Preclinical Evaluation of [ ²¹² Pb]Pb-ADVC001: A Prostate-Specific Membrane Antigen–Targeted α-Therapy for Prostate Cancer

Prostate-specific membrane antigen (PSMA)-directed radiopharmaceutical therapies continue to improve treatment outcomes in patients with metastatic castration-resistant prostate cancer. Here, we report the in vitro and in vivo characterization of a PSMA-targeted therapy (ADVC001) specifically designed for targeted α-therapy with ²¹²Pb. <b>Methods:</b> The binding affinity to PSMA was determined by PSMA enzymatic assays and by radioligand binding assays using PSMA-high prostate cancer (PC) cells. In vitro cytotoxicity against PC cell lines with high and medium PSMA expression was evaluated using clonogenic, metabolic, and imaging-based cytotoxic assays. Pharmacokinetics and biodistribution were assessed using PSMA-high subcutaneous tumor xenografts. In vivo single-dose and multidose efficacy was assessed in subcutaneous PC xenograft models expressing various levels of PSMA. <b>Results:</b> A high binding affinity to PSMA was observed for ADVC001 with nanomolar inhibitory concentration of 50% values. In cellular assays, [²¹²Pb]Pb-ADVC001 (²¹²Pb-ADVC001 hereafter for simplicity) exhibited specific cytotoxic activity against PSMA-expressing cells with nanomolar effective concentration of 50% values. In vivo biodistribution of ²¹²Pb-ADVC001 in the PC3-PIP xenograft model revealed rapid and persistent tumor uptake, fast renal clearance, and low retention in normal tissues. Single-dose efficacy studies of ²¹²Pb-ADVC001 (0.46 MBq) showed improved survival compared with [¹⁷⁷Lu]Lu-PSMA-I&T (¹⁷⁷Lu-PSMA-I&T hereafter for simplicity) (20 MBq) treatment. In a multidose experiment, 2 doses of ²¹²Pb-ADVC001 (0.5 MBq) significantly increased median survival (86 d vs. 45.5 d, <i>P</i> < 0.05) compared with 2 doses of ¹⁷⁷Lu-PSMA-I&T (15 MBq). Treatment with ²¹²Pb-ADVC001 (0.5 MBq) after initial ¹⁷⁷Lu-PSMA-I&T (15 MBq) relapse showed an enhanced survival benefit (59.5 d). In a C4-2 xenograft model with medium-level PSMA expression, single doses of 0.3, 0.8, and 1.1 MBq of ²¹²Pb-ADVC001 significantly extended median survival to 34, 57, and 62.5 d, compared with untreated cohorts (16 d). All treatments were well tolerated. <b>Conclusion:</b> The preclinical results support the clinical development of ²¹²Pb-ADVC001 as a targeted α-therapy for the treatment of patients with PC.