Vegf antagonist formulations suitable for intravitreal administration

Patent metadata

Field	Value
Publication number	US-2020017572-A1
Application number	US-201916582486-A
Country	US
Kind code	A1
Filing date	Sep 25, 2019
Priority date	Jun 16, 2006
Publication date	Jan 16, 2020
Grant date	—

Abstract

Ophthalmic formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist are provided suitable for intravitreal administration to the eye. The ophthalmic formulations include a stable liquid formulation and a lyophilizable formulation. Preferably, the protein antagonist has an amino acid sequence of SEQ ID NO:4.

First claim

1 .- 11 . (canceled)

12 . A vial comprising:
a vascular endothelial growth factor (VEGF) antagonist; polysorbate; a buffer; and sucrose; wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

13 . The vial of claim 12 wherein the polysorbate is polysorbate 20.

14 . The vial of claim 13 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

15 . The vial of claim 14 wherein about 99% or more of the weight of the fusion protein is in native conformation.

16 . A vial comprising:
a vascular endothelial growth factor (VEGF) antagonist; 0.01% polysorbate 20 or polysorbate 80; a buffer; and sucrose, trehalose, mannitol or glucose; wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

17 . The vial of claim 16 wherein the concentration of vascular endothelial growth factor (VEGF) antagonist is about 40 mg/ml.

18 . The vial of claim 17 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

19 . The vial of claim 18 wherein about 99% or more of the weight of the fusion protein is in native conformation.

20 . The vial of claim 12 comprising
vascular endothelial growth factor (VEGF) antagonist;
30-150 mM NaCl;
0.03% polysorbate 20;
5% sucrose; and
a buffer;
wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and
wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography

21 . The vial of claim 20 comprising about 40 mg/ml of the vascular endothelial growth factor (VEGF) antagonist.

22 . The vial of claim 21 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

23 . The vial of claim 22 wherein about 99% or more of the weight of the fusion protein is in native conformation.

24 . A formulation comprising:
a vascular endothelial growth factor (VEGF) antagonist; polysorbate; a buffer; and sucrose; wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

25 . The formulation of claim 24 wherein the polysorbate is polysorbate 20.

26 . The formulation of claim 25 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

27 . The formulation of claim 26 wherein about 99% or more of the weight of the fusion protein is in native conformation.

28 . A formulation comprising:
a vascular endothelial growth factor (VEGF) antagonist; 0.01% polysorbate 20 or polysorbate 80; a buffer; and sucrose, trehalose, mannitol or glucose; wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

29 . The formulation of claim 28 wherein the concentration of vascular endothelial growth factor (VEGF) antagonist is about 40 mg/ml.

30 . The formulation of claim 29 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

31 . The formulation of claim 30 wherein about 99% or more of the weight of the fusion protein is in native conformation.

32 . The formulation of claim 24 comprising
vascular endothelial growth factor (VEGF) antagonist;
30-150 mM NaCl;
0.03% polysorbate 20;
5% sucrose; and
a buffer;
wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of Flt1 and Ig domain 3 of Flk1, and a multimerizing component; and
wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography

33 . The formulation of claim 32 comprising about 40 mg/ml of the vascular endothelial growth factor (VEGF) antagonist.

34 . The formulation of claim 33 wherein the vascular endothelial growth factor (VEGF) antagonist is a dimer of a fusion protein comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:4.

35 . The formulation of claim 34 wherein about 99% or more of the weight of the fusion protein is in native conformation.

Assignees

• Regeneron Pharma

Inventors

• Furfine Eric
• Dix Daniel
• Graham Kenneth
• Frye Kelly

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K38/1793

  for cytokines; for lymphokines; for interferons · CPC title

• C07K14/71 Primary

  for growth factors; for growth regulators · CPC title