Stabilized liquid anti-RSV antibody formulations
View Patent ↗The present invention provides liquid formulations of SYNAGIS® or an antigen-binding fragment thereof that immunospecifically bind to a respiratory syncytial virus (RSV) antigen, which formulations exhibit stability, low to undetectable levels of aggregation, and very little to no loss of the biological activities of SYNAGIS® or an antigen-binding fragment thereof, even during long periods of storage. In particular, the present invention provides liquid formulations of SYNAGIS® or an antigen-binding fragment thereof which immunospecifically binds to a RSV antigen, which formulations are substantially free of surfactant, inorganic salts, and/or other common excipients. Furthermore, the invention provides method of preventing, treating or ameliorating symptoms associated with RSV infection utilizing liquid formulations of the present invention.
1. A method of preventing a RSV infection or a symptom thereof in a human subject, said method comprising administering to the subject a prophylactically effective amount of an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 40 mg/ml of palivizumab, or an antigen-binding fragment thereof; and (b) histidine, wherein said formulation does not comprise mannitol.
2. A method of preventing a RSV infection or a symptom thereof in a human subject, said method comprising administering to the subject a prophylactically effective amount of an aqueous palivizumab formulation comprising, in an aqueous carrier: (a) at least 75 mg/mi of palivizumab, or an antigen-binding fragment thereof; (b) histidine at a concentration of about 20 mM to about 30 mM; and (c) glycine at a concentration of less than 2 mM, wherein said formulation does not comprise mannitol.
3. A method of preventing a RSV infection or a symptom thereof in a subject, said method comprising administering to the subject a prophylactically effective amount of an aqueous palivizumab formulation comprising at least 40 mg/ml of palivizumab or an antigen-binding fragment thereof in an aqueous carrier, said formulation (i) having been prepared by a process in which, for each step of said process, said palivizumab or palivizumab-antigen-binding fragment is in an aqueous phase; and (ii) being suitable for injection in a human subject.
4. The method of claim 1 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of at least 50 mg/ml, at least 55 mg/mi, at least 60 mg/ml, at least 70 mg/ml, or at least 75 mg/ml.
5. The method of claim 1 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of at least 75 mg/mi, at least 80 mg/mi or at least 85 mg/ml.
6. The method of claim 1 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of at least 90 mg/mi, at least 95 mg/ml or at least 100 mg/ml.
7. The method of claim 1 , 2 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is at a concentration of at least 125 mg/mi or at least 150 mg/ml.
8. The method of claim 1 or 3 , wherein said formulation comprises histidine at a concentration of about 1 mM to about 100 mM.
9. The method of claim 1 or 3 , wherein said formulation comprises histidine at a concentration of about 10 mM to about 50 mM.
10. The method of claim 1 or 3 , wherein said formulation is substantially free of surfactants and inorganic salts.
11. The method of claim 2 , wherein said formulation is substantially free of surfactants and inorganic salts.
12. The method of claim 10 , wherein said formulation is substantially free of other excipients.
13. The method of claim 11 , wherein said formulation is substantially free of other excipients.
14. The method of claim 1 or 3 , wherein said formulation further comprises an excipient other than a surfactant.
15. The method of claim 10 , wherein said formulation further comprises an excipient other than a surfactant.
16. The method of claim 2 or 11 , wherein said formulation further comprises an excipient other than a surfactant.
17. The method of claim 14 , wherein said excipient is glycine.
18. The method of claim 15 , wherein said excipient is glycine.
19. The method of claim 17 , wherein glycine is at a concentration of less than 150 mM, less than 100 mM or less than 50 mM.
20. The method of claim 18 , wherein glycine is at a concentration of less than 150 mM, less than 100 mM or less than 50 mM.
