Formulation of human antibodies for treating TNF-α associated disorders
A liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.
1. A liquid aqueous pharmaceutical formulation having a pH of about 4.5 to about 6, comprising an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody, or an antigen-binding portion thereof, at a concentration of 35-115 mg/ml, a polyol, a surfactant, and a buffer system comprising citrate and phosphate, wherein the antibody, or antigen-binding portion thereof, comprises
a light chain variable region comprising a CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO:7; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:5; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO:3; and
a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO:8; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:6; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO:4.
2. The liquid aqueous pharmaceutical formulation of claim 1 , comprising about 45 to 105 mg/ml of the antibody, or antigen-binding portion thereof.
3. The liquid aqueous pharmaceutical formulation of claim 1 , wherein the concentration of the antibody is about 50 mg/ml.
4. The liquid aqueous pharmaceutical formulation of claim 1 , which further is suitable for single use subcutaneous injection.
5. The liquid aqueous pharmaceutical formulation of claim 1 , wherein the antibody, or antigen-binding portion thereof, has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
6. The liquid aqueous pharmaceutical formulation of claim 1 , wherein the antibody, or antigen-binding portion thereof, is the antibody D2E7 or an antigen binding portion thereof.
7. The liquid aqueous pharmaceutical formulation of claim 1 , wherein the polyol is a sugar alcohol.
8. The liquid aqueous pharmaceutical formulation of claim 7 , wherein the sugar alcohol is mannitol.
9. The liquid aqueous pharmaceutical formulation of claim 1 , wherein the surfactant is a polysorbate.
10. A liquid aqueous pharmaceutical formulation comprising
(a) 35-115 mg/ml of an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody, or an antigen-binding portion thereof,
(b) 5-20 mg/ml of mannitol,
(c) 0.1-10 mg/ml of polysorbate-80, and
(d) a buffer system comprising citrate and phosphate, with a pH of 4.5 to 6.0,
wherein the antibody, or antigen-binding portion thereof, comprises
a light chain variable region comprising a CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO:7; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:5; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO:3; and
a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO:8; a CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:6; and a CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO:4.
11. The liquid aqueous pharmaceutical formulation of claim 10 , wherein the pH is between about 4.8 to about 5.5.
12. The liquid aqueous pharmaceutical formulation of claim 10 , which contains
(a) about 50 mg/ml of the antibody, or antigen-binding portion thereof;
(b) about 12 mg/ml of mannitol, and
(c) about 1 mg/ml of polysorbate-80.
13. The liquid aqueous pharmaceutical formulation of claim 10 , wherein the buffer system comprises citric acid and sodium citrate.
14. The liquid aqueous pharmaceutical formulation of claim 10 or 13 , wherein the buffer system comprises disodium phosphate dihydrate and sodium dihydrogen phosphate dihydrate.
15. The liquid aqueous pharmaceutical formulation of claim 10 , wherein the antibody or antigen-binding portion thereof is D2E7 or an antigen binding portion thereof.
16. The liquid aqueous pharmaceutical formulation of claim 10 , wherein the antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
17. A liquid pharmaceutical formulation having a pH of about 4 to about 8, comprising an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody at a concentration of 35-115 mg/ml, a sugar alcohol, a polysorbate, and a buffer system comprising citrate and phosphate,
wherein the antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2.
18. The liquid aqueous pharmaceutical formulation of claim 17 , wherein the sugar alcohol is mannitol.
19. The liquid aqueous pharmaceutical formulation of claim 17 or 18 , wherein the polysorbate is polysorbate 80.
20. The liquid aqueous pharmaceutical formulation of claim 19 , wherein the antibody is D2E7.
21. The liquid aqueous pharmaceutical formulation of claim 17 , wherein the pH is 4.5 to 6.
22. The liquid aqueous pharmaceutical formulation of claim 17 , wherein the buffer system comprises disodium phosphate dihydrate and sodium dihydrogen phosphate dihydrate.
23. The liquid aqueous pharmaceutical formulation of claim 17 or 22 , wherein the buffer system further comprises citric acid and sodium citrate.
