Anti A beta antibody formulation

• US 8,318,164 B2
• Filed: 12/14/2009
• Issued: 11/27/2012
• Est. Priority Date: 01/28/2005
• Status: Expired due to Fees

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Inventors: Warne, Nicholas W., Luisi, Donna, Kantor, Angela
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US12/637,508
• Publication Number:
  US 20100166752A1
• Time in Patent Office: 1,079 Days
• Field of Search: None
• 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 stable formulation, comprising:

(a) a humanized 3D6 antibody or antigen binding fragment thereof at a concentration of from 1 mg/ml to 100 mg/ml, wherein the humanized antibody or antigen binding fragment comprises a light chain variable region having an amino acid sequence as set forth in residues 1-112 of SEQ ID NO;

1 and a heavy chain variable region having an amino acid sequence as set forth in residues 1-119 of SEQ ID NO;

2;

(b) histidine at a concentration of from 5 mM to 15 mM;

(c) mannitol in an amount of from 2% w/v to 6% w/v;

(d) methionine at a concentration of from 5 mM to 15 mM; and

(e) polysorbate in an amount of from 0.001% w/v to 0.01% w/v, wherein the formulation has a pH of from 5.5 to 6.5.

2. The formulation of claim 1, wherein the histidine is present at a concentration of from 8 mM to 12 mM.

3. The formulation of claim 2, wherein the mannitol is present in an amount of from 3% w/v to 5% w/v.

4. The formulation of claim 3, wherein the methionine is present at a concentration of from 8 mM to 12 mM.

5. The formulation of claim 4, wherein the polysorbate is present in an amount of from 0.003% w/v to 0.007% w/v.

6. The formulation of claim 5, wherein the pH is from 5.8 to 6.2.

7. The formulation of claim 6, wherein the antibody is present at a concentration of from 17 mg/ml to 23 mg/ml.

8. The formulation of claim 6, wherein the antibody is present at a concentration of from 75 mg/ml to 100 mg/ml.

9. The formulation of claim 1, further comprising 2% sucrose.

10. A stable unit dosage form, comprising:

(a) a humanized 3D6 antibody or antigen binding fragment thereof in an amount of from 10 mg to 250 mg, wherein the humanized antibody or antigen binding fragment comprises a light chain variable region having an amino acid sequence as set forth in residues 1-112 of SEQ ID NO;

1 and a heavy chain variable region having an amino acid sequence as set forth in residues 1-119 of SEQ ID NO;

2;

(b) histidine at a concentration of from 5 mM to 15 mM;

(c) mannitol in an amount of from 2% w/v to 6% w/v;

(d) methionine at a concentration of from 5 mM to 15 mM; and

(e) polysorbate in an amount of from 0.001% w/v to 0.01% w/v,

at a pH of from about 5.5 to 6.5.

11. The unit dosage form of claim 10, wherein the antibody is present in an amount of from 80 mg to 120 mg.

12. The unit dosage form of claim 11, wherein the histidine is present at a concentration of from 8 mM to 12 mM.

13. The unit dosage form of claim 12, wherein the mannitol is present in an amount of from 3% w/v to 5% w/v.

14. The unit dosage form of claim 13, wherein the methionine is present at a concentration of from 8 mM to 12 mM.

15. The unit dosage form of claim 14, wherein the polysorbate is present in an amount of from 0.003% w/v to 0.007% w/v.

16. The unit dosage form of claim 15, wherein the pH is from 5.8 to 6.2.

17. The unit dosage form of claim 10, wherein the antibody is present at a concentration of from 17 mg/ml to 23 mg/ml.

18. The unit dosage form of claim 10, wherein the antibody is present at a concentration of from 75 mg/ml to 100 mg/ml.

19. The unit dosage form of claim 10, further comprising 2% sucrose.

20. A pharmaceutical product, comprising:

(i) a glass vial comprising a stable humanized 3D6 antibody formulation, the formulation comprising;

(a) a humanized 3D6 antibody or antigen binding fragment thereof in an amount of from 10 mg to 250 mg, wherein the humanized antibody or antigen binding fragment comprises a light chain variable region having an amino acid sequence as set forth in residues 1-112 of SEQ ID NO;

1 and a heavy chain variable region having an amino acid sequence as set forth in residues 1-119 of SEQ ID NO;

2;

(b) histidine at a concentration of from 5 mM to 15 mM;

(c) mannitol in an amount of from 2% w/v to 6% w/v;

(d) methionine at a concentration of from 5 mM to 15 mM; and

(e) polysorbate in an amount of from 0.001% w/v to 0.01% w/v,

wherein the formulation has a pH of from 5.5 to 6.5; and

(ii) labeling for use comprising instructions to use the appropriate volume of the antibody formulation necessary to achieve a dose of from 0.01 mg to 20 mg per kg of patient body weight.

