Anti a beta antibody formulation

• US 20060193850A1
• Filed: 01/27/2006
• Published: 08/31/2006
• Est. Priority Date: 01/28/2005
• Status: Active Grant

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Wyeth LLC (Pfizer Inc.)
• Inventors: Warne, Nicholas W., Kantor, Angela, Luisi, Donna
• Granted Patent: US 7,635,473 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4172 Imidazole-alkanecarboxylic acids, e.g. histidine
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

The present invention provides formulations for maintaining the stability of Aβ binding polypeptides, for example, Aβ antibodies. Exemplary formulations include a tonicity agent such as mannitol and a buffering agent or amino acid such as histidine. Other exemplary formulations include an antioxidant in a sufficient amount as to inhibit by-product formation, for example, the formation of high molecular weight polypeptide aggregates, low molecular weight polypeptide degradation fragments, and mixtures thereof. The formulations of the invention optionally comprise a tonicity agent, such as mannitol, and a buffering agent or amino acid such as histidine. The formulations are suitable for several different routes of administration.

Claims

1. A stabilized formulation comprising at least one Aβ

binding polypeptide, at least one tonicity agent, wherein the tonicity agent is present in an amount sufficient to render the formulation suitable for administration, and at least one buffering agent in an amount sufficient to maintain a physiologically suitable pH.

2. The formulation of claim 1, further comprising at least one antioxidant.

3. The formulation of claim 2, wherein at least one antioxidant is methionine.

4. The formulation of claim 1, wherein at least one tonicity agent is mannitol.

5. The formulation of claim 4, wherein at least one tonicity agent is NaCl.

6. The formulation of claim 1, wherein at least one buffering agent is histidine.

7. The formulation of claim 1, wherein at least one buffering agent is succinate.

8. The formulation of claim 1, wherein at least one buffering agent is sodium phosphate.

9. The formulation of claim 1, further comprising at least one stabilizer.

10. The formulation of claim 9, wherein at least one stabilizer is polysorbate 80.

11. The formulation of claim 1, wherein at least one Aβ

binding polypeptide is selected from the group consisting of an anti Aβ

antibody, an anti Aβ

antibody Fv fragment, an anti Aβ

antibody Fab fragment, an anti Aβ

antibody Fab′

(2) fragment, an anti Aβ

antibody Fd fragment, a single-chain anti Aβ

antibody (scFv), a single domain anti Aβ

antibody fragment (Dab), a beta-pleated sheet polypeptide comprising at least one antibody complementarity determining region (CDR) from an anti Aβ

antibody, and a non-globular polypeptide comprising at least one antibody CDR from an anti Aβ

antibody.

12. The formulation of claim 11, wherein at least one Aβ

binding polypeptide is an anti Aβ

antibody.

13. The formulation of claim 12, wherein the anti Aβ

antibody specifically binds to an epitope within residues selected from the group consisting of 1-7, 1-5, 3-7, 3-6, 13-28, 15-24, 16-24, 16-21, 19-22, 33-40, and 33-42 of Aβ

.

14. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 1-7.

15. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 1-5.

16. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 3-6.

17. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 3-7.

18. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 13-28.

19. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 16-24.

20. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 16-21.

21. The formulation of claim 13, wherein the anti Aβ

antibody specifically binds to an epitope within residues 19-22.

22. The formulation of claim 12, wherein the anti Aβ

antibody is selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, a humanized 266 antibody, a humanized 12A11 antibody, and a humanized 15C11 antibody.

23. The formulation of claim 22, further comprising a stabilizer and an antioxidant.

24. The formulation of claim 23, wherein the stabilizer is polysorbate 80, the antioxidant is methionine, the tonicity agent is mannitol, sorbitol or NaCl, and the buffering agent is histidine.

25. The formulation of claim 22, wherein the formulation is a lyophilized formulation.

26. The formulation of claim 22, wherein the formulation is a liquid formulation.

27. The formulation of claim 22, wherein the antibody is of isotype human IgG1.

28. The formulation of claim 22, wherein the antibody is of isotype human IgG4.

29. The formulation of claim 12, wherein the anti Aβ

antibody is present at a concentration of about 0.1 mg/ml to about 60 mg/ml.

30. The formulation of claim 12, wherein the anti Aβ

antibody is present at a concentration of about 20 mg/ml.

31. The formulation of claim 12, wherein the anti Aβ

antibody is present at a concentration of about 10 mg/ml.

