the stability of anti-IL-33 antibody

[0124] mAb1 can be contained in a prefilled syringe (PFS) and delivered by a delivery device (such as an automatic injector). Viscosity is related to the ease of injection through a prefilled syringe (PFS). Maintaining a reasonably low viscosity is conducive to the development of a delivery device (such as an automatic injector).

[0125] The effect of pH on the viscosity of 150 mg / mL mAb1 in 10 mM L-histidine buffer was examined. Figure 1As shown, mAb1 viscosity is highly dependent on pH in 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 examined in mAb1 liquid formulations with the following possible viscosity modifiers, namely sodium acetate, L-arginine hydrochloride, sodium L-glutamate, and magnesium chloride (up to 200 mM). The base formulation contained 150 mg / mL mAb1, 27 mM acetate, and 5% sucrose, pH 5.3. The results were Figure 2 All of these excipients at 25-150 mM reduced the viscosity of 150 mg / mL mAb1 by 2-5 cP at pH 5.3.

[0126] The effect of viscosity modifiers on the stability of 150 mg / mL mAb1 was also examined by incubating the formulations at 37°C for 34 days. The formation of HMW species was the main degradation pathway and resulted in Figure 3 The addition of magnesium chloride or sodium acetate promoted the formation of HMWs after incubation at 37°C compared to the control formulation without any viscosity modifier. On the other hand, L-arginine hydrochloride and sodium L-glutamate did not adversely affect mAb1 stability. In contrast, 75 mM L-arginine hydrochloride improved mAb1 stability with respect to HMW formation.

[0127] Based on the viscosity lowering effect and the impact on thermal stability, L-arginine hydrochloride was selected as the viscosity modifier for mAbl formulations. Example 4: Effect of formulation parameters on viscosity and stability

[0128] A custom experimental design was applied to understand the effects of each formulation component and pH on the stability and viscosity of mAb1, as well as the interaction of parameters on the stability and viscosity. The formulation parameters in this study included 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, the surfactant was kept constant at 0.1%.

[0129] The viscosity of the formulations remained unchanged before and after incubation at 40°C / 75%RH for 28 days.

[0130] The relationship of viscosity to the main formulation parameters was analyzed by fitting models using JMP 12 with standard least squares personality and effect leverage emphasis. The main factors affecting formulation viscosity were mAb1 concentration, pH and L-arginine hydrochloride concentration, as Figure 4A shown.

[0131] The stability of the formulations after 28 days of incubation at 40°C / 75% RH was also explored. No meaningful differences were observed in color and appearance, turbidity, pH changes, protein recovery, or charge variant changes for the 14 formulations after 28 days of incubation at 40°C / 75% RH. The representative attribute of the main stability was the formation of HMW species.

[0132] The relationship between the HMW formation rate and the main formulation parameters was analyzed by fitting models using JMP 12 with standard least squares specificity and effect lever emphasis. The main factors affecting HMW formation were pH, L-arginine HCl concentration, and sucrose concentration, such as Figure 4B shown.

[0133] The selection of formulation composition was based on minimizing formulation viscosity and HMW formation rate using JMP12 expectation function. Using multi-parameter analysis, a composition containing 5% sucrose and 70mM L-arginine hydrochloride (pH 5.3) at a concentration of 150mg / ml of antibody (mAb1) was generated. This formulation minimized formulation viscosity and HMW formation. The sensitivity of viscosity and stability changes to excipient composition changes was also reduced. Example 5: Effect of surfactant concentration on the stability of anti-IL-33 antibodies

[0134] In the study discussed in Example 2 above, polysorbate 80 was identified as a stabilizing surfactant. The basic formulation of this study was 150 mg / mL mAb1, 10 mM acetate buffer, 5% (w / v) sucrose and 70 mM L-arginine hydrochloride. In the initial assessment, the concentration of polysorbate 80 was 0.01%, 0.02%, 0.04%, 0.05%, 0.06%, 0.08% and 0.1%. The results are summarized in Table 6. After 48 hours of orbital shaking at 250 rpm, for samples containing lower levels of polysorbate 80, an increase in HMW relative percentage was observed. The addition of ≥0.055% polysorbate 80 prevents the formation of this aggregate species after 48 hours of orbital shaking. Table 6: Effect of polysorbate 80 concentration on the stability of 150 mg / mL mAb1 after 48 h of orbital oscillation a Reported as change in purity relative to the starting material. The starting material (unincubated) contained 98.6% of the native peak (obtained by SE-UPLC).

