Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed on prostate cancer as well as on the neovasculature of many non-prostate solid tumors. Lately, several small molecular PSMA binding ligands chelated to various radionuclides have been studied for imaging and treatment of prostate cancer lesions. One such clinically tested agent is PSMA-617, a DOTA derivative of a PSMA-specific targeting ligand. In our hands, radiochemical yields of PSMA-617 labeled with either 177Lu (β emitter) or 225Ac (α emitter) were greater than 97%. Binding experiments with 177Lu and 225Ac chelates of PSMA-617 and D-Glu PSMA-617 (a predicted non-PSMA binding, D-glutamic acid isomer of PSMA-617) were performed using the PSMA-positive, 22RV1 cell line. PSMA-617, was found to bind in a concentration dependent manner with very high affinity, whereas the cellular association of D-Glu PSMA-617 was found to be > 60-fold lower. The in vivo biodistribution of these two agents were investigated in BALB/c nu/nu mice bearing subcutaneous 22RV1 xenografts. Organ distribution revealed specific PSMA-617 uptake in the 22RV1 tumors and the PSMA+ kidneys, while the uptake of D-Glu PSMA-617 remained near background in both of these tissues. Different from tumor, PSMA-617 exhibited a rapid clearance from the kidneys to yield a high tumor-to-background contrast (tumor:blood = 300; tumor:muscle = 290; and tumor:kidney = 15) at 24 h post dose. Complementary antitumor activity studies were performed with 225Ac-labeled PSMA-617. Here, significant tumor growth inhibition was observed without detectable hematologic or renal toxicity to the mice. These data provide additional support for a phase 3 prospective trial currently being planned to evaluate 177Lu-PSMA-617 in patients with metastatic PSMA+ prostate cancers, along with the continued clinical investigation of 225Ac-PSMA-617 in a similar patient population.

Citation Format: Joseph A. Reddy, Melissa Nelson, LeCun Xu, Elaine Westrick, Marilynn Vetzel, Leroy Wheeler, Albert Felten, Hari Santhapuram, Iontcho Vlahov, Christopher P. Leamon. Specificity of PSMA-617 radiotherapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 852.