Antibody formulation

• US 6,171,586 B1
• Filed: 06/12/1998
• Issued: 01/09/2001
• Est. Priority Date: 06/13/1997
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Wong, Rita L., Weissburg, Robert P., Shahrokh, Zahra, Oeswein, James Q., Lam, Xanthe M., Wang, Sharon X., Ongpipattanakul, Boonsri
• Primary Examiner(s): Nolan, Patrick
• Assistant Examiner(s): DiBrino, Marianne
• Application Number:
  US09/097,171
• Time in Patent Office: 942 Days
• Field of Search: 424/130.1, 424/152.1, 424/136.1, 424/141.1, 424/154.1, 424/173.1, 424/133.1, 530/388.75
• US Class Current: 424/130.1
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: C07K 16/2845 against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/54 F(ab')2

Abstract

A stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol is described, along with uses for such a formulation.

Claims

1. A stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, an acetate buffer from about pH 4.8 to about 5.5, a surfactant and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.

2. The formulation of claim 1 which is isotonic.

3. The formulation of claim 1 which is stable at a temperature of about 2-8°

C. for at least one year.

4. The formulation of claim 1 which is stable following freezing and thawing of the formulation.

5. The formulation of claim 1 which is stable at about 30°

C. for at least one month.

6. The formulation of claim 1 wherein the polyol is a nonreducing sugar.

7. The formulation of claim 6 wherein the nonreducing sugar is trehalose.

8. The formulation of claim 6 wherein the nonreducing sugar is sucrose.

9. The formulation of claim 1 wherein the antibody is an antibody fragment.

10. The formulation of claim 9 wherein the antibody fragment is a F(ab′

)₂.

11. The formulation of claim 1 wherein the antibody binds CD18.

12. The formulation of claim 1 which is stable at a temperature of about 2-8°

C. for at least two years.

13. The formulation of claim 1 wherein the antibody concentration in the formulation is from about 0.1 to about 50 mg/mL.

14. The formulation of claim 1 wherein the surfactant is a polysorbate.

15. The formulation of claim 1 wherein the antibody binds CD20.

16. The formulation of claim 15 wherein the acetate is present in an amount of about 5-30 mM.

17. The formulation of claim 16 wherein the acetate is present in an amount of 10-30 mM.

18. The formulation of claim 15 further comprising a preservative.

19. The formulation of claim 18 wherein the preservative is benzyl alcohol.

20. The formulation of claim 15 wherein the antibody is present in an amount of about 30-50 mg/mL.

21. The formulation of claim 20 wherein the buffer is 10-30 mM sodium acetate at pH 5, the polyol is trehalose in an amount of about 2-10% w/v, the surfactant is polysorbate in an amount of about 0.01-0.1% v/v, wherein the formulation further comprises benzyl alcohol as a preservative and wherein the formulation is stable at a temperature of about 2-8°

C. for at least two years.

28. The formulation of claim 1, wherein the acetate buffer is at pH 5.0.

29. The formulation of claim 28, wherein the antibody binds CD20.

22. An article of manufacture comprising a container holding a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, an acetate buffer from about pH 4.8 to about 5.5, a surfactant and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.

23. A method for stabilizing an antibody in an aqueous pharmaceutical formulation by combining a therapeutically effective amount of an antibody not subjected to prior lyophilization, an acetate buffer from about pH 4.8 to about 5.5, a surfactant and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.

24. A stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, a 10-30 mM acetate buffer at pH 5.0, a surfactant, and trehalose at a concentration of at least 134 mM, wherein the formulation lacks a tonicifying amount of sodium chloride.

25. The formulation of claim 24 wherein the antibody binds CD18 or CD20.

26. The formulation of claim 25 wherein the CD18 binding antibody is a F(ab′

)₂ fragment.

27. An article of manufacture comprising a container holding the formulation of claim 25.