Abstract 6736: Preclinical development of ADCT-241, a novel exatecan-based antibody-drug conjugate targeting PSMA for the treatment of prostate cancer

Abstract Prostate specific membrane antigen (PSMA) is a 750 amino acid, homodimeric type II transmembrane glycoprotein expressed mainly in prostate tissues, but also at low levels in renal proximal tubules, the small intestine, and the brain. PSMA is known to have two enzymatic functions, firstly in the removal of glutamate from dietary folates in the small intestine, and secondly in hydrolysis of the peptidic neurotransmitter N-acetylaspartylglutamate. In the oncology setting PSMA is a clinically validated target with its expression being upregulated in prostate cancer as well an association with progression and aggressiveness of the disease. Here, the generation and preclinical characterization of ADCT-241, a novel antibody-drug conjugate (ADC) targeting PSMA is described. ADCT-241 is composed of a fully human IgG1 antibody directed against PSMA (anti-PSMA mAb), to which the PL2202 payload, containing the topoisomerase I inhibitor exatecan, has been stochastically conjugated via a cleavable valine-alanine linker with a drug:Ab ratio of 4 (DAR 4). In vitro, anti-PSMA mAb showed good binding affinity for human PSMA and cross-reactivity to rat and cynomolgus monkey PSMA. In addition, ADCT-241 showed specific and potent killing of prostate cancer cell lines, including LNCaP and C4-2, in in vitro cytotoxicity assays when compared to a non-binding control DAR 4 ADC containing the PL2202 payload. ADCT-241 showed bystander activity in in vitro assays employing PSMA-positive prostate cancer cell lines and PSMA-negative PC-3 cells. In vivo, administration of a single intravenous (IV) dose of ADCT-241 was associated with potent anti-tumor activity in prostate cancer xenograft models. Finally, in toxicology studies in rats and cynomolgus monkeys, ADCT-241 was well tolerated at dose levels up to 150 and 75 mg/kg, respectively, following dosing on Day 1 and 22. Circulating serum total antibody, total ADC, and free exatecan concentrations were determined, and showed good in vivo stability for ADCT-241 and a half-life of ∼8.5 days in cynomolgus monkeys. In summary, ADCT-241 is a novel, stable PSMA-targeting ADC that mediates potent and specific anti-tumor activity in mouse xenograft models and exhibits an excellent tolerability profile in rats and cynomolgus monkeys. The data presented support future clinical development of ADCT-241 for the treatment of prostate cancer indications. Citation Format: Ben Leatherdale, Beccie Martin, Banusha Rajeenthira, Cecile Oblette, Lara Montolio, Abigail Kimpalu, Pedro L. Alves, Hafsah Omar, Alison Faid, Elizabeth Horsley, Lina Baxter, Valenti Gomez, Charlie Britten, Lolke de Haan, Paul W. Hogg, Chris Pickford, Patrick H. van Berkel. Preclinical development of ADCT-241, a novel exatecan-based antibody-drug conjugate targeting PSMA for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6736.