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

TL;DR

This study evaluates a new prostate cancer treatment using a radioactive compound that targets a specific protein on cancer cells, showing promising results in preclinical tests.

Contribution

The paper introduces a novel PSMA-targeted alpha therapy, 212Pb-ADVC001, and demonstrates its efficacy and safety in preclinical prostate cancer models.

Findings

212Pb-ADVC001 showed high binding affinity to PSMA and specific cytotoxic activity against PSMA-expressing cells.

In vivo tests showed improved survival with 212Pb-ADVC001 compared to existing treatments like 177Lu-PSMA-I&T.

The treatment was well tolerated and showed enhanced survival benefits even after relapse from prior therapy.

Abstract

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.

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