JPWO2020191270A5 - - Google Patents

Claims (67)

A stable liquid pharmaceutical formulation comprising:
(i) a human antibody that specifically binds to human interleukin-33 (hIL-33), the heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of SEQ ID NOS: 4, 6 and 8, respectively; , and light chain complementarity determining region LCDR1, LCDR2 and LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12, 14 and 16, respectively;
(ii) a buffer, said buffer being acetate or histidine at a concentration of 1 mM to 40 mM;
(iii) an amino acid, said amino acid being arginine or glutamic acid at a concentration of 30 mM to 110 mM;
(iv) a heat stabilizer which is sucrose at a concentration of 1% w/v to 20% w/v; and (v) an organic co-solvent which is 0.01% w/v. the organic co-solvent, which is a surfactant at a concentration of /v to 0.15% w/v;
The stable liquid pharmaceutical formulation comprising: 2. The stable liquid pharmaceutical formulation of claim 1, wherein said buffer is acetate or histidine at a concentration of 1 mM to 20 mM. 2. The stable liquid pharmaceutical formulation of Claim 1, wherein said heat stabilizer is sucrose at a concentration of 1% w/v to 10% w/v. 2. The stable liquid pharmaceutical formulation of claim 1, wherein said surfactant is polysorbate 80. 2. The stable liquid pharmaceutical formulation of claim 1, wherein said antibody is present in a concentration of 1 mg/ml to 200 mg/ml. 6. The stable liquid pharmaceutical formulation of claim 5, wherein said antibody is present in a concentration of 15 mg/ml to 150 mg/ml. 2. The stable liquid of claim 1, wherein said antibody comprises a heavy chain variable region (HCVR) comprising said amino acid sequence of SEQ ID NO:2 and a light chain variable region (LCVR) comprising said amino acid sequence of SEQ ID NO:10. Pharmaceutical formulation. 8. The stable liquid pharmaceutical formulation of claim 7, wherein said antibody has a human IgG heavy chain constant region. 9. The stable liquid pharmaceutical formulation of claim 8, wherein said heavy chain constant region is of isotype IgGl. 9. The stable liquid pharmaceutical formulation of claim 8, wherein said heavy chain constant region is of isotype IgG4. 8. The stable liquid pharmaceutical formulation of Claim 7, wherein said 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. (i) about 15 mg/ml to about 150 mg/mL of said antibody, (ii) about 5 mM to about 15 mM acetate, (iii) about 60 mM to about 80 mM arginine hydrochloride, (iv) about 3% w/v 2. The stable liquid pharmaceutical formulation of claim 1, comprising from to about 7% w/v sucrose, and (v) from about 0.06% w/v to about 0.1% w/v polysorbate 80. (i) about 15 mg/ml ± 1.5 mg/ml of said antibody, (ii) about 10 mM ± 2 mM acetate, (iii) about 70 mM ± 14 mM arginine hydrochloride, (iv) about 5% w/v ± 2. The stable liquid pharmaceutical formulation of claim 1, comprising 1% w/v sucrose, and (iv) about 0.08% ± 0.016% w/v polysorbate 80. (i) about 75 mg/ml ± 5 mg/ml of said antibody, (ii) about 10 mM ± 2 mM acetate, (iii) about 70 mM ± 14 mM arginine hydrochloride (iv) about 5% w/v ± 1% w /v of sucrose, and (iv) about 0.08% ± 0.016% w/v of polysorbate 80. (i) about 150 mg/ml ± 15 mg/ml of said antibody, (ii) about 10 mM ± 2 mM acetate, (iii) about 70 mM ± 14 mM arginine hydrochloride (iv) about 5% w/v ± 1% w /v of sucrose, and (iv) about 0.08% ± 0.016% w/v of polysorbate 80. 2. The stable liquid pharmaceutical formulation of Claim 1, wherein said pH of said formulation is between 5.2 and 5.4. 17. The stable liquid pharmaceutical formulation of Claim 16, wherein said pH of said formulation is about 5.3. (i) a human antibody that specifically binds human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg/ml to 150±15 mg/ml, comprising SEQ ID NOS: 4, 6, and HCVR comprising HCDR1, HCDR2 and HCDR3 regions comprising the amino acid sequence of 8 and LCDR1, LCDR2 and LCDR3 regions comprising the amino acid sequences of SEQ ID NOs: 12, 14 and 16, respectively;
(ii) 10 mM ± 2 mM acetate;
(iii) 70 mM ± 14 mM arginine hydrochloride;
(iv) 5% w/v ± 1% w/v sucrose;
(iv) about 0.08% ± 0.016% w/v polysorbate 80;
Said stable liquid pharmaceutical formulation, having a pH of 5.1-5.5. 19. The stable liquid of claim 18, wherein said antibody comprises a heavy chain variable region (HCVR) comprising said amino acid sequence of SEQ ID NO:2 and a light chain variable region (LCVR) comprising said amino acid sequence of SEQ ID NO:10. Pharmaceutical formulation. 20. The stable liquid pharmaceutical formulation of claim 19, wherein said antibody has a human IgG heavy chain constant region. 21. The stable liquid pharmaceutical formulation of claim 20, wherein said heavy chain constant region is of isotype IgGl. 21. The stable liquid pharmaceutical formulation of claim 20, wherein said heavy chain constant region is of isotype IgG4. 20. The stable liquid pharmaceutical formulation of Claim 19, wherein said 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. (i) a human antibody that specifically binds to human interleukin-33 (hIL-33) at a concentration of 15±1.5 mg/ml to 150±15 mg/ml, said antibody comprising the amino acid sequence of SEQ ID NO:18; a human antibody comprising a chain and a light chain comprising the amino acid sequence of SEQ ID NO:20;
(ii) 10 mM ± 2 mM acetate;
(iii) 70 mM ± 14 mM arginine hydrochloride;
(iv) 5% w/v ± 1% w/v sucrose;
(iv) about 0.08% ± 0.016% w/v polysorbate 80;
