Anti Aβ antibody formulation

• US 7,635,473 B2
• Filed: 01/27/2006
• Issued: 12/22/2009
• Est. Priority Date: 01/28/2005
• Status: Active Grant

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth (Pfizer Inc.)
• Inventors: Luisi, Donna, Warne, Nicholas W., Kantor, Angela
• Primary Examiner(s): Kolker; Daniel E.
• Assistant Examiner(s): Emch; Gregory S
• Application Number:
  US11/342,353
• Publication Number:
  US 20060193850A1
• Time in Patent Office: 1,425 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 version of monoclonal antibody 3D6 at a concentration of from about 1 mg/ml, to about 50 mg/ml, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

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

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

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

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

2. The formulation of claim 1, wherein the antibody is present at a concentration of from about 17 mg/ml to about 23 mg/ml.

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

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

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

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

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

8. A stable unit dosage form, comprising:

(a) a humanized version of monoclonal antibody 3D6 in an amount of from about 10 mg to about 250 mg, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

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

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

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

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

9. The unit dosage form of claim 8, wherein the antibody is present in an amount of from 80 mg to 120 mg.

10. The unit dosage form of claim 9, wherein the histidine is present at a concentration of from 8 mM to 12 mM.

11. The unit dosage form of claim 10, wherein the mannitol is present in an amount of from 3% w/v to 5% w/v.

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

13. The unit dosage form of claim 12, wherein the polysorbate is present in an amount of from 0.003% w/v to 0.007% w/v.

14. The unit dosage form of claim 13, wherein the pH is from 5.8 to 6.2.

15. The unit dosage form of claim 8, wherein the 3D6 antibody is present at a concentration of from about 17 mg/ml to about 23 mg/ml.

16. A pharmaceutical product, comprising:

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

(a) a humanized version of monoclonal antibody 3D6 in an amount of from about 10 mg to about 250 mg, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

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

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

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

(e) polysorbate in an amount of from about 0.001% w/v to about 0.01% w/v, wherein the formulation has a pH of from about 5.5 to about 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 about 0.15 mg to about 5 mg per kg of patient body weight.

17. The pharmaceutical product of claim 16, wherein the antibody is present in an amount of from 80 mg to 120 mg.

18. The pharmaceutical product of claim 17, wherein the histidine is present at a concentration of from 8 mM to 12 mM.

19. The pharmaceutical product of claim 18, wherein the mannitol is present in an amount of from 3% w/v to 5% w/v.

20. The pharmaceutical product of claim 19, wherein the methionine is present at a concentration of from 8 mM to 12 mM.

21. The pharmaceutical product of claim 20, wherein the polysorbate is present in an amount of from 0.003% w/v to 0.007% w/v.

22. The pharmaceutical product of claim 21, wherein the pH is from 5.8 to 6.2.

23. The pharmaceutical product of claim 22, wherein the dose is from about 0.5 mg to about 3 mg per kg of patient body weight.

24. The pharmaceutical product of claim 23, wherein the dose is from about 1 mg to about 2 mg per kg of patient body weight.

25. The pharmaceutical product of claim l6, wherein the 3D6 antibody is present at a concentration of from about 17 mg/ml to about 23 mg/ml.

26. A stable formulation, comprising:

(a) a humanized version of monoclonal antibody 3D6 at a concentration of about 20 mg/ml, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

(b) L-histidine at a concentration of about 10 mM;

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

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

(e) polysorbate-80 in an amount of about 0.005% w/v,

wherein the formulation has a pH of about 6.0.

27. A stable unit dosage form, comprising:

(a) a humanized version of monoclonal antibody 3D6 in an amount of about 100 mg, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

(b) L-histidine at a concentration of about 10 mM;

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

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

(e) polysorbate-80 in an amount of about 0.005% w/v,

wherein the formulation has a pH of about 6.0.

28. A pharmaceutical product, comprising:

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

(a) a humanized version of monoclonal antibody 3D6 in an amount of about 100 mg, wherein the humanized 3D6 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain comprising the amino acid sequence of residues 1-448 of SEQ ID NO;

2;

(b) L-histidine at a concentration of about 10 mM;

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

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

(e) polysorbate-80 in an amount of about 0.005% w/v,

wherein the formulation has a pH of from about 5.5 to about 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 about 0.5 mg to about 3 mg per kg of patient body weight.