VEGF superagonists and methods of use
Modified VEGF proteins that inhibit VEGF-mediated activation or proliferation of endothelial cells are disclosed. The analogs may be used to inhibit VEGF-mediated activation of endothelial cells in angiogenesis-associated diseases such as cancer, inflammatory diseases, eye diseases, and skin disorders.
1. A modified vascular endothelial growth factor (VEGF) protein comprising substitutions at amino acid residues E44, E72, and E73 of SEQ ID NO: 4 or SEQ ID NO: 13 with a positively charged amino acid, wherein the modified VEGF has an increased receptor binding affinity when compared to wild-type VEGF.
2. The modified VEGF-of claim 1 , wherein the substitutions are in SEQ ID NO: 4.
3. The modified VEGF of claim 1 , wherein the substitutions are in SEQ ID NO: 13.
4. The modified VEGF of claim 1 , wherein the positive amino acid is lysine, arginine or histidine.
5. The modified VEGF of claim 1 , wherein the modified VEGF is expressed as a homodimer or heterodimer.
6. The modified VEGF of claim 1 , further comprising a substitution at C146.
7. The modified VEGF of claim 1 , further comprising a substitution at C160.
8. The modified VEGF of claim 1 , further comprising substitutions at C146 and C160.
9. The modified VEGF of claim 1 , further comprising a substitution at A111.
10. The modified VEGF of claim 1 , further comprising a substitution at A148.
11. The modified VEGF of claim 1 , further comprising substitutions at A111 and A148.
12. The modified VEGF of claim 1 , further comprising a substitution at Q87.
13. The modified VEGF of claim 1 , further comprising a substitution at E67.
14. A pharmaceutical composition comprising the modified VEGF of claim 1 .
15. The modified VEGF of claim 1 , further comprising a N-terminal or C-terminal extension.
16. The modified VEGF of claim 1 , wherein at least one of the positive amino acid substitutions at E44, E72 and E73 is arginine.
17. The modified VEGF of claim 1 , wherein the amino acid substitutions at E44, E72 and E73 are arginine.