Prostate cancer is the most common cancer in men and results in the second highest cancer death rate. Effective treatment options exist for localized prostate cancer, however there are few available treatment options once the disease has spread outside the prostate. As a result, accurate diagnosis and staging is critical for effective treatment and management of the disease. Imaging for occult prostate cancer has utilized bone and CT scans with limited success. More recently, the ProstaScint scan has been utilized with improved results. The ProstaScint scan utilizes the 7E11 antibody specific for an intracellular epitope of Prostate-Specific Membrane Antigen (PSMA). Because of the inaccessibility of the epitope in live prostate cancer cells, this test is relatively insensitive as tumors must reach a size wherein a substantial portion is composed of dead or apoptotic cells for detection. In this application, we propose to conduct preclinical studies aimed at developing an improved imaging reagent utilizing monoclonal antibodies specific for extracellular PSMA epitopes. These antibodies have been shown to strongly bind to live prostatic cancer cells. Studies will be conducted to obtain preclinical data on a selected antibody, designated 3C6, specific for a protein conformational epitope that has been determined to have optimal cell and antigen binding properties to conduct a phase I clinical imaging trial. Methods for coupling of the chelator CHX-A""""""""-DTPA to the antibody without loss in binding properties will be determined. Antibody manufactured under cGMP conditions will be analyzed for structural integrity, specificity, and potency. Biodistribution of the labeled antibody will be tested in mice bearing PSMA-expressing human prostate cancer cell tumors. Stability of the antibody in vivo and in normal human serum will be tested. Finally, general safety tests will be conducted with the final antibody product. The results will form a body of basic preclinical results to guide the next phase of this work involving clinical studies in humans. An imaging reagent utilizing antibodies capable of strong and efficient binding to live prostate cancer cells would be expected to provide dramatically improved capability compared to current methods ? ?
