Preclinical Characterization of ADCT-241, an Exatecan-Based Antibody–Drug Conjugate Against PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Abstract Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with elevated expression in primary and metastatic prostate cancer (PCa) compared with normal prostate tissues; with low levels in renal proximal tubules, small intestine, and the brain. PSMA is a clinically validated target and is associated with progression and aggressiveness of disease. ADCT-241 is a novel antibody–drug conjugate (ADC) composed of the fully human monoclonal antibody (mAb) 2A10, directed against PSMA, to which the exatecan-containing PL2202 payload was stochastically conjugated with a drug-to-antibody ratio of 4. 2A10 was selected over J591, as it showed good binding affinity, a better half-life, and superior internalization properties and antitumor activity compared with a J591-based ADC. ADCT-241 showed specific, potent killing of PCa cell lines in vitro and antitumor efficacy in vivo in PCa cell line and patient-derived xenografts. ADCT-241 showed target-dependent internalization, topoisomerase 1 (TOP1) inhibition, cell cycle arrest at G2/M phase followed by apoptosis-induced cell death, and in vitro bystander activity. In rats and cynomolgus monkeys, ADCT-241 was well tolerated at dose levels ≤150 and 75 mg/kg, respectively, following dosing on day 1 and 22. Circulating serum total antibody, total ADC, and free exatecan concentrations showed good in vivo stability and a half-life of 8 to 10 days in cynomolgus monkeys. ADCT-241 demonstrated potent, specific in vitro and in vivo antitumor activity and it was stable and well tolerated in rats and cynomolgus monkeys, warranting progression of ADCT-241 into clinical trials in patients with metastatic castration-resistant PCa.