21. The method of claim 19 , wherein glycine is at a concentration of less than 3 mM or less than 2 mM.
22. The method of claim 20 , wherein glycine is at a concentration of less than 3 mM or less than 2 mM.
23. The method of claim 1 or 3 , wherein said formulation has a pH of between about 5.5 to about 7.0.
24. The method of claim 23 , wherein said formulation has a pH of between about 5.5 to about 6.5.
25. The method of claim 2 , wherein histidine is at a concentration of about 25 mM and glycine is at a concentration of 1.6 mM.
26. The method of claim 2 , wherein said formulation has a pH of between about 5.5 to about 7.0.
27. The method of claim 2 , wherein said formulation has a pH of about 5.5 to about 6.5.
28. The method of claim 2 , wherein said formulation has a pH of about 6.0.
29. The method of claim 25 , wherein said formulation has a pH of about 6.0.
30. The method of claim 14 , wherein said excipient is a saccharide.
31. The method of claim 30 , wherein said saccharide is sucrose.
32. The method of claim 14 , wherein said excipient is a polyol other than mannitol.
33. The method of claim 32 , wherein said polyol is polysorbate.
34. The method of claim 1 , 2 or 3 , wherein said aqueous carrier is distilled water.
35. The method of claim 28 , wherein said aqueous carrier is distilled water.
36. The method of claim 29 , wherein said aqueous carrier is distilled water.
37. The method of claim 1 , 2 or 3 , wherein said formulation is homogenous.
38. The method of claim 1 , 2 or 3 , wherein said palivizumab or an antigen-binding fragment thereof is stable at 40° C. for at least 100 days as determined by High Performance Size Exclusion Chromatography (HPSEC).
39. The method of claim 1 , 2 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is stable at about ambient temperature for at least 1 year as determined by HPSEC.
40. The method of claim 1 , 2 or 3 , wherein said palivizumab or palivizumab antigen-binding fragment is stable at 40° C. for at least 3 years as determined by HPSEC.
41. The method of claim 1 , 2 or 3 , wherein less than 2% of said palivizumab or palivizumab antigen-binding fragment forms an aggregate as measured by HPSEC.
42. The method of claim 1 or 2 , which has been prepared by a process in which, for each step of said process, said palivizumab or palivizumab antigen-binding fragment is in an aqueous phase.
43. The method of claim 1 or 2 , which has been prepared by a process that does not have a drying step.
44. The method of claim 1 or 2 , which has been prepared by a process that does not have a lyophilization step.
45. The method of claim 10 , wherein said formulation comprises histidine at a concentration of 1 mM to 100 mM.
46. The method of claim 45 , wherein said formulation is substantially free of other excipients.
47. The method of claim 8 , wherein said formulation has a pH of between about 5.5 to about 7.0.
48. The method of claim 45 , wherein said formulation has a pH of between about 5.5 to about 7.0.
49. The method of claim 46 , wherein said formulation has a pH of between about 5.5 to about 7.0.
50. The method of claim 29 , wherein said formulation is substantially free of surfactants, inorganic salts and other excipients.
51. The method of claim 1 , 2 or 3 , wherein said formulation is administered parenterally or intranasally.
52. The method of claim 29 , wherein said formulation is administered parenterally or intranasally.
53. The method of claim 51 , wherein said prophylactically effective amount is a dose of 15 mg/kg.
54. The method of claim 52 , wherein said prophylactically effective amount is a dose of 15 mg/kg.
55. The method of claim 53 , further comprising administering another therapy.
56. The method of claim 54 , further comprising administering another therapy.
57. The method of claim 1 , 2 , 3 or 29 , wherein said human subject is a human in an nursing home, a human in an orphanage, a human with cystic fibrosis, bronchopulmonary dysplasia, congenital heart disease, congenital immunodeficiency or acquired immunodeficiency, or a human who has had a bone marrow transplant.
58. The method of claim 1 , 2 , 3 or 29 , wherein said human subject is a human infant.
59. The method of claim 1 , 2 , 3 or 29 , wherein said human subject is a human infant born prematurely or a human infant susceptible to an RSV infection.
60. The method of any one of claims 1 , 2 , 3 or 29 , wherein said formulation is administered by a nebulizer or inhaler.