Formulation for anti-α4β7 antibody

Patent metadata

Field	Value
Publication number	US-11560434-B2
Application number	US-202016787521-A
Country	US
Kind code	B2
Filing date	Feb 11, 2020
Priority date	May 2, 2011
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

Antibody formulations are described comprising a mixture of an anti-α4β7 antibody, an antioxidant or chelator, and at least one free amino acid. The disclosed formulations may have improved stability, reduced aggregate formation, or both. 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 liquid pharmaceutical formulation comprising a humanized anti-α4β7 antibody, citrate, at least one free amino acid, and a buffering agent, wherein the humanized anti-α4β7 antibody is an IgG1 isotype and comprises a light chain variable region comprising a CDR1 comprising SEQ ID NO:11, a CDR2 comprising SEQ ID NO: 12, and a CDR3 comprising SEQ ID NO: 13, and comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO:8, a CDR2 comprising SEQ ID NO: 9, and a CDR3 comprising SEQ ID NO: 10, wherein the liquid formulation has a pH of 6 to 7, wherein the liquid formulation comprises 100 mg/ml to 180 mg/ml of the humanized anti-α4β7 antibody, and wherein the liquid formulation has less than or equal to 2.5% aggregate determined by size exclusion chromatography (SEC) after storage at 40 degrees Celsius for 4 weeks.

2. The stable liquid pharmaceutical formulation of claim 1 , wherein the molar ratio of the humanized anti-α4β7 antibody to citrate is about 1:4 to about 1:100.

3. The stable liquid pharmaceutical formulation of claim 1 , wherein said free amino acid is selected from the group consisting of histidine, alanine, arginine, glycine, glutamic acid and combinations thereof.

4. The stable liquid pharmaceutical formulation of claim 1 , wherein said formulation further comprises a surfactant.

5. The stable liquid pharmaceutical formulation of claim 4 , wherein the molar ratio of citrate to the surfactant is about 3:1 to about 156:1.

6. The stable liquid pharmaceutical formulation of claim 1 , wherein said humanized anti-α4β7 antibody is vedolizumab.

7. The stable liquid pharmaceutical formulation of claim 1 , wherein the humanized anti-α4β7 antibody comprises a heavy chain variable region comprising amino acids that are at least 95% identical to amino acids 20 to 140 of SEQ ID NO:2, and a light chain variable region comprising amino acids that are at least 95% identical to amino acids 20 to 131 of SEQ ID NO:4.

8. The stable liquid pharmaceutical formulation of claim 1 , wherein the humanized 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 to to 131 of SEQ ID NO:4.

9. The stable liquid pharmaceutical formulation of claim 1 , wherein the liquid formulation has less than 2.0% antibody aggregate formation at about 25° C. after 12 months as determined by size exclusion chromatography (SEC).

10. A stable liquid pharmaceutical formulation comprising a humanized anti-α4β7 antibody, citrate, arginine, and a buffering agent, wherein the humanized anti-α4β7 antibody is an IgG1 isotype and comprises a light chain variable region comprising a CDR1 comprising SEQ ID NO:11, a CDR2 comprising SEQ ID NO: 12, and a CDR3 comprising SEQ ID NO: 13, and comprises a heavy chain variable region comprising a CDR1 comprising SEQ ID NO:8, a CDR2 comprising SEQ ID NO: 9, and a CDR3 comprising SEQ ID NO: 10, wherein the formulation has a pH of 6 to 7, wherein the liquid formulation comprises 100 mg/ml to 180 mg/ml of the humanized anti-α4β7 antibody, and wherein the liquid formulation has less than or equal to 2.5% aggregate determined by size exclusion chromatography (SEC) after storage at 40 degrees Celsius for 4 weeks.

11. The stable liquid pharmaceutical formulation of claim 10 , wherein the humanized anti-α4β7 antibody comprises a heavy chain variable region comprising amino acids that are at least 95% identical to amino acids 20 to 140 of SEQ ID NO:2, and a light chain variable region comprising amino acids that are at least 95% identical to amino acids 20 to 131 of SEQ ID NO:4.

12. The stable liquid pharmaceutical formulation of claim 10 , wherein the humanized 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 to to 131 of SEQ ID NO:4.

13. The stable liquid pharmaceutical formulation of claim 10 , wherein the humanized anti-α4β7 antibody is vedolizumab.

14. The stable liquid pharmaceutical formulation of claim 10 , further comprising a surfactant.

15. The stable liquid pharmaceutical formulation of claim 14 , wherein the molar ratio of surfactant to antibody is form about 0.7:1 to about 1.5:1.

16. The stable liquid pharmaceutical formulation of claim 14 , wherein the surfactant is a polysorbate.

17. The stable liquid pharmaceutical formulation of claim 10 , wherein the buffering agent is histidine.

18. The stable liquid pharmaceutical formulation of claim 17 , comprising 10 mM to 75 mM histidine.

19. The stable liquid pharmaceutical formulation of claim 10 , wherein the liquid formulation has less than 2.0% antibody aggregate formation at about 25° C. after 12 months as determined by size exclusion chromatography (SEC).

20. The stable liquid pharmaceutical formulation of claim 10 , comprising 20 mM to 30 mM citrate.

21. The stable liquid pharmaceutical formulation of claim 10 , comprising 50 to 150 mM arginine.

22. The stable liquid pharmaceutical formulation of claim 1 , comprising a dose of 108 mg of the humanized anti-α4β7 antibody.

23. The stable liquid pharmaceutical formulation of claim 10 , comprising a dose of 108 mg of the humanized anti-α4β7 antibody.

24. The stable liquid pharmaceutical formulation of claim 4 , wherein the molar ratio of surfactant to antibody is form about 0.7:1 to about 1.5:1.

25. The stable liquid pharmaceutical formulation of claim 4 , wherein the surfactant is a polysorbate.

26. A container comprising the stable liquid pharmaceutical formulation of claim 1 , wherein the container is selected from the group consisting of an autoinjector, a preloaded syringe, or a cartridge.

27. A container comprising the stable liquid pharmaceutical formulation of claim 10 , wherein the container is selected from the group consisting of an autoinjector, a preloaded syringe, or a cartridge.

28. The stable liquid pharmaceutical formulation of claim 1 , wherein the formulation is prepared for self-administration by a human subject.

29. The stable liquid pharmaceutical formulation of claim 10 , wherein the formulation is prepared for self-administration by a human subject.

30. The stable liquid pharmaceutical formulation of claim 1 , wherein the liquid formulation has less than about 2.5% aggregate at 25 degrees Celsius as determined by size exclusion chromatography (SEC).

31. The stable liquid pharmaceutical formulation of claim 10 , wherein the liquid formulation has less than about 2.5% aggregate at 25 degrees Celsius as determined by size exclusion chromatography (SEC).

32. The stable liquid pharmaceutical formulation of claim 1 , comprising 5 mM to 50 mM citrate.

33. The stable liquid pharmaceutical formulation of claim 10 , comprising 5 mM to 50 mM citrate.

Assignees

• Millennium Pharm Inc

Inventors

• Diluzio Willow
• Nguyen Phoung M
• Varga Csanad M
• Palaniappan Vaithianathan
• Brown Jason

Classifications

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• C07K16/2839 Primary

  against the integrin superfamily · CPC title

• A61K39/39591 Primary

  Stabilisation, fragmentation · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title