Abstract 1158: Preclinical characterization of AZD0516, a novel STEAP2 antibody-drug conjugate (ADC) for the treatment of prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) continues to pose a significant clinical challenge and is associated with poor survival rates in patients who failed previous lines of androgen receptor axis-targeted therapies and taxanes. Antibody drug conjugates (ADCs) provide a novel approach to traditional chemotherapy by targeting tumor-specific antigens to deliver cytotoxic payloads while sparing normal tissue and enhancing the therapeutic index. Herein, we describe the preclinical characterization of AZD0516, a first-in-class ADC directed against six-transmembrane epithelial antigen of the prostate-2 (STEAP2), a novel tumor associated antigen that is highly and homogenously expressed across all stages of prostate cancer. The anti-STEAP2 monoclonal antibody (mAb) is conjugated via interchain cysteines to a maleimide-reactive, β-glucuronidase-cleavable linker bearing the topoisomerase 1 inhibitor (TOP1i) payload, exatecan. The STEAP2 antibody binds specifically to the extracellular domains of human, cynomolgus monkey, mouse, and rat STEAP2, but exhibits no detectable binding to other STEAP family members. The fragment crystallizable (Fc) domain of the antibody binder portion carries three amino acid point mutations designed to reduce Fc-mediated immune effector functions. In vitro characterization of the STEAP2 mAb in prostate cancer cells demonstrated specific binding, rapid internalization, and efficient lysosomal trafficking. In vitro cytotoxicity assays with AZD0516 revealed IC50 values in the low nM range and the ADC induced both single- and double-strand DNA breaks, characteristic of the proposed primary mechanism of action (MoA) of the TOP1i payload, namely, DNA damage and apoptotic cell death. Exatecan-driven bystander cell killing from intracellular release of payload was demonstrated in co-culture systems involving STEAP2-positive and negative cell lines. Murine plasma pharmacokinetic data suggest minimal impact of linker-payload conjugation on antibody clearance, while maintaining high plasma stability. The mechanistic and pharmacodynamic effects of AZD0516 were observed in a prostate cancer cell line-derived xenograft (CDX) model via a dose-dependent increase in positive staining for γH2AX foci, indicative of DNA damage. AZD0516 monotherapy administration in prostate cancer CDX and patient-derived xenograft models led to sustained tumor responses. AZD0516 was well-tolerated in both rats and cynomolgus monkeys with no unexpected toxicities observed. Safety findings included hematological and gastrointestinal effects, consistent with the MoA and known effects of TOP1i payloads. Together, these data support exploring AZD0516 clinically for patients with mCRPC. Citation Format: Darlene Monlish, Vanessa Muniz-Medina, Mel Ehudin, Dewald van Dyk, Claire Myers, Rachel Lawrence, Liang Zhang, Linda Irons, Chara Stavraka, Wardha Qureshi, Ruoyan Chen, Asurayya Worrede, Nicolas Giraldo, Miljenka Vuko, Melody Handali, Ali Saleh, Balakumar Vijayakrishnan, Maximillian Lee, Jeong Min Han, Crystal Cheung, Ariel Endlich-Frazier, Amber Lee, Mark Hutchinson, Andrew Dippel, Gilad Kaplan, Keith Rickert, Shraddha Kale, Ryan Fleming, Clare Hoover, Benedicte Recolin, Jan Zaucha, Sreedevi Kesavan, John` Meekin, Aida Mariani, Christian Eisen, John Bullen, Eric Gangl, Jay Harper, Andreas Maderna, Edward Rosfjord, Frank Comer, Elaine Hurt, Neil Gibson, Puja Sapra. Preclinical characterization of AZD0516, a novel STEAP2 antibody-drug conjugate (ADC) for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 1158.