The goal of this application is to create immunoconjugates that home to the vasculature of solid tumors, coagulate the tumor's blood supply and induce tumor infarction. The key advantage of this approach over direct tumor cell targeting is that the vascular endothelial cells of the tumor are freely accessible through the blood whereas the tumor cells are relatively inaccessible. Also, endothelial cells are normal cells making the outgrowth of resistant mutants unlikely, and are similar in different tumors, making it feasible to develop a single reagent for treating numerous types of cancer. The applicant previously established """"""""proof of principle"""""""" by inducing major tumor regressions in mice bearing large solid tumors with immunoconjugates prepared from antibodies that recognize an experimentally-induced tumor endothelial cell marker (MHC Class II). The effectors were ricin A-chain, which kills the tumor endothelial cells and induces platelet adhesion on the injured vessels, or a genetically engineered form of the coagulation initiating protein tissue factor, which directly induces thrombotic occlusion of the vessels. In this application, the applicant will synthesize vascular targeting agents that recognize the naturally occurring tumor endothelial cell marker, vascular endothelial cell growth factor (VEGF). VEGF is present in the receptors on tumor endothelial cells but not in those on endothelial cells in normal tissues and, hence, non-blocking antibodies to VEGF home selectively to tumor vessels in vivo. Monoclonal antibodies to human VEGF will be raised; their ability to localize to vessels in solid tumors in mice and guinea pigs will be confirmed; toxin-containing immunotoxins and tissue factor-containing """"""""coaguligands"""""""" will be synthesized; and the pharmacokinetics, toxicity and anti-tumor activity of the drugs in murine and guinea pig tumor models will be determined. These studies will pave the way to clinical trials of anti-VEGF vascular targeting agents in patients with solid tumors.
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