TARGETING EXTRACELLULAR MATRIX, A NOVEL ANTIANGIOGENIC

Angiogenesis inhibitors hold great promise as therapies for solid tumors. Degraded extracellular matrix (ECM) proteins play an active and essential role in angiogenesis. We found that several monoclonal antibodies (Mabs) against denatured collagen were potent inhibitors of angiogenesis / tumor growth in animal models. We hypothesize that cryptic sites in other extracellular matrix proteins play an active role in angiogenesis. Antagonists of these sites will block angiogenesis / tumor growth. Because remodeling of the ECM is specifically extensive at angiogenic sites, Mabs to degraded ECM protein may prove useful for target drug delivery. Further, such Mabs could have diagnostic use for detecting the degraded ECM Protein fragments in sera of patients with angiogenic conditions. We propose the following Specific Aims: 1) Use subtractive immunization to isolate a set of Mabs that react specifically with the denatured forms of three different ECM. 2) Identify Mabs which inhibit vascular endothelial cell adhesion or migration on denatured ECM Proteins. 3) Test the Mabs identified in Aim 2 in CAM assays for antiangiogenic activity. The results of these studies will lead to the discovery of reagents for antiangiogenic therapies and diagnostic markers. PROPOSED COMMERCIAL APPLICATION: The aims of this proposal are to discover monoclonal antibodies that block angiogenesis. These reagents could provide a means to treat most solid tumors and other diseases with aberrant vessel formation. Further, because ECM remodeling occurs during angiogesesis, these studies have the potential to generate reagents for a sensitibe assay to detet angiogenic markers in serum or urine.