Stabilized formulations containing anti-PCSK9 antibodies

• US 8,795,669 B2
• Filed: 07/27/2012
• Issued: 08/05/2014
• Est. Priority Date: 07/28/2011
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Walsh, Scott, Dix, Daniel
• Primary Examiner(s): Ford, Vanessa L
• Assistant Examiner(s): DILLAHUNT, SANDRA E
• Application Number:
  US13/559,862
• Publication Number:
  US 20130189277A1
• Time in Patent Office: 739 Days
• Field of Search: None
• US Class Current: 424/158.1
• 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 47/22 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: A61M 5/31513 Piston constructions to improve sealing or sliding
• CPC Class Codes: A61M 5/3202 Devices for protection of the needle before use, e.g. caps A61M5/50 takes precedence; for infusion spikes A61M5/1626; protectors for sharps A61B50/3001
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9). The formulations may contain, in addition to an anti-PCSK9 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.

Claims

1. A liquid pharmaceutical formulation comprising:

(a) 50±

7.5 mg/mL to 250±

37.5 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO;

2, an HCDR2 of SEQ ID NO;

3, an HCDR3 of SEQ ID NO;

4, a light chain complementarity determining region (LCDR) 1 of SEQ ID NO;

6, an LCDR2 of SEQ ID NO;

7, and an LCDR3 of SEQ ID NO;

8;

(b) 10±

1.5 mM histidine (pH 6.0±

0.3);

(c) 0.01±

0.0015% w/v polysorbate 20; and

(d) 10±

1.5% sucrose.

2. The liquid pharmaceutical formulation of claim 1, wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:

1, and a light chain variable domain (LCVD) comprising SEQ ID NO;

5.

3. The liquid pharmaceutical formulation of claim 1, wherein:

over 90% of the antibodies have a molecular weight of 155 kpa±

1 kpa;

over 50% of the antibodies have an isoelectric point of about 8.5; and

from 75% to 90% of the antibodies are fucosylated.

4. The liquid pharmaceutical formulation of claim 1, wherein at least 91% of the antibody has native conformation after 28 days at 45°

C.

5. The liquid pharmaceutical formulation of claim 1, wherein at least 35% of the antibody is the main charge variant of the antibody after 28 days at 45°

C.

6. The liquid pharmaceutical formulation of claim 1, wherein at least 94% of the antibody has native conformation after six months at 25°

C.

7. The liquid pharmaceutical formulation of claim 1, wherein at least 45% of the antibody is the main charge variant of the antibody after six months at 25°

C.

8. The liquid pharmaceutical formulation of claim 1, wherein at least 96% of the antibody has native conformation after six months at 5°

C.

9. The liquid pharmaceutical formulation of claim 1, wherein at least 58% of the antibody is the main charge variant of the antibody after six months at 5°

C.

10. The liquid pharmaceutical formulation of claim 1, wherein at least 96% of the antibody is the main charge variant of the antibody after three months at −

20°

C., −

30°

C., or −

80°

C.

11. The liquid pharmaceutical formulation of claim 1, wherein at least 56% of the antibody is the main charge variant of the antibody after three months at −

20°

C., −

30°

C., or −

80°

C.

12. The liquid formulation of claim 1, wherein the formulation comprises about 175 mg/mL of the antibody.

13. The liquid formulation of claim 1, wherein the formulation comprises about 150 mg/mL of the antibody.

14. The liquid formulation of claim 1, wherein the formulation comprises about 100 mg/mL of the antibody.

15. The liquid formulation of claim 1, wherein the formulation comprises about 75 mg/mL of the antibody.

16. The liquid formulation of claim 1, wherein the formulation comprises about 50 mg/mL of the antibody.