24. The liquid aqueous pharmaceutical formulation of claim 23 , wherein the sugar alcohol is mannitol.
25. A liquid aqueous pharmaceutical formulation having a pH of about 4.5 to about 6, comprising an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody, or an antigen-binding portion thereof, at a concentration of 35-115 mg/ml, a polyol, a surfactant, and a buffer system comprising citrate and phosphate, wherein the antibody, or antigen-binding portion thereof, comprises
a light chain variable region comprising the light chain complementarity determining region (CDR) 1, CDR2, and CDR3 of D2E7; and a heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 of D2E7.
26. The liquid aqueous pharmaceutical formulation of claim 25 , comprising about 45 to 105 mg/ml of the antibody, or antigen-binding portion thereof.
27. The liquid aqueous pharmaceutical formulation of claim 25 , wherein the concentration of the antibody is about 50 mg/ml.
28. The liquid aqueous pharmaceutical formulation of claim 25 , which further is suitable for single use subcutaneous injection.
29. The liquid aqueous pharmaceutical formulation of claim 25 , wherein the antibody, or antigen-binding portion thereof, comprises the light and heavy chain variable regions of D2E7.
30. The liquid aqueous pharmaceutical formulation of claim 25 , wherein the antibody, or antigen-binding portion thereof, is the antibody D2E7 or an antigen binding portion thereof.
31. The liquid aqueous pharmaceutical formulation of claim 25 , wherein the polyol is a sugar alcohol.
32. The liquid aqueous pharmaceutical formulation of claim 31 , wherein the sugar alcohol is mannitol.
33. The liquid aqueous pharmaceutical formulation of claim 25 , wherein the surfactant is a polysorbate.
34. A liquid aqueous pharmaceutical formulation comprising
(a) 35-115 mg/ml of an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody, or an antigen-binding portion thereof,
(b) 5-20 mg/ml of mannitol,
(c) 0.1-10 mg/ml of polysorbate-80, and
(d) a buffer system comprising citrate and phosphate, with a pH of 4.5 to 6.0,
wherein the antibody, or antigen-binding portion thereof, comprises
a light chain variable region comprising the light chain complementarity determining region (CDR) 1, CDR2, and CDR3 of D2E7; and a heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 of D2E7.
35. The liquid aqueous pharmaceutical formulation of claim 34 , wherein the pH is between about 4.8 to about 5.5.
36. The liquid aqueous pharmaceutical formulation of claim 34 , which contains
(a) about 50 mg/ml of the antibody, or antigen-binding portion thereof;
(b) about 12 mg/ml of mannitol, and
(c) about 1 mg/ml of polysorbate-80.
37. The liquid aqueous pharmaceutical formulation of claim 34 , wherein the buffer system comprises citric acid and sodium citrate.
38. The liquid aqueous pharmaceutical formulation of claim 34 or 37 , wherein the buffer system comprises disodium phosphate dihydrate and sodium dihydrogen phosphate dihydrate.
39. The liquid aqueous pharmaceutical formulation of claim 34 , wherein the antibody or antigen-binding portion thereof is D2E7 or an antigen binding portion thereof.
40. The liquid aqueous pharmaceutical formulation of claim 34 , wherein the antibody comprises the light and heavy chain variable regions of D2E7.
41. A liquid pharmaceutical formulation having a pH of about 4 to about 8, comprising an isolated human IgG1 anti-human Tumor Necrosis Factor alpha (hTNFα) antibody at a concentration of 35-115 mg/ml, a sugar alcohol, a polysorbate, and a buffer system comprising citrate and phosphate,
wherein the antibody comprises the light and heavy chain variable regions of D2E7.
42. The liquid aqueous pharmaceutical formulation of claim 41 , wherein the sugar alcohol is mannitol.
43. The liquid aqueous pharmaceutical formulation of claim 41 or 42 , wherein the polysorbate is polysorbate 80.
44. The liquid aqueous pharmaceutical formulation of claim 43 , wherein the antibody is D2E7.
45. The liquid aqueous pharmaceutical formulation of claim 41 , wherein the pH is 4.5 to 6.
46. The liquid aqueous pharmaceutical formulation of claim 41 , wherein the buffer system comprises disodium phosphate dihydrate and sodium dihydrogen phosphate dihydrate.
47. The liquid aqueous pharmaceutical formulation of claim 41 or 46 , wherein the buffer system further comprises citric acid and sodium citrate.
48. The liquid aqueous pharmaceutical formulation of claim 47 , wherein the sugar alcohol is mannitol.