Targeted Radioimmunotherapy of Prostate Cancer Using Monoclonal Antibodies to the Extracelluar Domain of Prostate-Specific Membrane Antigen

Abstract : The purpose of this research proposal was to evaluate the potential diagnostic and therapeutic value of radiolabeled monoclonal antibodies (J591, J533, J415) specific to the extracellular domain of PSMA (PSMA(sub ext)). We previously reported all the in vitro studies and some preliminary biodistribution and radioimmunotherapy studies in nude mice. This final report describes all the in vivo studies including biodistribution and radioimmunotherapy evaluations. The pharmacokinetics, biodistribution, and tumor uptake of (131)I and (111)In- labeled MAbs were performed in nude mice bearing LNCaP tumors. There were significant differences in the absolute tumor uptake (%ID/g) among the (131)I-MAbs. By contrast, the tumor uptake of (111)In and (177)Lu labeled MAbs was similar. However, the T/B and tumor/muscle (TIM) ratios were significantly higher with (111)In and (177)Lu compared to (131)I-MAbs. In addition, the ratios were significantly higher with J591 and J415 compared to that of 7E11 (antibody specific to intracellular domain of PSMA). Radioimmunotherapy studies with (131)I-J59l, (90)Y-DOTA-J591, and (177)Lu-DOTA-J591 produced an unambiguous dose-response resulting in tumor shrinkage or slowing the growth over a period of 4-6 weeks. The most important finding is that this therapeutic response was specific since (90)Y-non-specific MAb had no response. These results clearly demonstrate that radiolabeled MAbs specific PSMA(sub ext) are useful for RID and RIT of prostate cancer.