Stabilized formulations containing anti-Ang2 antibodies
The present invention provides pharmaceutical formulations comprising an antibody that specifically binds to angiopoietin 2 (Ang-2). The formulations may contain, in addition to an anti-Ang-2 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 and after being subjected to thermal and other physical stress.
1. A stable pharmaceutical formulation comprising:
(i) an antibody at a concentration of from 20±3 mg/ml to 60±9 mg/ml that binds specifically to human angiopoietin 2 (human Ang-2), wherein the antibody comprises a heavy chain variable domain (HCVD) having the amino acid sequence of SEQ ID NO:18 and a light chain variable domain (LCVD) having the amino acid sequence of SEQ ID NO:20;
(ii) histidine at a concentration of 10±1.5 mM;
(iii) polysorbate 20 in an amount of 0.2% w/v±0.03% w/v; and
(iv) sucrose in an amount of 10% w/v±1.5% w/v,
wherein the formulation has a pH of 6±0.3, and at least 92% of the antibody has native conformation when the formulation is kept at about 45° C. for up to about 28 days.
2. The pharmaceutical formulation of claim 1 , wherein
(a) over 96% of the antibodies have a molecular weight of 151 kDa±1 kDa;
(b) at least 53% of the antibodies have an isoelectric point of about 8.13±0.01; and
(c) from about 90% to about 92% of the antibodies are fucosylated.
3. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is about 25 mg/mL±0.375 mg/mL.
4. The pharmaceutical formulation of claim 1 , wherein the antibody concentration is about 50 mg/mL±7.5 mg/mL.
5. The pharmaceutical formulation of claim 1 , wherein at least 93% of the antibody has native conformation after 28 days at 45° C.
6. The pharmaceutical formulation of claim 1 , wherein at least 32% of the antibody is the main charge variant of the antibody after 28 days at 45° C.
7. The pharmaceutical formulation of claim 1 , wherein at least 97% of the antibody has native conformation after 28 days at 25° C.
8. The pharmaceutical formulation of claim 1 , wherein at least 53% of the antibody is the main charge variant of the antibody after 28 days at 25° C.
9. The pharmaceutical formulation of claim 1 , wherein at least 96% of the antibody has native conformation after 28 days at 37° C.
10. The pharmaceutical formulation of claim 1 , wherein at least 45% of the antibody is the main charge variant of the antibody after 28 days at 37° C.
11. The pharmaceutical formulation of claim 1 , wherein at least 97% of the antibody has native conformation after six months at 5° C.
12. The pharmaceutical formulation of claim 1 , wherein at least 55% of the antibody is the main charge variant of the antibody after six months at 5° C.
13. The pharmaceutical formulation of claim 1 , wherein the percent relative potency of the antibody after six months at 5° C. is at least 100% of the potency of the antibody prior to storage.
14. The pharmaceutical formulation of claim 1 , wherein at least 97% of the antibody has native conformation after six months at −80° C.
15. The pharmaceutical formulation of claim 1 , wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −80° C.
16. The pharmaceutical formulation of claim 1 , wherein the percent relative potency of the antibody after six months at −80° C. is at least 85% of the potency of the antibody prior to storage.
17. The pharmaceutical formulation of claim 1 , wherein at least 96% of the antibody has native conformation after six months at −30° C.
18. The pharmaceutical formulation of claim 1 , wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −30° C.
19. The pharmaceutical formulation of claim 1 , wherein the percent relative potency of the antibody after six months at −30° C. is at least 84% of the potency of the antibody prior to storage.
20. The pharmaceutical formulation of claim 1 , wherein at least 96% of the antibody has native conformation after six months at −20° C.
21. The pharmaceutical formulation of claim 1 , wherein at least 55% of the antibody is the main charge variant of the antibody after six months at −20° C.
22. The pharmaceutical formulation of claim 1 , wherein the percent relative potency of the antibody after six months at −20° C. is at least 90% of the potency of the antibody prior to storage.
23. A pharmaceutical formulation comprising (a) 25 mg/mL±3.75 mg/mL of an anti-Ang-2 antibody, (b) 10 mM±1.5 mM histidine, pH 6±0.3, (c) 0.2% w/v±0.03% polysorbate 20, and (d) 10% w/v±1.5% sucrose, wherein:
(a) the antibody comprises an HCVD of SEQ ID NO: 18 and an LCVD of SEQ ID NO: 20;
(b) over 96% of the antibodies have a molecular weight of 151 kDa±1 kDa;
(c) at least 53% of the antibodies have an isoelectric point of about 8.13±0.01; and
(d) from about 90% to about 92% of the antibodies are fucosylated.
24. The pharmaceutical formulation of claim 23 consisting of (a) 25 mg/mL±3.75 mg/mL of the antibody, (b) 10 mM±1.5 mM histidine, pH 6±0.3, (c) 0.2% w/v±0.03% polysorbate 20, and (d) 10% w/v±1.5% sucrose, in water.
25. A pharmaceutical formulation comprising (a) 50 mg/mL±7.5 mg/mL of an anti-Ang-2 antibody, (b) 10 mM±1.5 mM histidine, pH 6±0.3, (c) 0.2% w/v±0.03% polysorbate 20, and (d) 10% w/v±1.5% sucrose, wherein:
(a) the antibody comprises an HCVD of SEQ ID NO: 18 and an LCVD of SEQ ID NO: 20;
(b) over 96% of the antibodies have a molecular weight of 151 kDa±1 kDa;
(c) at least 53% of the antibodies have an isoelectric point of about 8.13±0.01; and
(d) from about 90% to about 92% of the antibodies are fucosylated.
26. The pharmaceutical formulation of claim 25 consisting of (a) 50 mg/mL±7.5 mg/mL of the antibody, (b) 10 mM±1.5 mM histidine, pH 6±0.3, (c) 0.2% w/v±0.03% polysorbate 20, and (d) 10% w/v±1.5% sucrose, in water.
27. A pharmaceutical composition comprising the formulation of claim 1 , wherein said composition is contained in a container.
28. The pharmaceutical composition of claim 27 , wherein the container is a vial.
29. The pharmaceutical composition of claim 28 , wherein the vial is glass.
30. The pharmaceutical composition of claim 27 , wherein the container is an intravenous drip bag.
31. The pharmaceutical composition of claim 30 , wherein the bag is made of polyvinyl chloride.
32. The pharmaceutical composition of claim 30 , wherein the bag is made of polyolefin.
33. A kit comprising a pharmaceutical composition of claim 27 , and instructions.
34. The kit of claim 33 , wherein the container is a glass vial fitted with a fluorocarbon coated rubber stopper.