Formulation for anti-α4β7 antibody

Patent metadata

Field	Value
Publication number	US-9764033-B2
Application number	US-201214114832-A
Country	US
Kind code	B2
Filing date	May 2, 2012
Priority date	May 2, 2011
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Diluzio Willow
• Truong Nobel T
• Varga Csanad M
• Palaniappan Vaithianathan
• Brown Jason
• Scholz Catherine
• Millennium Pharm Inc

Inventors

• Diluzio Willow
• Truong Nobel T
• Varga Csanad M
• Palaniappan Vaithianathan
• Brown Jason
• Scholz Catherine

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title