Said stable liquid pharmaceutical formulation, having a pH of 5.1-5.5. 2. The stability of claim 1, wherein at least 90% of the native form of said antibody is recovered after 2 months of storage at 5°C as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC). liquid pharmaceutical formulation. 26. The stable liquid pharmaceutical formulation of Claim 25, wherein at least 95% of said native form of said antibody is recovered after 2 months of storage at 5°C as determined by SE-UPLC. 27. The stable liquid pharmaceutical formulation of Claim 26, wherein at least 99% of said native form of said antibody is recovered after 2 months of storage at 5°C as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of claim 1, wherein at least 95% of said native form of said antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC. 29. The stable liquid pharmaceutical formulation of Claim 28, wherein at least 97.5% of said native form of said antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC. 30. The stable liquid pharmaceutical formulation of claim 29, wherein at least 99% of said native form of said antibody is recovered after 9 months of storage at -20°C as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of claim 1, wherein at least 95% of said native form of said antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC. 32. The stable liquid pharmaceutical formulation of claim 31, wherein at least 97.5% of said native form of said antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC. 33. The stable liquid pharmaceutical formulation of claim 32, wherein at least 99% of said native form of said antibody is recovered after 9 months of storage at 2-8°C as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of Claim 1, wherein said formulation contains no more than 2% high molecular weight (HMW) species after storage at 5°C for 2 months as determined by SE-UPLC. 35. The stable liquid pharmaceutical formulation of claim 34, wherein said formulation contains 1% or less HMW species after 2 months of storage at 5°C as determined by SE-UPLC. 36. The stable liquid pharmaceutical formulation of Claim 35, wherein said formulation contains no more than 0.6% HMW species after storage at 5°C for 2 months as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of claim 1, wherein said formulation contains no more than 2% HMW species after 9 months of storage at -20°C as determined by SE-UPLC. 38. The stable liquid pharmaceutical formulation of Claim 37, wherein said formulation contains 1% or less HMW species after 9 months of storage at -20°C as determined by SE-UPLC. 39. The stable liquid pharmaceutical formulation of Claim 38, wherein said formulation contains no more than 0.5% HMW species after 9 months of storage at -20°C as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of Claim 1, wherein said formulation contains no more than 2% HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC. 41. The stable liquid pharmaceutical formulation of claim 40, wherein said formulation contains no more than 1% HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC. 42. The stable liquid pharmaceutical formulation of claim 41, wherein said formulation contains no more than 0.7% HMW species after 9 months of storage at 2-8°C as determined by SE-UPLC. 2. The stable liquid pharmaceutical formulation of Claim 1, wherein said formulation exhibits a viscosity of less than about 15 cPoise. 44. The stable liquid pharmaceutical formulation of any one of claims 1-43, contained in a glass vial. 44. The stable liquid pharmaceutical formulation of any one of claims 1-43, contained in a syringe. 46. The stable liquid pharmaceutical formulation of Claim 45, wherein said syringe comprises a fluorocarbon coated plunger. 46. The stable liquid pharmaceutical formulation of claim 45, wherein said syringe is a low tungsten syringe. 46. The stable liquid pharmaceutical formulation of Claim 45, which is a pre-filled syringe. 46. The stable liquid pharmaceutical formulation of claim 45, which is a prefilled staked needle syringe. 44. The stable liquid pharmaceutical formulation of any one of claims 1-43 contained in a large volume device or bolus syringe. 44. The stable liquid pharmaceutical formulation of any one of claims 1-43 contained in a pen delivery device. 44. The stable liquid pharmaceutical formulation of any one of claims 1-43 contained in an auto-injector delivery device. A pen or auto-injector delivery device comprising a stable liquid pharmaceutical formulation according to any one of claims 1-43. 54. The delivery device of Claim 53, which is a disposable pen delivery device. 54. The delivery device of Claim 53, which is a reusable pen delivery device. A container containing a stable liquid pharmaceutical formulation according to any one of claims 1-43. 44. A kit comprising (i) a container containing the stable liquid pharmaceutical formulation of any one of claims 1-43, and (ii) labeling for the use of said stable liquid pharmaceutical formulation. 58. The kit of claim 57, wherein said labeling recites subcutaneous administration of said stable liquid pharmaceutical formulation. 58. The kit of claim 57, wherein said labeling recites intravenous administration of said stable liquid pharmaceutical formulation. A unit dosage form comprising the stable liquid pharmaceutical formulation of any one of claims 1-43, wherein said anti-IL-33 antibody is present in an amount of 1 mg to 500 mg. 61. The unit dosage form of claim 60, wherein said anti-IL-33 antibody is present in an amount of about 150 mg. 61. The unit dosage form of claim 60, wherein said anti-IL-33 antibody is present in an amount of about 300 mg. 61. The unit dosage form of claim 60, wherein said stable liquid pharmaceutical formulation is contained in a syringe. 64. The unit dosage form of claim 63, wherein said syringe is a pre-filled syringe. A safety system delivery device comprising the stable liquid pharmaceutical formulation of any one of claims 1-43. 66. The safety system delivery device of claim 65, including a safety sleeve configured to be extended by manual manipulation. 66. The safety system delivery device of claim 65, comprising a safety sleeve configured to automatically extend after injection of the stable liquid pharmaceutical formulation.