Stabilized formulations containing anti-PCSK9 antibodies

• US 9,193,801 B2
• Filed: 06/30/2014
• Issued: 11/24/2015
• Est. Priority Date: 07/28/2011
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Walsh, Scott M., Dix, Daniel B.
• Primary Examiner(s): Ford, Vanessa L.
• Assistant Examiner(s): DILLAHUNT, SANDRA E
• Application Number:
  US14/319,730
• Publication Number:
  US 20140341928A1
• Time in Patent Office: 512 Days
• Field of Search: None
• US Class Current: 1/1
• 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 pre-filled syringe composition comprising a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises:

(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;

wherein said liquid pharmaceutical formulation is contained within a syringe.

2. The pre-filled syringe composition of claim 1, wherein the syringe is a normal tungsten syringe.

3. The pre-filled syringe composition of claim 1, wherein the syringe is a low tungsten syringe.

4. The pre-filled syringe composition of claim 1, wherein the syringe comprises a coated plunger.

5. The pre-filled syringe composition of claim 4, wherein the coated plunger is coated with a fluorocarbon film.

6. The pre-filled syringe composition of claim 1, wherein the syringe is a low tungsten syringe, and wherein the syringe comprises a coated plunger.

7. The pre-filled syringe composition of claim 1, wherein the syringe is a 1 mL long glass syringe comprising a 27 gauge thin wall needle, a fluorocarbon coated rubber plunger, and a rubber needle shield.

8. The pre-filled syringe composition 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.

9. The pre-filled syringe composition of claim 1, wherein:

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

1 kDa;

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

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

10. The pre-filled syringe composition of claim 1, wherein at least 91% of the antibody has native conformation after 28 days at 45°

C.

11. The pre-filled syringe composition of claim 1, wherein at least 35% of the antibody is the main charge variant of the antibody after 28 days at 45°

C.

12. The pre-filled syringe composition of claim 1, wherein at least 94% of the antibody has native conformation after six months at 25°

C.

13. The pre-filled syringe composition of claim 1, wherein at least 45% of the antibody is the main charge variant of the antibody after six months at 25°

C.

14. The pre-filled syringe composition of claim 1, wherein at least 96% of the antibody has native conformation after six months at 5°

C.

15. The pre-filled syringe composition of claim 1, wherein at least 58% of the antibody is the main charge variant of the antibody after six months at 5°

C.

16. The pre-filled syringe composition 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.

17. The pre-filled syringe composition 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.

18. The pre-filled syringe composition of claim 1, wherein the formulation comprises about 175 mg/mL of the antibody.

19. The pre-filled syringe composition of claim 1, wherein the formulation comprises about 150 mg/mL of the antibody.

20. The pre-filled syringe composition of claim 1, wherein the formulation comprises about 100 mg/mL of the antibody.

21. The pre-filled syringe composition of claim 1, wherein the formulation comprises about 75 mg/mL of the antibody.

22. The pre-filled syringe composition of claim 1, wherein the formulation comprises about 50 mg/mL of the antibody.