Stabilized formulations containing anti-interleukin-6 receptor (IL-6R) antibodies

• US 10,072,086 B2
• Filed: 09/22/2015
• Issued: 09/11/2018
• Est. Priority Date: 01/08/2010
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Dix, Daniel B., Graham, Kenneth S., Kamen, Douglas, Walsh, Scott M.
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US14/861,565
• Publication Number:
  US 20160002341A1
• Time in Patent Office: 1,085 Days
• Field of Search: None
• CPC Class Codes: A61J 1/065 Rigid ampoules, e.g. glass ampoules
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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: 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: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• 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 interleukin-6 receptor (hIL-6R). The formulations may contain, in addition to an anti-hIL-6R antibody, at least one amino acid, at least one sugar, and/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 stable pharmaceutical formulation comprising:

(i) a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein the antibody is at a concentration of from about 25 mg/ml to about 200 mg/ml and comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO;

18 and a light chain variable region having the amino acid sequence of SEQ ID NO;

26;

(ii) histidine at a concentration of from about 10 mM to about 25 mM;

(iii) arginine at a concentration of from about 25 mM to about 50 mM;

(iv) sucrose in an amount of from about 5% to about 10% w/v; and

(v) polysorbate in an amount of from about 0.1% to about 0.2% w/v, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45°

C., as determined by size exclusion chromatography.

2. The pharmaceutical formulation of claim 1, wherein the histidine is at a concentration of 21 mM.

3. The pharmaceutical formulation of claim 2, wherein the arginine is present at a concentration of 45 mM.

4. The pharmaceutical formulation of claim 3, wherein the sucrose is present in an amount of 5% w/v.

5. The pharmaceutical formulation of claim 4, wherein the polysorbate is present at a concentration of 0.2% w/v.

6. The pharmaceutical formulation of claim 5 that has a pH of 6.

7. The pharmaceutical formulation of claim 1, comprising from 50 mg/mL to 180 mg/mL of the human antibody that specifically binds to hIL-6R.

8. The pharmaceutical formulation of claim 7, comprising 150 mg/mL of said human antibody that specifically binds to hIL-6R.

9. The pharmaceutical formulation of claim 7, comprising 175 mg/mL of said human antibody that specifically binds to hIL-6R.

10. The pharmaceutical formulation of claim 9, wherein at least 90% of the native form of said antibody is recovered after nine months of storage at 5°

C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

11. The pharmaceutical formulation of claim 10, wherein at least 95% of the native form of said antibody is recovered after nine months of storage at 5°

C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

12. The pharmaceutical formulation of claim 11, wherein at least 96% of the native form of said antibody is recovered after nine months of storage at 5°

C., as determined by size exclusion-high performance liquid chromatography (SE-HPLC).

13. The pharmaceutical formulation of claim 9, wherein the formulation exhibits a viscosity of less than about 15 cPoise.

14. The pharmaceutical formulation of claim 9, wherein the formulation exhibits a viscosity of less than about 12 cPoise.

15. The pharmaceutical formulation of claim 9, wherein the formulation exhibits a viscosity of less than about 9 cPoise.

16. The pharmaceutical formulation of claim 1, wherein the formulation is contained in a glass vial.

17. The pharmaceutical formulation of claim 1, wherein the formulation is contained in a syringe.

18. The pharmaceutical formulation of claim 1, wherein the formulation is contained in a microinfusor.

19. The pharmaceutical formulation of claim 17, wherein said syringe comprises a fluorocarbon-coated plunger.

20. The pharmaceutical formulation of claim 17, wherein said syringe is a low tungsten syringe.

26. The pharmaceutical composition of claim 1, wherein the polysorbate is polysorbate 20.

21. A stable pharmaceutical formulation comprising:

(i) 25 to 200 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO;

18 and a light chain variable region having the amino acid sequence of SEQ ID NO;

26;

(ii) about 21, 22, 23, 24 or 25 mM histidine;

(iii) about 3%, 4% or 5% w/v sucrose;

(iv) about 0.18%, 0.19% or 0.2% w/v polysorbate 20; and

(v) about 45 or 50 mM arginine,

wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45°

C., as determined by size exclusion chromatography.

22. A stable pharmaceutical formulation comprising:

(i) about 150 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein said antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs;

18/26;

(ii) about 21 mM histidine;

(iii) about 5% sucrose;

(iv) about 0.2% polysorbate 20; and

(v) about 45 mM arginine,

wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45°

C., as determined by size exclusion chromatography.

23. A stable pharmaceutical formulation comprising:

(i) about 175 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein said antibody comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs;

18/26;

(ii) about 21 mM histidine;

(iii) about 5% sucrose;

(iv) about 0.2% polysorbate 20; and

(v) about 45 mM arginine,

wherein the formulation has a pH of about 6, and at least 90% of the native form of the antibody is recovered after 1 month of storage at 45°

C., as determined by size exclusion chromatography.

24. The pharmaceutical formulation of claim 23, wherein the formulation is contained in a stacked needle prefilled syringe.

25. The pharmaceutical formulation of claim 23, wherein at least 96% of native form of said antibody is recovered after two months of storage at 5°

C., as determined by size exclusion-high performance liquid chromatography.