Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies
The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-4 receptor (hIL-4R). The formulations may contain, in addition to an anti-hIL-4R 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.
1. A stable pharmaceutical formulation comprising:
(i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα) and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5;
(ii) acetate at a concentration of from 10 mM to 15 mM;
(iii) histidine at a concentration of from 15 mM to 25 mM;
(iv) sucrose at a concentration of from 2.5% w/v to 10% w/v;
(v) polysorbate at a concentration of from 0.1% w/v to 0.3% w/v; and
(vi) arginine at a concentration of from 20 mM to 100 mM, wherein the formulation has a pH of from 5.6 to 6.2.
2. The pharmaceutical formulation of claim 1 , wherein the acetate is present at a concentration of 12.5 mM±1.85 mM and the histidine is present at a concentration of 20 mM±0.3 mM.
3. The pharmaceutical formulation of claim 1 , wherein the polysorbate is polysorbate 20, or polysorbate 80.
4. The pharmaceutical formulation of claim 3 , wherein the polysorbate is polysorbate 20 at a concentration of 0.2%±0.03% w/v.
5. The pharmaceutical formulation of claim 3 , wherein the polysorbate is polysorbate 80 at a concentration of 0.2%±0.03% w/v.
6. The pharmaceutical formulation of claim 1 , wherein the sucrose is present at a concentration of 5%±0.75% w/v.
7. The pharmaceutical formulation of claim 1 , wherein the arginine is present at a concentration of 25 mM±3.75 mM.
8. The pharmaceutical formulation of claim 1 , wherein the arginine is present at a concentration of 50 mM±7.5 mM.
9. The pharmaceutical formulation of claim 1 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise.
10. The pharmaceutical formulation of claim 1 , wherein the osmolality of the liquid is 290±20 mOsm/kg.
11. The pharmaceutical formulation of claim 1 , wherein:
(a) at least about 98% of the native form of the antibody is recovered after about six months of storage at about 5° C., as determined by size exclusion chromatography;
(b) at least about 90% of the native form of the antibody is recovered after about eight weeks of storage at about 45° C., as determined by size exclusion chromatography;
(c) less than about 45% of the antibody recovered after about eight weeks of storage at about 45° C. is an acidic form, as determined by cation exchange chromatography; or
(d) less than about 4% of the antibody recovered after six months of storage at 25° C. is aggregated, as determined by size exclusion exchange chromatography.
12. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is contained in a glass vial.
13. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is contained in a syringe.
14. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is contained in a microinfusor.
15. The pharmaceutical formulation of claim 13 , wherein the syringe comprises a fluorocarbon-coated plunger.
16. The pharmaceutical formulation of claim 13 , wherein the syringe is a low tungsten syringe.
17. A stable pharmaceutical formulation comprising:
(i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to hIL-4Rα, and comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:1/5;
(ii) 12.5 mM±2 mM acetate;
(iii) 20 mM±3 mM histidine;
(iv) 5%±0.75% sucrose;
(v) 0.2%±0.03% polysorbate 20; and
(vi) 25 mM±3.75 mM arginine,
at a pH of 5.9±0.5.
18. The pharmaceutical formulation of claim 17 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise, and the osmolality of the liquid is 290±20 mOsm/kg.
19. The pharmaceutical formulation of claim 17 , wherein:
(a) at least about 98% of the native form of the antibody is recovered after six months of storage at 5° C., as determined by size exclusion chromatography;
(b) at least about 90% of the native form of the antibody is recovered after eight weeks of storage at 45° C., as determined by size exclusion chromatography;
(c) less than about 45% of the antibody recovered after eight weeks of storage at 45° C. is an acidic form, as determined by cation exchange chromatography; or
(d) less than about 4% of the antibody recovered after six months of storage at 25° C. is aggregated, as determined by size exclusion exchange chromatography.
20. A stable pharmaceutical formulation comprising:
(i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to hIL-4Rα, and comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:1/5;
(ii) 12.5 mM±2 mM acetate;
(iii) 20 mM±3 mM histidine;
(iv) 5%±0.75% sucrose;
(v) 0.2%±0.03% polysorbate 80; and
(vi) 50 mM±3.75 mM arginine,
at a pH of 5.9±0.5.
21. A stable pharmaceutical formulation comprising:
(i) a human antibody at a concentration of from 15 mg/ml to 200 mg/ml, wherein the antibody specifically binds to hIL-4Rα, and comprises a heavy chain and light chain variable region (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs:1/5;
(ii) 12.5 mM±2 mM acetate;
(iii) 20 mM±3 mM histidine;
(iv) 5%±0.75% sucrose;
(v) 0.2%±0.03% polysorbate 80; and
(vi) 25 mM±3.75 mM arginine,
at a pH of 5.9±0.5.