32. The formulation of claim 23, wherein at least one tonicity agent is D-mannitol at a concentration of about 1% w/v to about 10% w/v.

33. The formulation of claim 32, wherein the concentration of D-mannitol is about 2% w/v to about 6% w/v.

34. The formulation of claim 23, wherein at least one buffering agent is histidine at a concentration of about 0.1 mM to about 25 mM.

35. The formulation of claim 23, wherein the formulation has a pH of about 5.5 to about 6.5.

36. The formulation of claim 22, wherein the anti Aβ

antibody is a humanized 3D6 antibody.

37. The formulation of claim 22, wherein the anti Aβ

antibody is a humanized 12A11 antibody.

38. The formulation of claim 22, wherein the anti Aβ

antibody is a humanized 266 antibody.

39. The formulation of claim 22, wherein the anti Aβ

antibody is a humanized 15C11 antibody.

40. A formulation stable for at least about 12 months at a temperature of above freezing to about 10°

C. and having a pH of about 5.5 to about 6.5, comprising;

i. at least one Aβ

antibody at a concentration of about 1 mg/ml to about 30 mg/ml;

ii. mannitol at a concentration of about 4% w/v or NaCl at a concentration of about 150 mM;

iii. about 5 mM to about 10 mM histidine or succinate; and

iv. 10 mM methionine.

41. The formulation of claim 40, wherein the formulation is stable for at least about 24 months at a temperature of about 2°

C. to 8°

C., and comprises polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.

42. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to about 6.5 and comprises about 10 mg/ml Aβ

antibody, about 10 mM histidine and about 4% w/v mannitol and about 0.005% w/v polysorbate 80.

43. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to about 6.2 and comprises about 20 mg/ml Aβ

antibody, about 10 mM histidine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.

44. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to about 6.2 and comprises about 30 mg/ml Aβ

antibody, about 10 mM histidine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.

45. The formulation of claim 40, wherein the Aβ

antibody is selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, a humanized 266 antibody, a humanized 12A11 antibody, and a humanized 15C11 antibody.

46. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 4% w/v mannitol and about 2 mg/ml to about 20 mg/ml of an Aβ

antibody selected from the group consisting of a humanized 3D6 antibody, a humanized 10D5 antibody, a humanized 12B4 antibody, and a humanized 12A11 antibody.

47. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 150 mM NaCl and about 2 mg/ml to about 20 mg/ml of an Aβ

antibody selected from the group consisting of a humanized 12B4 antibody, and a humanized 12A11 antibody.

48. The formulation of claim 40, wherein the formulation has a pH of about 6.0 to 6.5 and comprises about 10 mM histidine, about 4% w/v mannitol and about 2 mg/ml to about 20 mg/ml of an Aβ

antibody selected from the group consisting of a humanized 266 antibody and a humanized 15C11 antibody.

49. A formulation stable for at least about 24 months at a temperature of about 2°

C. to about 8°

C. and having a pH of about 5.5 to about 6.5, comprising about 2 mg/ml to about 23 mg/ml of a humanized 3D6 antibody, about 10 mM histidine and about 10 mM methionine.

50. The formulation of claim 49, further comprising about 4% w/v mannitol.

51. The formulation of claim 49, further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.

52. The formulation of claim 51, comprising about 0.005% w/v polysorbate 80.

53. The formulation of claim 49, wherein the humanized 3D6 antibody is present at a concentration of about 17 mg/ml to about 23 mg/ml.

54. A formulation stable for at least about 24 months at a temperature of about 2°

C. to about 8°

C. and having a pH of about 5.5 to about 6.5, comprising about 2 mg/ml to about 23 mg/ml of a humanized 3D6 antibody, about 10 mM succinate, about 10 mM methionine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.

55. A formulation stable for at least about 24 months at a temperature of about 2°

C. to about 8°

C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 30 mg/ml of a humanized 266 antibody, about 10 mM histidine and about 10 mM methionine.

56. The formulation of claim 55, further comprising about 4% w/v mannitol.

57. The formulation of claim 55, further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.

58. A formulation stable for at least about 24 months at a temperature of about 2°

C. to about 8°

C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 30 mg/ml of a humanized 12A11 antibody, about 10 mM histidine and about 10 mM methionine.

59. The formulation of claim 58, further comprising about 150 mM NaCl.

60. The formulation of claim 58, further comprising polysorbate 80 at a concentration of about 0.001% w/v to about 0.01% w/v.

