Anti A beta antibody formulation
View Patent ↗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.
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.