[0135] By studying the stirring stability and thermal stability, the acceptable range of polysorbate 80 in the 150mg / mL mAb1 formulation was further examined. In the case of the same base formulation, the concentration of polysorbate 80 was 0.02%, 0.05%, 0.08% and 0.12% in this range study. The formulation was subjected to 250rpm orbital oscillation and thermal stress for 48 hours at 40°C / 75% RH for one month. The results of orbital oscillation confirmed that ≥0.05% polysorbate 80 prevented the formation of this aggregate species after 48 hours of orbital oscillation (see Table 7). The thermal stability of mAb1 was not affected by the polysorbate concentration studied (see Table 7). These results show that 0.05-0.12% polysorbate 80 provides stability sufficient to prevent the formation of aggregates under stirring stress without adversely affecting formulation stability. Based on these results, a target concentration of 0.08% polysorbate 80 was selected for the 150 mg / mL mAb1 formulation. Table 7: Effect of polysorbate 80 concentration on the stability of 150 mg / mL mAb1 after 48 h of orbital oscillation a Reported as change in purity relative to the starting material. The starting material (unincubated) contained 97.7% of the native peak (obtained by SE-UPLC). Example 6: Stability of Liquid Formulated Anti-IL-33 Antibody Drug Substance

[0136] A continuous long-term storage stability study was conducted to evaluate the stability of the formulation of mAb1 stored at -80°C, -30°C and -20°C for 36 months. When stored at -80°C, -30°C and -20°C for 24 months, the composition containing 150 mg / ml of mAb1 was physically and chemically stable, as shown in Tables 9 to 10. No significant changes in physical or chemical stability were detected in any of the monitored attributes. In addition, it has been shown that the composition containing 150 mg / ml mAb1 is stable when stored at -80°C, -30°C and -20°C for at least 9 months (see Tables 11 to 13). Finally, it has been shown that the composition containing 15 mg / ml mAb1 is stable when stored at -80°C, -30°C and -20°C for at least 9 months (see Tables 16 to 18). All results collected so far are shown in Tables 8 to 20 below. Table 8: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -80°C Table 9: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -30°C Table 10: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -20°C Table 11: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -80°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 12: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -30°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 13: Stability study of 150 mg / mL mAb1 formulated drug substance stored at -20°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 14: Stability of 150 mg / mL mAb10 formulated drug substance - Effect of accelerated conditions study CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 15: Stability of drug substance formulated at 150 mg / mL mAb1 - Effect of stress conditions study CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 16: Stability study of 15 mg / mL mAb1 formulated drug substance stored at -80°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 17: Stability study of 15 mg / mL mAb1 formulated drug substance stored at -30°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 18: Stability study of 15 mg / mL mAb1 formulated drug substance stored at -20°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 19: Stability of 15 mg / mL mAb1 formulated drug substance - Effect of accelerated conditions study CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 20: Stability of 15 mg / mL mAb1 formulated drug substance - Effect of stress conditions study CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Example 7: Stability of liquid formulated anti-IL-33 antibody drug product

[0137] Nine months of stability study data are available to date for 15 mg / mL and 150 mg / mL drug product formulations 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). Another stability study of the 150 mg / ml mAb1 drug product was observed to be physically and chemically stable when stored at 2-8°C for 24 months (see Table 23). No significant changes in physical or chemical stability were detected in any of the monitored attributes.

[0138] The results of the analysis of the mAbl drug product formulations at 15 mg / mL and 150 mg / mL after incubation under accelerated and stress conditions are provided in Tables 24 and 25, respectively. When stirred (orbital oscillation at 250 rpm at ambient temperature) for 48 hours, the mAbl drug product formulation was physically and chemically stable. No significant changes in physical or chemical stability were detected in any of the monitored attributes. For the 15 mg / mL and 150 mg / mL drug product formulations, no significant changes in HMW and LMW species were observed when incubated at 25°C for 1 month, indicating that the mAbl drug product formulation can be exposed for a short time at room temperature. After incubation for 2 months at 40°C / 75% RH, significant formation of HMW species and charge variants was detected (the relative percentage of acidic species increased). The results of this accelerated condition indicate that the increase in HMW species and the formation of charge variants are the main degradation pathways of the drug product formulations.

