STVTs (Selective Tumor Vascular Thrombogens) are (i) engineered to selectively initiate the thrombogenic cascade only on tumor associated vascular endothelium, (ii) incorporate modifications to the structure human tissue factor (TF), which acts as a cofactor for factor VIIA, that have been shown to increase the safety and decrease the toxicity of TF and (iii) use structural elements extracted from various sources to facilitate TF function. These molecules are (A) based on extensive knowledge about the structural and geometrical requirements to assemble TF-associated functions on the surface of cells and are (B) designed to react transiently and cause the formation of thrombii that restricts the flow of nutrients to the tumor cells to result in infarctive apoptosis and necrosis of tumors. A key feature of STVT function is their ability to selectively activate factor VIIa substrates only on endothelium structure and function caused by the process of tumor- associated angiogenesis. This proposal addresses the subclass of STVTs defined by NV129, NV143, and NV144 that are based on fragments of plasminogen. NV143, and NV129, to a lesser extent, strongly inhibits the growth of large tumors in mice. Additional variants within this subclass will be designed and produced for testing in animal models of cancer. Various features of the candidate will be optimized and the best candidate will advanced into clinical development. PROPOSED COMMERCIAL APPLICATIONS: Development of anti-cancer agents remains one of the most important activities of the biopharmaceutical industry. The need for more effective cancer therapy is readily apparent, as more than 1.5 million people in the U.S. get some type of cancer each year. This market is more than $10 billion per year.
