Antagonist anti-CD40 antibody pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-8945564-B2
Application number	US-29738207-A
Country	US
Kind code	B2
Filing date	Apr 17, 2007
Priority date	Apr 21, 2006
Publication date	Feb 3, 2015
Grant date	Feb 3, 2015

Abstract

Stable liquid pharmaceutical compositions comprising an antagonist anti-CD40 antibody as a therapeutically or prophylactically active component and methods useful in their preparation are provided. These compositions comprise the antagonist anti-CD40 antibody, a buffering agent to maintain the pH of the composition between about pH 5.0 and about pH 7.0, and an amount of arginine-HCl sufficient to render the liquid composition near isotonic. The stable liquid antagonist anti-CD40 antibody-containing pharmaceutical compositions of the invention find use in methods for treating proliferative diseases and diseases having an autoimmune and/or inflammatory component.

First claim

That which is claimed:

1. A stable liquid pharmaceutical composition comprising:
a) an antagonist anti-CD40 monoclonal antibody as a therapeutically or prophylactically active component, wherein said monoclonal antibody is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell;
b) an amount of an isotonizing agent sufficient to render said composition as having an osmolality of about 240 mmol/kg to about 360 mmol/kg, wherein said isotonizing agent is arginine in its acidic form (arginine-HCl), and wherein said composition does not include NaCl as an additional isotonizing agent; and
c) a buffering agent to maintain the pH of said composition within a range from about pH 5.0 to about pH 7.0, wherein said buffering agent is a citrate/citric acid buffer;
wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 0.1 mg/ml to about 50.0 mg/ml and is selected from the group consisting of:
i) a monoclonal antibody comprising the variable and constant region sequences shown in SEQ ID NO:2 and the variable and constant region sequences shown in SEQ ID NO:4;
ii) a monoclonal antibody comprising the variable and constant region sequences shown in SEQ ID NO:2 and the variable and constant region sequences shown in SEQ ID NO:5;
iii) a monoclonal antibody comprising the leader, variable and constant region sequences shown in SEQ ID NO:2 and the leader, variable and constant region sequences shown in SEQ ID NO:4; and
iv) a monoclonal antibody comprising the leader, variable and constant region sequences shown in SEQ ID NO:2 and the leader, variable and constant region sequences shown in SEQ ID NO:5;

wherein the concentration of said buffering agent is about 5 mM to about 100 mM, and wherein said composition comprises arginine-HCl at a concentration of about 50 mM to about 200 mM.

2. The composition of claim 1 , wherein the concentration of said buffering agent is about 5 mM to about 20 mM.

3. The composition of claim 2 , wherein the concentration of said buffering agent is about 10 mM.

4. The composition of claim 1 , wherein said buffering agent is a sodium citrate/citric acid buffer.

5. The composition of claim 4 , wherein said composition has a pH of about pH 5.5.

6. The composition of claim 1 , wherein said composition comprises arginine-HCl at a concentration of about 100 mM to about 175 mM.

7. The composition of claim 6 , wherein said composition comprises arginine-HCl at a concentration of about 150 mM.

8. The composition of claim 1 , wherein said buffering agent is a sodium citrate/citric acid buffer, and wherein the concentration of said buffering agent is about 10 mM, and said composition has a pH of about pH 5.5.

9. The composition of claim 8 , wherein said composition comprises arginine-HCl at a concentration of about 150 mM.

10. The composition of claim 1 , further comprising a surfactant.

11. The composition of claim 10 , wherein said surfactant is polysorbate 20.

12. The composition of claim 11 , wherein said surfactant is polysorbate 20 at a concentration of about 0.001% to about 1.0% (w/v).

13. The composition of claim 12 , wherein said composition comprises polysorbate 20 at a concentration of about 0.025% to about 0.1% (w/v).

14. The composition of claim 1 , further comprising methionine in an amount sufficient to inhibit oxidation of at least one oxidizable amino acid residue in said anti-CD40 monoclonal antibody during storage of said composition.

15. The composition of claim 14 , wherein said composition comprises methionine at a concentration of about 0.5 mM to about 20.0 mM.

16. The composition of claim 15 , wherein said composition comprises methionine at a concentration of about 1.0 mM to about 20.0 mM.

17. The composition of claim 16 , wherein said composition comprises methionine at a concentration of about 5.0 mM.

18. The composition of claim 1 , wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 1.0 mg/ml to about 35.0 mg/ml.

19. The composition of claim 18 , wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 10.0 mg/ml to about 35.0 mg/ml.

20. The composition of claim 1 , wherein said composition is stable at a temperature of about 2° C. to about 8° C. for a period of at least 18 months.

21. The composition of claim 1 , wherein said composition is stable at about 25° C. for a period of at least 3 months.

22. The composition of claim 1 , wherein said composition comprises arginine-HCl at a concentration of about 150 mM, and the buffering agent is sodium citrate/citric acid at a concentration of about 5 mM to about 20 mM, wherein said composition has a pH of about 5.0 to about 6.0 and an osmolality of about 250 mmol/kg to about 330 mmol/kg.

23. The composition of claim 1 , wherein said composition further comprises methionine, polysorbate 20, or both methionine and polysorbate 20, wherein said methionine when present is present in said composition at a concentration of about 0.5 mM to about 20.0 mM, and wherein said polysorbate 20 when present is present in said composition at a concentration of about 0.025% to about 0.1% (w/v).

24. The composition of claim 22 , wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 10.0 mg/ml to about 35.0 mg/ml.

25. The composition of claim 24 , wherein said antagonist anti-CD40 monoclonal antibody is the monoclonal antibody CHIR-12.12 produced by the hybridoma cell line deposited with the ATCC as Patent Deposit No. PTA-5543.

26. A method for increasing stability of an anti-CD40 monoclonal antibody in a liquid pharmaceutical composition, said method comprising formulating said composition by combining said anti-CD40 monoclonal antibody, an amount of an isotonizing agent sufficient to render to said composition as having an osmolality of about 240 mmol/kg to about 360 mmol/kg, wherein said isotonizing agent is arginine in its acidic form (arginine-HCl) and wherein said composition does not include NaCl as an additional isotonizing agent, and a buffering agent to maintain the pH of said composition between about pH 5.0 and about pH 7.0, wherein said buffering agent is a citrate/citric acid buffer, and wherein said anti-CD40 monoclonal antibody is present in said composition at a concentration of about 0.1 mg/ml to about 50.0 mg/ml and is selected from the group consisting of:
i) a monoclonal antibody comprising the variable and constant region sequences shown in SEQ ID NO:2 and the variable and constant region sequences shown in SEQ ID NO:4;
ii) a monoclonal antibody comprising the variable and constant region sequences shown in SEQ ID NO:2 and the variable and constant region sequences shown in SEQ ID NO:5;
iii) a monoclonal antibody comprising the leader, variable and constant region sequences shown in SEQ ID NO:2 and the leader, variable and constant region sequences shown in SEQ ID NO:4; and
iv) a monoclonal antibody comprising the leader, variable and constant region sequences shown in SEQ ID NO:2 and the leader, variable and constant region sequences shown in SEQ ID NO:5;
wherein the concentration of said buffering agent is abo

Assignees

• Lu Xiaofeng
• Chen Bao-Lu
• Araya Kidisti
• Okhamafe Augustus
• Novartis Ag
• Xoma Technology Ltd

Inventors

• Lu Xiaofeng
• Chen Bao-Lu
• Araya Kidisti
• Okhamafe Augustus

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/06

  Antianaemics · CPC title