Antibody formulations

• US 8,372,396 B2
• Filed: 09/04/2009
• Issued: 02/12/2013
• Est. Priority Date: 10/20/2004
• Status: Active Grant

• Current Assignee: Genetec Incorporated (Noritsu Koki Co., Ltd.)
• Original Assignee: Genetec Incorporated (Noritsu Koki Co., Ltd.)
• Inventors: Andya, James, Gwee, Shiang C., Liu, Jun, Shen, Ye
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US12/554,194
• Publication Number:
  US 20100015157A1
• Time in Patent Office: 1,257 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present application describes antibody formulations, including monoclonal antibodies formulated in histidine-acetate buffer, as well as a formulation comprising an antibody that binds to domain II of HER2 (for example, Pertuzumab), and a formulation comprising an antibody that binds to DR5 (for example, Apomab).

Claims

1. A pharmaceutical formulation comprising an antibody that binds to domain II of HER2 in a histidine-acetate buffer at a pH from about 5.5 to about 6.5, a saccharide, and a surfactant, wherein the antibody concentration is from 20 mg/mL to 40 mg/mL, the antibody comprises the variable light and variable heavy amino acid sequences in SEQ ID Nos. 3 and 4, respectively, the saccharide is sucrose at a concentration from about 60 mM to about 250 mM, and the surfactant is polysorbate 20 at a concentration from about 0.01% to about 0.1%.

2. The formulation of claim 1 wherein the HER2 antibody comprises a light chain amino acid sequence selected from SEQ ID No. 15 and 23, and a heavy chain amino acid sequence selected from SEQ ID No. 16 and 24.

3. The formulation of claim 1 wherein the pH of the formulation is from about 5.8 to about 6.2.

4. The formulation of claim 1 wherein the antibody binds to the junction between domains I, II and III of HER2.

5. The formulation of claim 1 wherein the antibody is a full length antibody.

6. The formulation of claim 1 which is aqueous and has not been subjected to prior lyophilization, and is administered to a subject.

9. A vial with a stopper pierceable by a syringe comprising the formulation of claim 1.

10. A stainless steel tank comprising the formulation of claim 1 in the tank.

13. A method of making a pharmaceutical formulation comprising:

(a) preparing the formulation of claim 1; and

(b) evaluating physical stability, chemical stability, or biological activity of the HER2 antibody in the formulation.

14. The formulation of claim 5 wherein the antibody is an IgG1 antibody.

15. The formulation of claim 1 wherein the antibody is a humanized antibody.

16. The formulation of claim 1 wherein the formulation is adapted for intravenous administration.

17. The formulation of claim 1 which is not lyophilized and has not been subjected to prior lyophilization.

18. The formulation of claim 17 which is aqueous.

19. The formulation of claim 18 which is administered to a subject.

20. The formulation of claim 17 which is frozen.

21. The formulation of claim 1 wherein the antibody is Pertuzumab.

22. The formulation of claim 1 which is sterile.

23. The formulation of claim 1 which is stable upon storage at about 40°

C. for at least 4 weeks.

24. The formulation of claim 1 which is stable upon storage at about 5°

C. or about 15°

C. for at least 3 months.

25. The formulation of claim 1 which is stable upon storage at about −

20°

C. for at least 3 months.

26. The formulation of claim 1 which is stable upon freezing and thawing.

7. A pharmaceutical formulation comprising Pertuzumab in an amount from 20 mg/mL to 40 mg/mL, histidine-acetate buffer, sucrose, and polysorbate 20, wherein the pH of the formulation is from about 5.5 to about 6.5.

8. The formulation of claim 7 comprising about 30 mg/mL Pertuzumab, about 20 mM histidine-acetate about 120 mM sucrose, and about 0.02% polysorbate 20, wherein the pH of the formulation is about 6.0.

11. An aqueous pharmaceutical formulation which has not been subjected to prior lyophilization, for intravenous administration to a human patient, comprising about 30 mg/mL Pertuzumab, about 20 mM histidine-acetate, about 120 mM sucrose, and about 0.02% polysorbate 20, wherein the pH of the formulation is about 6.0.

12. A vial with a stopper pierceable by a syringe comprising the formulation of claim 11.

27. An aqueous pharmaceutical formulation adapted for intravenous administration comprising Pertuzumab at concentration from 20 mg/mL to 40 mg/mL, saccharide, surfactant, and histidine-acetate buffer, wherein the pH of the formulation is from about 5.8 to about 6.2.