Abstract ND03: ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer

Prostate cancer is the second leading cause of male cancer deaths in the US. There is currently no curative therapy available for advanced prostate cancer, indicating an urgent need for novel therapeutics. ABBV-969 is intended to address this critical need by delivering cytotoxin to tumor cells highly expressing prostate tumor antigens, STEAP1 (six transmembrane epithelial antigen of the prostate-1) and PSMA (prostate specific membrane antigen). STEAP1, minimally expressed on normal tissue, is highly enriched in over 85% of prostate tumors, where it promotes proliferation and invasion. As a prostate lineage marker PSMA expression is up to 100-fold higher on tumor versus healthy prostate tissue and correlates with tumor stage, aggressiveness, and recurrence. High expression and prevalence in prostate cancer identifies both antigens as attractive targets for antibody drug conjugates (ADCs). Since heterogeneous expression throughout and among tumors may limit effectiveness, a bispecific antibody that binds both STEAP1 and PSMA was designed using a dual variable domain immunoglobulin (DVD-Ig) format. This format enables bivalent engagement of both targets, potentially increasing tumor coverage and durability of therapy. ABBV-969 is a conjugate of the DVD-Ig with a proprietary topoisomerase-1 (Top1) inhibitor linker-drug identical to that used in two assets in clinical development, ABBV-400, targeting c-Met, and ABBV-706, targeting SEZ6. ABBV-969 binds to STEAP1 and PSMA with high affinity and is cytotoxic to cells expressing either or both antigens. ABBV-969 exhibits favorable drug-like properties, pharmacokinetics, and efficacy against patient-derived xenografts from castrate resistant prostate tumors and has broader activity than standard ADCs targeting either STEAP1 or PSMA. Furthermore, ABBV-969 is well tolerated in cynomolgus monkeys with bone marrow and gastrointestinal toxicities common to other Top1 inhibitor ADCs. ABBV-969 is currently in dose escalation in a Phase 1 clinical study (NCT06318273). Citation Format: Regina M. Reilly. ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND03.