21. The pharmaceutical product of claim 20, wherein the antibody is present in an amount of from 80 mg to 120 mg.

22. The pharmaceutical product of claim 21, wherein the histidine is present at a concentration of from 8 mM to 12 mM.

23. The pharmaceutical product of claim 22, wherein the mannitol is present in an amount of from 3% w/v to 5% w/v.

24. The pharmaceutical product of claim 23, wherein the methionine is present at a concentration of from 8 mM to 12 mM.

25. The pharmaceutical product of claim 24, wherein the polysorbate is present in an amount of from 0.003% w/v to 0.007% w/v.

26. The pharmaceutical product of claim 25, wherein the pH is from 5.8 to 6.2.

27. The pharmaceutical product of claim 26, wherein the dose is from 0.15 mg to 3 mg per kg of patient body weight.

28. The pharmaceutical product of claim 27, wherein the dose is from 0.5 mg to 2 mg per kg of patient body weight.

29. The pharmaceutical product of claim 20, wherein the antibody is present at a concentration of from 17 mg/ml to 23 mg/ml.

30. The pharmaceutical product of claim 20, wherein the antibody is present at a concentration of from 75 mg/ml to 100 mg/ml.

31. The pharmaceutical product of claim 20, wherein the formulation further comprises 2% sucrose.

32. The pharmaceutical product of claim 20, wherein the dose is 0.15 mg per kg of patient body weight.

33. The pharmaceutical product of claim 20, wherein the dose is 0.5 mg per kg of patient body weight.

34. The pharmaceutical product of claim 20, wherein the dose is 1 mg per kg of patient body weight.

35. The pharmaceutical product of any one of claims 32 to 34, wherein the labeling further comprises instructions to administer the dose as an intravenous infusion.

36. The pharmaceutical product of claim 20, wherein the dose is 5 mg.

37. The pharmaceutical product of claim 36, wherein the labeling further comprises instructions to administer the dose as a subcutaneous injection.

38. The pharmaceutical product of claim 37, wherein the labeling further comprises instructions to administer the dose weekly.

39. The pharmaceutical product of claim 38, wherein the labeling further comprises instructions to administer multiple doses over a period of at least six months.

40. The pharmaceutical product of claim 20, wherein the dose is 10 mg.

41. The pharmaceutical product of claim 40, wherein the labeling further comprises instructions to administer the dose as a subcutaneous injection.

42. The pharmaceutical product of claim 41, wherein the labeling further comprises instructions to administer the dose weekly.

43. The pharmaceutical product of claim 42, wherein the labeling further comprises instructions to administer multiple doses over a period of at least six months.

44. A pharmaceutical product, comprising:

(i) a glass vial comprising a stable humanized 3D6 antibody formulation, the formulation comprising;

(a) a humanized 3D6 antibody in an amount of from 10 mg to 250 mg, wherein the humanized 3D6 antibody comprises a light chain having an amino acid sequence as set forth in SEQ ID NO;

1 and a heavy chain having an amino acid sequence as set forth in residues 1-448 of SEQ ID NO;

2;

(b) histidine at a concentration of 10 mM;

(c) mannitol in an amount of 4% w/v;

(d) methionine at a concentration of 10 mM; and

(e) polysorbate in an amount of 0.005% w/v,

wherein the formulation has a pH of 6.0; and

(ii) labeling for use comprising instructions to use the appropriate volume of the antibody formulation necessary to achieve a dose of from 0.1 mg to 25 mg.

45. The pharmaceutical product of claim 44, wherein the dose is 5 mg.

46. The pharmaceutical product of claim 45, wherein the labeling further comprises instructions to administer the dose as a subcutaneous injection.

47. The pharmaceutical product of claim 46, wherein the labeling further comprises instructions to administer the dose weekly.

48. The pharmaceutical product of claim 47, wherein the labeling further comprises instructions to administer multiple doses over a period of at least six months.

49. The pharmaceutical product of claim 44, wherein the dose is 10 mg.

50. The pharmaceutical product of claim 49, wherein the labeling further comprises instructions to administer the dose as a subcutaneous injection.

51. The pharmaceutical product of claim 50, wherein the labeling further comprises instructions to administer the dose weekly.

52. The pharmaceutical product of claim 51, wherein the labeling further comprises instructions to administer multiple doses over a period of at least six months.