[0139] In addition, for the 150 mg / mL drug product formulation in the prefilled syringe (PFS), six months of stability study data are available to date. Stability was tested in five PFSs. The stability data are provided in Tables 26 to 34. For the 75 mg / mL drug product formulation in the glass vial, three months of stability study data are available (see Table 36). Table 21: Stability study of 15 mg / mL mAb1 drug product in glass vials stored at 2-8°C CEX = cation exchange; DS = drug substance; FDG = Formulation Development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 22: Stability study of 150 mg / mL mAb1 drug product in glass vials stored at 2-8°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 23: Stability study of 150 mg / mL mAb1 drug product in glass vials stored at 2-8°C CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 24: Stability study of 15 mg / mL mAb1 drug product in glass vials stored under accelerated and stressed conditions and with stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 25: Stability study of 150 mg / mL mAb1 drug product in glass vials stored under accelerated and stressed conditions and with stirring CEX = cation exchange; DS = drug substance; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 26: Stability study of 150 mg / mL mAb1 drug product in 1 mL gOmpi syringes stored at 2-8°C ° CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 27: Stability study of 150 mg / mL mAbl drug product in 1 mL gOmpi syringes stored under accelerated and stressed conditions and for stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 28: Stability Study of 150 mg / mL mAb1 Drug Product in 1 mL BD Neopak Syringes Stored at 2-8°C CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 29: Stability study of 150 mg / mL mAb1 drug product in 1 mL BD Neopak syringes stored under accelerated and stressed conditions and with stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 30: Stability study of 150 mg / mL mAb1 drug product in 2.25 mL gOmpi syringes stored at 2-8°C ° CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 31: Stability study of 150 mg / mL mAb1 drug product in 2.25 mL gOmpi syringes stored under accelerated and stressed conditions and for stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 32: Stability Study of 150 mg / mL mAb1 Drug Product in 2.25 mL BD Neopak Syringes Stored at 2-8°C ° CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 33: Stability study of 150 mg / mL mAb1 drug product in 2.25 mL BD Neopak syringes stored under accelerated and stressed conditions and with stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 34: Stability Study of 150 mg / mL mAb1 Drug Product in 1 mL SiOPlasma Syringes Stored at 2-8°C CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 35: Stability study of 150 mg / mL mAb1 drug product in 1 mL SiOPlasma syringes stored under accelerated and stressed conditions and for stirring CEX = cation exchange; DS = drug substance; FDG = formulation development group; HMW = high molecular weight; iCIEF = imaged capillary isoelectric focusing; LMW = low molecular weight; MCE-SDS = microchip capillary electrophoresis-sodium dodecyl sulfate; MFI = microfluidics imaging; NR = not required; OD = optical density; RH = relative humidity; RP = reversed phase; SE = size exclusion; UPLC = ultra-performance liquid chromatography Table 36: Stability study of 75 mg / mL mAb1 drug product in glass vials stored at 2-8°C CEX, cation exchange; DS, drug substance; FDG, formulation development group; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; MFI, microfluidics imaging; monomer, intact antibody; NA, not available; NR, not required; OD, optical density; RP, reversed phase; SE, size exclusion; UPLC, ultra-performance liquid chromatography

[0140] The results of long-term storage, accelerated and stress stability studies demonstrated that the mAbl formulation was stable during manufacturing (formulation, fill / finish and labeling operations) and could withstand short-term exposure to room temperature without loss of physical or chemical stability.

[0141] The present invention is not limited to a certain scope by the specific embodiments described herein. In fact, various modifications of the present invention, except those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

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 cosolvent.

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

10.

3. A pen or auto-injector delivery device comprising the stable liquid drug formulation of any one of claims 1-2.

4. A kit comprising (i) a container comprising the stable liquid pharmaceutical formulation of any one of claims 1-2, and (ii) a label for use of the pharmaceutical formulation.

5. A unit dosage form comprising the stable liquid pharmaceutical formulation of any one of claims 1-2, wherein the anti-IL-33 antibody is present in an amount of 1 mg to 500 mg.

6. A safe system delivery device comprising the stable liquid drug formulation of any one of claims 1-2.

7. A syringe comprising the stable liquid drug formulation of any one of claims 1-2.

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