Stabilized formulations containing anti-Ang2 antibodies

• US 9,402,898 B2
• Filed: 01/22/2013
• Issued: 08/02/2016
• Est. Priority Date: 01/23/2012
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Walsh, Scott M., Dix, Daniel B.
• Primary Examiner(s): Gangle, Brian J
• Assistant Examiner(s): MCCOLLUM, ANDREA K
• Application Number:
  US13/746,669
• Publication Number:
  US 20130186797A1
• Time in Patent Office: 1,288 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61J 1/06 Ampoules or carpules syringe ampoules or carpules A61M5/28
• CPC Class Codes: A61J 1/10 Bag-type containers
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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: B65D 85/00 Containers, packaging elements or packages, specially adapted for particular articles or materials B65D71/00, B65D83/00 take precedence; hand implements or travelling equipment A45C; cosmetic or toiletry equipment A45D; packages for surgical knives, scalpels or blades therefor A61B17/3215; containers specially adapted for medical or pharmaceutical purposes A61J1/00; paint cans B44D3/12; oil cans F16N3/04; containers for carrying small arms F41C33/06; packaging of ammunition or explosive charges F42B39/00; containers for record carriers, specially adapted for cooperation with the recording or reproducing apparatus G11B23/00
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention provides pharmaceutical formulations comprising an antibody that specifically binds to angiopoietin 2 (Ang-2). The formulations may contain, in addition to an anti-Ang-2 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months and after being subjected to thermal and other physical stress.

Claims

1. A stable pharmaceutical formulation comprising:

(i) an antibody at a concentration of from 20±

3 mg/ml to 60±

9 mg/ml that binds specifically to human angiopoietin 2 (human Ang-2), wherein the antibody comprises a heavy chain variable domain (HCVD) having the amino acid sequence of SEQ ID NO;

18 and a light chain variable domain (LCVD) having the amino acid sequence of SEQ ID NO;

20;

(ii) histidine at a concentration of 10±

1.5 mM;

(iii) polysorbate 20 in an amount of 0.2% w/v±

0.03% w/v; and

(iv) sucrose in an amount of 10% w/v±

1.5% w/v,

wherein the formulation has a pH of 6±

0.3, and at least 92% of the antibody has native conformation when the formulation is kept at about 45°

C. for up to about 28 days.

2. The pharmaceutical formulation of claim 1, wherein

(a) over 96% of the antibodies have a molecular weight of 151 kDa±

1 kDa;

(b) at least 53% of the antibodies have an isoelectric point of about 8.13±

0.01; and

(c) from about 90% to about 92% of the antibodies are fucosylated.

3. The pharmaceutical formulation of claim 1, wherein the antibody concentration is about 25 mg/mL±

0.375 mg/mL.

4. The pharmaceutical formulation of claim 1, wherein the antibody concentration is about 50 mg/mL±

7.5 mg/mL.

5. The pharmaceutical formulation of claim 1, wherein at least 93% of the antibody has native conformation after 28 days at 45°

C.

6. The pharmaceutical formulation of claim 1, wherein at least 32% of the antibody is the main charge variant of the antibody after 28 days at 45°

C.

7. The pharmaceutical formulation of claim 1, wherein at least 97% of the antibody has native conformation after 28 days at 25°

C.

8. The pharmaceutical formulation of claim 1, wherein at least 53% of the antibody is the main charge variant of the antibody after 28 days at 25°

C.

9. The pharmaceutical formulation of claim 1, wherein at least 96% of the antibody has native conformation after 28 days at 37°

C.

10. The pharmaceutical formulation of claim 1, wherein at least 45% of the antibody is the main charge variant of the antibody after 28 days at 37°

C.

11. The pharmaceutical formulation of claim 1, wherein at least 97% of the antibody has native conformation after six months at 5°

C.

12. The pharmaceutical formulation of claim 1, wherein at least 55% of the antibody is the main charge variant of the antibody after six months at 5°

C.

