Stabilized formulations containing anti-DLL4 antibodies

• US 9,675,692 B2
• Filed: 05/31/2013
• Issued: 06/13/2017
• Est. Priority Date: 05/31/2012
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Walsh, Scott, Dix, Daniel
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US13/906,479
• Publication Number:
  US 20130323260A1
• Time in Patent Office: 1,474 Days
• Field of Search: None
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention provides pharmaceutical formulations comprising an antibody that specifically binds to human delta-like ligand 4 (Dll4). The formulations may contain, in addition to an anti-Dll4 antibody, a phosphate buffer, an organic cosolvent, a disaccharide, and a salt. 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 pharmaceutical formulation consisting of

(a) 25 mg/mL±

3.75 mg/mL of an anti-Dll4 antibody comprising the HCVD of SEQ ID NO;

1 and the LCVD of SEQ ID NO;

5,

(b) 10 mM±

3 mM phosphate, pH 6±

0.5,

(c) 0.2%±

0.03% polysorbate 20,

(d) 150 mM±

22.5 mM sodium chloride, and

(e) 10%±

1.5% sucrose, in water

wherein the antibody a molecular weight of about 150 kDa; and

about 82% to about 87% of the antibodies are fucosylated.

2. A pharmaceutical composition of claim 1, wherein said composition is contained in a container.

3. The pharmaceutical composition of claim 2, wherein the container is a vial.

4. The pharmaceutical composition of claim 3, wherein the vial is glass.

5. The pharmaceutical composition of claim 2, wherein the container is an IV drip bag.

6. The pharmaceutical composition of claim 5, wherein the bag is made of polyvinyl chloride.

7. The pharmaceutical composition of claim 5, wherein the bag is made of poly olefin.

8. A kit comprising a pharmaceutical composition of claim 1, a container, and instructions.

9. The kit of claim 8, wherein the container is a glass vial fitted with a fluorocarbon-coated 4023/50 rubber stopper.

10. The pharmaceutical formulation of claim 1, wherein after 28 days of storage at 45°

C., at least 94% of the antibody has native conformation, or at least 45% of the antibody is the main charge form.

11. The pharmaceutical formulation of claim 1, wherein after 28 days of storage at 25°

C., at least 97% of the antibody has native conformation, or at least 57% of the antibody is the main charge form.

12. The pharmaceutical formulation of claim 1, wherein after 28 days of storage at 37°

C., at least 97% of the antibody has native conformation, or at least 51% of the antibody is the main charge form.

13. The pharmaceutical formulation of claim 1, wherein after six months of storage at 5°

C., at least 98% of the antibody has native conformation, at least 61% of the antibody is the main charge form, or the antibody retains about 100% of the potency of the antibody prior to storage.

14. The pharmaceutical formulation of claim 1, wherein after six months of storage at −

80°

C., at least 99% of the antibody has native conformation, at least 57% of the antibody is the main charge form, or the antibody retains about 100% of the potency of the antibody prior to storage.

15. The pharmaceutical formulation of claim 1, wherein after six months of storage at −

30°

C., at least 99% of the antibody has native conformation, at least 57% of the antibody is the main charge variant, or the antibody retains at least 65% of the potency of the antibody prior to storage.

16. The pharmaceutical formulation of claim 1, wherein after six months of storage at −

20°

C., at least 98% of the antibody has native conformation, at least 60% of the antibody is the main charge variant, or the antibody retains about 100% of the potency of the antibody prior to storage.