Fusion proteins for inhibiting angiogenesis
The present invention relates to a biologic that inhibits angiogenesis. In particular, the present invention relates to fusion proteins that inhibit the integrin activated pathway and one other angiogenic factor-activated pathway, the compositions of these fusion proteins, as well as methods for producing and using the same.
1. A fusion protein comprising, from N-terminus to C-terminus in the following order:
an extracellular domain of a Vascular Endothelial Growth Factor (VEGF) receptor comprising an Ig-like domain D2 of a VEGFR1 having the amino acid sequence of SEQ ID NO: 8 and an Ig-like domain D3 of VEGFR2 having the amino acid sequence of SEQ ID NO: 9;
a Fc domain; and
an integrin binding peptide having the amino acid sequence selected from a group consisting of SEO ID NO: 12, 13, and 14.
2. The fusion protein of claim 1 , wherein the integrin binding peptide comprises the amino acid sequence of SEQ ID NO: 12.
3. The fusion protein of claim 1 , wherein the integrin binding peptide comprises the amino acid sequence of SEQ ID NO: 13.
4. The fusion protein of claim 1 , wherein the integrin binding peptide comprises the amino acid sequence of SEQ ID NO: 14.
5. A composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable adjuvant, carrier or excipient.
6. A fusion protein comprising:
an integrin binding peptide comprising the amino acid sequence of SEQ ID NO:13;
an extracellular domain of a Vascular Endothelial Growth Factor (VEGF) receptor comprising the amino acid sequence of SEQ ID NO: 10; and
a Fc domain.
7. The fusion protein of claim 6 , comprising the amino acid sequence of SEQ ID NO: 18.
8. The fusion protein of claim 7 , consisting of the amino acid sequence of SEQ ID NO: 18.
9. The fusion protein of claim 6 , consisting of the amino acid sequence of SEQ ID NO: 16.
10. A composition comprising the fusion protein of claim 6 and a pharmaceutically acceptable adjuvant, carrier or excipient.
11. The fusion protein of claim 1 , further comprising a GS linker between the Fc domain and the integrin binding peptide.
12. The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 15.
13. The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 16.
14. The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 17.
15. The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 18.
16. A method of treating vascular leakage in a subject in need thereof, comprising administering to the subject the fusion protein of claim 6 .
17. A method of treating retinal vascular leakage in a subject in need thereof, comprising administering to the subject the fusion protein of claim 6 .
18. A method of reducing lesion size in laser-induced choroidal neovascularization (CNV) in a subject in need thereof, comprising administering to the subject the fusion protein of claim 6 .