Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies

1. A pen delivery device containing a stable liquid 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 pen delivery device of claim 1 , wherein the human antibody is present at a concentration of 150 mg/ml±25 mg/ml.

3. The pen delivery device of claim 1 , wherein the human antibody is present at a concentration of about 150 mg/ml.

4. The pen delivery device of claim 1 , wherein the human antibody is present at a concentration of about 175 mg/ml.

5. The pen delivery device 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.

6. The pen delivery device of claim 1 , wherein the polysorbate is polysorbate 20 or polysorbate 80.

7. The pen delivery device of claim 6 , wherein the polysorbate is polysorbate 20 at a concentration of 0 . 2 %±0.03% w/v.

8. The pen delivery device of claim 6 , wherein the polysorbate is polysorbate 80 at a concentration of 0.2%±0.03% w/v.

9. The pen delivery device of claim 1 , wherein the sucrose is present at a concentration of 5%±0.75% w/v.

10. The pen delivery device of claim 1 , wherein the arginine is present at a concentration of 25 mM±3.75 mM.

11. The pen delivery device of claim 1 , wherein the arginine is present at a concentration of 50 mM±7.5 mM.

12. The pen delivery device of claim 1 , wherein the viscosity of the liquid is less than 15 cPoise.

13. The pen delivery device of claim 12 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise.

14. The pen delivery device of claim 1 , wherein the osmolality of the liquid is 290±20 mOsm/kg.

15. The pen delivery device 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.

16. The pen delivery device of claim 1 , containing from about 1 ml to about 2.5 ml of the stable liquid pharmaceutical formulation.

17. The pen delivery device of claim 1 , containing 1 ml±0.15 ml of the stable liquid pharmaceutical formulation.

18. The pen delivery device of claim 1 , wherein the pen delivery device is a disposable pen delivery device that is prefilled with the stable liquid pharmaceutical formulation.

19. A pen delivery device containing a stable liquid 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.

20. The pen delivery device of claim 19 , wherein the human antibody is present at a concentration of about 150 mg/ml.

21. The pen delivery device of claim 19 , wherein the pen delivery device is a disposable pen delivery device that is prefilled with the stable liquid pharmaceutical formulation.

22. A pen delivery device containing a stable liquid 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.

23. The pen delivery device of claim 22 , wherein the human antibody is present at a concentration of about 175 mg/ml.

24. The pen delivery device of claim 22 , wherein the pen delivery device is a disposable pen delivery device that is prefilled with the stable liquid pharmaceutical formulation.

25. An autoinjector delivery device containing a stable liquid 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.

26. The autoinjector delivery device of claim 25 , wherein the human antibody is present at a concentration of 150 mg/ml±25 mg/ml.

27. The autoinjector delivery device of claim 25 , wherein the human antibody is present at a concentration of about 150 mg/ml.

28. The autoinjector delivery device of claim 25 , wherein the human antibody is present at a concentration of about 175 mg/ml.

29. The autoinjector delivery device of claim 25 , 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.

30. The autoinjector delivery device of claim 25 , wherein the polysorbate is polysorbate 20 or polysorbate 80.

31. The autoinjector delivery device of claim 30 , wherein the polysorbate is polysorbate 20 at a concentration of 0.2%±0.03% w/v.

32. The autoinjector delivery device of claim 30 , wherein the polysorbate is polysorbate 80 at a concentration of 0.2%±0.03% w/v.

33. The autoinjector delivery device of claim 25 , wherein the sucrose is present at a concentration of 5%±0.75% w/v.

34. The autoinjector delivery device of claim 25 , wherein the arginine is present at a concentration of 25 mM±3.75 mM.

35. The autoinjector delivery device of claim 25 , wherein the arginine is present at a concentration of 50 mM±7.5 mM.

36. The autoinjector delivery device of claim 25 , wherein the viscosity of the liquid is less than 15 cPoise.

37. The autoinjector delivery device of claim 36 , wherein the viscosity of the liquid is 11±1.1 cPoise or 8.5±0.85 cPoise.

38. The autoinjector delivery device of claim 25 , wherein the osmolality of the liquid is 290±20 mOsm/kg.

39. The autoinjector delivery device of claim 25 , 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.

40. The autoinjector delivery device of claim 25 , containing from about 1 ml to about 2.5 ml of the stable liquid pharmaceutical formulation.

41. The autoinjector delivery device of claim 25 , containing 1 ml±0.15 ml of the stable liquid pharmaceutical formulation.

42. An autoinjector delivery device containing a stable liquid 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.

43. The autoinjector delivery device of claim 42 , wherein the human antibody is present at a concentration of about 150 mg/ml.

44. An autoinjector delivery device containing a stable liquid 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.

45. The autoinjector delivery device of claim 44 , wherein the human antibody is present at a concentration of about 175 mg/ml.