Preclinical Evaluation of [212Pb]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.

Methods

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.

Results

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, P < 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.

Conclusion

The preclinical results support the clinical development of 212Pb-ADVC001 as a targeted α-therapy for the treatment of patients with PC.