TARGETING ANGIOGENESIS WITH TOXIN-VEGF FUSION PROTEINS

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The overall goal of this project is to develop a commercially viable bacterial toxin-VEGF (vascular endothelial growth factor) fusion protein for selective targeting of endothelial cells at the sites of angiogenesis in various pathologies. VEGF interacts with endothelial cells via endothelial cell specific KDR/flk-1 receptor that is overexpressed in endothelial cells at the sites of angiogenesis as compared with quiescent endothelial cells. Our data indicate the VEGF fusion proteins preferentially interact with cells overexpressing KDR/Flk-1 receptors. To exploit this targeting specificity we propose to make VEGF fusion protein carrying catalytic fragment of Shiga-like toxin I (SLT-I). SLT-I causes hemorrhagic colitis and hemolytic uremic syndrome by damaging endothelial cells suggesting that endothelial cells are particularly sensitive to SLT I. In Phase I we will construct and test two SLT-VEGF fusion proteins carrying different catalytic fragments of SLT-I. Our specific aims are designed to provide the "proof-of-principle" for a novel inhibitor of angiogenesis. Furthermore, information about binding and processing of SLT-VEGF fusion proteins by cells overexpressing KDR/flk-1 receptors will establish the routes for optimization of these proteins. In Phase II studies we will optimize SLT-VEGF fusion proteins and will test them in animal models of angiogenesis. PROPOSED COMMERCIAL APPLICATION: Toxin-VEGF fusion protein developed as a result of this project may be used for treatment of several major angiogenesis-dependent pathologies. The methodology developed in this project may be expanded to other cytokine-toxin fusion proteins.