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

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein with elevated expression in primary and metastatic prostate cancer 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 the progression and aggressiveness of the disease. ADCT-241 is a novel antibody-drug conjugate (ADC) composed of the fully human monoclonal antibody 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 prostate cancer cell lines in vitro and antitumor efficacy in vivo in prostate cancer cell line- and patient-derived xenografts. ADCT-241 showed target-dependent internalization, topoisomerase 1 inhibition, cell-cycle arrest at the 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 days 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 the progression of ADCT-241 into clinical trials in patients with metastatic castration-resistant prostate cancer.