61. A formulation stable for at least about 24 months at a temperature of about 2°

C. to about 8°

C. and having a pH of about 6.0 to about 6.5, comprising about 2 mg/ml to about 20 mg/ml of a humanized 12A11 antibody, about 5 mM histidine, about 10 mM methionine, about 4% w/v mannitol and about 0.005% w/v polysorbate 80.

62. A formulation stable when thawed from about −

50°

c. to about −

80°

c., comprising about 40 to about 60 mg/ml of an anti Aβ

antibody, about 1.0 mg/ml to about 2.0 mg/ml histidine, about 1.0 mg/ml to 2.0 mg/ml methionine and about 0.05 mg/ml polysorbate 80, wherein the formulation has a pH of about 6.0.

63. The formulation of claim 62, wherein mannitol is excluded.

64. The formulation of claim 63, wherein the Aβ

antibody is a humanized 3D6 antibody.

65. The formulation of claim 63, wherein the Aβ

antibody is a humanized 266 antibody.

66. A formulation comprising about 20 mg/mL anti Aβ

antibody, about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol and having a pH of about 6.

67. A formulation comprising about 30 mg/mL anti Aβ

antibody, about 10 mM succinate, about 10 mM methionine, about 6% mannitol and having a pH of about 6.2.

68. A formulation comprising about 20 mg/mL anti Aβ

antibody, about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.

69. A formulation comprising about 10 mg/mL anti Aβ

antibody, about 10 mM succinate, about 10 mM methionine, about 10% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.5.

70. A formulation comprising about 5 mg/mL to about 20 mg/mL anti Aβ

antibody, about 5 mM to about 10 mM L-histidine, about 10 mM methionine, about 4% mannitol, about 0.005% polysorbate 80, and having a pH of about 6.0 to about 6.5.

71. A formulation comprising about 5 mg/mL to about 20 mg/mL anti Aβ

antibody, about 5 mM to about 10 mM L-histidine, about 10 mM methionine, about 150 mM NaCl, about 0.005% polysorbate 80, and having a pH of about 6.0 to about 6.5.

72. A pharmaceutical unit dosage form, comprising a formulation comprising:

a. about 10 mg to about 250 mg of an anti Aβ

antibody;

b. about 4% mannitol or about 150 mM NaCl;

c. about 5 mM to about 10 mM histidine or succinate; and

d. about 10 mM methionine

73. The pharmaceutical unit dosage form of claim 72, comprising about 0.001% to about 0.1% polysorbate 80.

74. The pharmaceutical unit dosage form of claim 73, comprising about 40 mg to about 60 mg of the anti Aβ

antibody.

75. The pharmaceutical unit dosage form of claim 73, comprising about 60 mg to about 80 mg of the anti Aβ

antibody.

76. The pharmaceutical unit dosage form of claim 73, comprising about 80 mg to about 120 mg of the anti Aβ

antibody.

77. The pharmaceutical unit dosage form of claim 73, comprising about 120 mg to about 160 mg of the anti Aβ

antibody.

78. The pharmaceutical unit dosage form of claim 73, comprising about 160 mg to about 240 mg of the anti Aβ

antibody

79. A therapeutic product, comprising:

a. a glass vial, comprising a formulation comprising;

i. about 10 mg to about 250 mg of a humanized anti Aβ

antibody,

ii. about 4% mannitol or about 150 mM NaCl,

iii. about 5 mM to about 10 mM histidine, and

iv. about 10 mM methionine; and

b. labeling for use comprising instructions to use the appropriate volume necessary to achieve a dose of about 0.15 mg/kg to about 5 mg/kg.

80. The therapeutic product of claim 79, wherein the dose is about 0.5 mg/kg to about 3 mg/kg.

81. The therapeutic product of claim 79, wherein the dose is about 1 mg/kg to about 2 mg/kg.

82. The therapeutic product of claim 79, wherein the anti Aβ

antibody concentration is about 10 mg/ml to about 60 mg/ml.

83. The therapeutic product of claim 79, wherein the anti Aβ

antibody concentration is about 20 mg/ml.

84. The therapeutic product of claim 79, further comprising about 0.005% polysorbate 80.

85. The therapeutic product of claim 79, wherein the use is a subcutaneous administration.

86. The therapeutic product of claim 79, wherein the use is an intravenous administration.