13. The pharmaceutical formulation of claim 1, wherein the percent relative potency of the antibody after six months at 5°

C. is at least 100% of the potency of the antibody prior to storage.

14. The pharmaceutical formulation of claim 1, wherein at least 97% of the antibody has native conformation after six months at −

80°

C.

15. The pharmaceutical formulation of claim 1, wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −

80°

C.

16. The pharmaceutical formulation of claim 1, wherein the percent relative potency of the antibody after six months at −

80°

C. is at least 85% of the potency of the antibody prior to storage.

17. The pharmaceutical formulation of claim 1, wherein at least 96% of the antibody has native conformation after six months at −

30°

C.

18. The pharmaceutical formulation of claim 1, wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −

30°

C.

19. The pharmaceutical formulation of claim 1, wherein the percent relative potency of the antibody after six months at −

30°

C. is at least 84% of the potency of the antibody prior to storage.

20. The pharmaceutical formulation of claim 1, wherein at least 96% of the antibody has native conformation after six months at −

20°

C.

21. The pharmaceutical formulation of claim 1, wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −

20°

C.

22. The pharmaceutical formulation of claim 1, wherein the percent relative potency of the antibody after six months at −

20°

C. is at least 90% of the potency of the antibody prior to storage.

27. A pharmaceutical composition comprising the formulation of claim 1, wherein said composition is contained in a container.

28. The pharmaceutical composition of claim 27, wherein the container is a vial.

29. The pharmaceutical composition of claim 28, wherein the vial is glass.

30. The pharmaceutical composition of claim 27, wherein the container is an intravenous drip bag.

31. The pharmaceutical composition of claim 30, wherein the bag is made of polyvinyl chloride.

32. The pharmaceutical composition of claim 30, wherein the bag is made of polyolefin.

33. A kit comprising a pharmaceutical composition of claim 27, and instructions.

34. The kit of claim 33, wherein the container is a glass vial fitted with a fluorocarbon coated rubber stopper.

23. A pharmaceutical formulation comprising (a) 25 mg/mL±

3.75 mg/mL of an anti-Ang-2 antibody, (b) 10 mM±

1.5 mM histidine, pH 6±

0.3, (c) 0.2% w/v±

0.03% polysorbate 20, and (d) 10% w/v±

1.5% sucrose, wherein;

(a) the antibody comprises an HCVD of SEQ ID NO;

18 and an LCVD of SEQ ID NO;

20;

(b) over 96% of the antibodies have a molecular weight of 151 kDa±

1 kDa;

(c) at least 53% of the antibodies have an isoelectric point of about 8.13±

0.01; and

(d) from about 90% to about 92% of the antibodies are fucosylated.

24. The pharmaceutical formulation of claim 23 consisting of (a) 25 mg/mL±

3.75 mg/mL of the antibody, (b) 10 mM±

1.5 mM histidine, pH 6±

0.3, (c) 0.2% w/v±

0.03% polysorbate 20, and (d) 10% w/v±

1.5% sucrose, in water.

25. A pharmaceutical formulation comprising (a) 50 mg/mL±

7.5 mg/mL of an anti-Ang-2 antibody, (b) 10 mM±

1.5 mM histidine, pH 6±

0.3, (c) 0.2% w/v±

0.03% polysorbate 20, and (d) 10% w/v±

1.5% sucrose, wherein;

(a) the antibody comprises an HCVD of SEQ ID NO;

18 and an LCVD of SEQ ID NO;

20;

(b) over 96% of the antibodies have a molecular weight of 151 kDa±

1 kDa;

(c) at least 53% of the antibodies have an isoelectric point of about 8.13±

0.01; and

(d) from about 90% to about 92% of the antibodies are fucosylated.

26. The pharmaceutical formulation of claim 25 consisting of (a) 50 mg/mL±

7.5 mg/mL of the antibody, (b) 10 mM±

1.5 mM histidine, pH 6±

0.3, (c) 0.2% w/v±

0.03% polysorbate 20, and (d) 10% w/v±

1.5% sucrose, in water.