Formulation for anti-α4β7 antibody
Antibody formulations are described comprising a mixture of a non-reducing sugar, an anti-α4β7 antibody and at least one amino acid. The disclosed formulations have improved stability, reduced aggregate formation, and may retard degradation of the anti-α4β7 antibody therein or exhibit any combinations thereof. The present invention further provides a safe dosing regimen of these antibody formulations that is easy to follow, and which results in a therapeutically effective amount of the anti-α4β7 antibody in vivo.
1. A stable pharmaceutical formulation comprising sucrose, at least about 120 mg of an anti-α4β7 antibody, and arginine,
wherein the formulation is a lyophilized formulation,
wherein the formulation comprises at least 50% major isoform of the antibody as determined by Cation Exchange Chromatography (CEX),
wherein the molar ratio of sucrose to anti-α4β7 antibody (mole:mole) is at least about 650:1,
wherein the arginine to antibody-molar ratio (mole:mole) is greater than 250:1, and
wherein the antibody is humanized, comprises a heavy chain variable region comprising a complementarity determining region 1 (CDR1) as set forth in SEQ ID NO: 8, a CDR2 as set forth in SEQ ID NO: 9, and a CDR3 as set forth in SEQ ID NO: 10, and comprises a light chain variable region comprising a CDR1 as set forth in SEQ ID NO: 11, a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 13.
2. The formulation of claim 1 , wherein said formulation further comprises a buffering agent.
3. The formulation of claim 2 , wherein said buffering agent is histidine.
4. The formulation of claim 1 , wherein said formulation further comprises a surfactant.
5. The formulation of claim 1 , wherein said formulation comprises at least about 5% to about 10% anti-α4β7 antibody before lyophilization.
6. A stable pharmaceutical formulation comprising sucrose, at least about 120 mg of an anti-α4β7 antibody, histidine, arginine, and polysorbate 80,
wherein the formulation is a lyophilized formulation,
wherein the formulation comprises at least 50% major isoform of the antibody as determined by Cation Exchange Chromatography (CEX),
wherein the molar ratio of sucrose to anti-α4β7 antibody (mole:mole) is at least about 650:1, wherein the molar ratio of histidine and arginine to antibody (mole:mole) is about 200:1 to about 500:1 and
wherein the antibody is humanized, comprises a heavy chain variable region comprising a complementarity determining region 1 (CDR1) as set forth in SEQ ID NO: 8, a CDR2 as set forth in SEQ ID NO: 9, and a CDR3 as set forth in SEQ ID NO: 10, and comprises a light chain variable region comprising a CDR1 as set forth in SEQ ID NO: 11, a CDR2 as set forth in SEQ ID NO: 12, and a CDR3 as set forth in SEQ ID NO: 13.
7. The formulation of claim 1 , wherein said antibody is vedolizumab.
8. The formulation of claim 6 , wherein said antibody is vedolizumab.
9. The formulation of claim 1 , wherein the anti-α4β7 antibody comprises a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2 and a light chain variable region comprising amino acids 20 to 131 of SEQ ID NO: 4.
10. The formulation of claim 1 , wherein the formulation is in a vial, and the vial contains about 300 mg of the anti-α4β7 antibody.
11. The formulation of claim 3 , wherein the histidine amount is 3% to 6% (w/w of dry formulation).
12. The formulation of claim 1 , wherein the formulation is stable at 25° C. and 60% relative humidity (RH) for at least 12 months.
13. A stable pharmaceutical formulation comprising 45% to 55% sucrose (w/w of dry formulation), at least about 240 mg of a humanized anti-α4β7 antibody, histidine, about 10% to about 15% w/w of arginine, and polysorbate 80, wherein the formulation is a lyophilized formulation, wherein the formulation comprises at least 50% major isoform of the antibody as determined by Cation Exchange Chromatography (CEX), and wherein the antibody comprises a light chain variable region comprising amino acids 20-131 of SEQ ID NO: 4, and a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2.
14. The formulation of claim 13 , wherein the antibody is vedolizumab.
15. The formulation of claim 13 , wherein the sucrose to antibody ratio is at least 700:1.
16. The formulation of claim 6 , comprising 300 mg of the antibody.
17. A liquid, reconstituted formulation comprising about 50 mg/ml to about 80 mg/ml of an anti-α4β7 antibody, about 250 mM to about 325 mM sucrose, about 75 mM to about 200 mM arginine, about 25 mM to about 150 mM histidine, and about 0.01% to about 0.1% polysorbate 80, wherein the formulation comprises at least 50% major isoform of the antibody as determined by Cation Exchange Chromatography (CEX), wherein the antibody is an IgG1 and comprises a light chain variable region comprising amino acids 20-131 of SEQ ID NO: 4 and a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2, and wherein the formulation has a pH between about 5.5 to 6.5.
18. The formulation of claim 17 , having a pH between about 6.1 to 6.5.
19. The formulation of claim 17 , wherein the antibody is vedolizumab.
20. The formulation of claim 19 , comprising 300 mg of vedolizumab.
21. The formulation of claim 17 , comprising about 25 mM to about 65 mM histidine.
22. The formulation of claim 17 , comprising about 100 mM to about 150 mM arginine.
23. The formulation of claim 1 , comprising greater than about 13% arginine (w/w of the lyophilized formulation) when the protein amount is about 31% (w/w of the lyophilized formulation).
24. The formulation of claim 6 , comprising greater than about 13% arginine (w/w of the lyophilized formulation) when the protein amount is about 31% (w/w of the lyophilized formulation).
25. The formulation of claim 17 , comprising greater than about 13% arginine (w/w of the lyophilized formulation) when the protein amount is about 31% (w/w of the lyophilized formulation).
26. The formulation of claim 6 , wherein the anti-α4β7 antibody comprises a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2 and a light chain variable region comprising amino acids 20 to 131 of SEQ ID NO: 4.
27. The formulation of claim 1 , wherein said formulation comprises at least about 25% anti-α4β7 antibody (by weight).
28. The formulation of claim 1 , comprising at least 55% major isoform of the antibody as determined by CEX.
29. The formulation of claim 6 , wherein the formulation has a pH of about 5.5 to 6.5 upon reconstitution.
30. The formulation of claim 2 , wherein the formulation has a pH of about 5.5 to 6.5 upon reconstitution.
31. The formulation of claim 1 , wherein the antibody is an IgG1.
32. The formulation of claim 6 , wherein the antibody is an IgG1.
33. The formulation of claim 13 , wherein the antibody is an IgG1.