Radioimmunotherapy of prostate cancer in human xenografts using monoclonal antibodies specific to prostate specific membrane antigen (PSMA): Studies in nude mice

BACKGROUND. Prostate specific membrane antigen (PSMA), expressed by virtually all prostate cancers is an ideal target for targeted therapy of prostate cancer. Radiolabeled J591 monoclonal antibody (MAb) binds with high affinity to an extracellular epitope of PSMA and localizes specifically in PSMA positive LNCaP tumors in vivo. METHODS. Pre-clinical radioimmunotherapy (RIT) studies using I-131-huJ591 and Y-90-1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraaceticacid (DOTA)-huJ591 MAbs were studied in nude mice bearing LNCaP xenografts. RESULTS. A 15-90% reduction in mean tumor volume was observed after a single dose of I-131-huJ591 (3.7-11.1 MBq) or Y-90-DOTA-huJ591 (3.7-7.4 MBq). The median survival time increased 2-3 times relative to untreated controls. Multiple administrations of fractionated doses of Y-90-DOTA-huJ591 were even more effective with minimal toxicity. Radiation dose to blood and tumor was higher with Y-90 than with I-131. The maximum tolerated dose (MTD) is 5.55 MBq for Y-90-DOTA-huJ591 and more than 11.1 MBq for I-131-huJ591. For 90Y-DOTA-huJ591 at MTD, dose to the tumor was 2,753 cGy. CONCLUSIONS. In nude mice bearing PSMA positive tumors, radiation dose to the tumor with Y-90w-DOTA-J591 is greater for large tumors than with I-131-J591. The theoretical and practical considerations strongly suggest that 90Y-DOTA-huJ591 may be a suitable radiopharmaceutical for the treatment of prostate cancer.