Angiostatin is 38 kDa proteolytic internal fragment of plasminogen (kringles 1-4) and an endogenous inhibitor of angiogenesis and tumor growth. By inhibiting endothelial proliferation, angiostatin presumably keeps cancers in check by restricting the process of blood vessel formation. Recombinant human angiostatin when administered to mice inhibited the growth of both human and murine tumors with no observed toxicity or drug resistance. We propose to create modified angiostatin-like proteins that are superior to the present preparations of recombinant angiostatin. The modified angiostatin proteins should have improved stability, higher potency, greater solubility, longer circulating half-lives for less frequent dosing, reduced antigenicity, and lot to lot consistency. During Phase I we will identify sites in angiostatin that can be modified without significantly affecting the protein?s in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified angiostatin-like proteins for testing in animal models of cancer. The improved characteristics of these novel proteins will allow for the rapid validation of efficacy in both pre-clinical and clinical studies for cancer.
