Abstract 323: Preclinical evaluation of SDV2102, a novel PSMA-targeting DAR1 ADC for mCRPC treatment

Abstract Metastatic castration-resistant prostate cancer (mCRPC) presents a significant therapeutic challenge due to limited treatment options. Prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC tumors, making it a viable target for antibody-drug conjugates (ADCs). We developed SDV2102, a novel PSMA-targeting ADC designed to enhance tumor penetration and efficacy. SDV2102 utilizes a novel anti-PSMA antibody, D10, selected for its superior antigen-binding properties. The D10 antibody is conjugated with monomethyl auristatin E (MMAE), a tubulin-binding cytotoxic agent to which mCRPC tumors are inherently more sensitive than to topoisomerase I inhibitors. Notably, SDV2102 has a drug-to-antibody ratio (DAR) of 1, allowing for higher dosing and increased efficacy without proportional increases in systemic toxicity, thereby improving the therapeutic index. In vivo efficacy was assessed using the C4-2 cell-derived xenograft (CDX) model, characterized by high PSMA expression. SDV2102 demonstrated significantly greater anti-tumor efficacy than classical DAR4 ADCs constructed with either the generic J591 antibody or the D10 antibody when administered at equivalent doses of MMAE. Additionally, SDV2102 showed potent activity in patient-derived xenograft (PDX) models with low to moderate PSMA expression levels, with some tumors expressing as few as 25, 000 receptors per cell. This indicates that SDV2102 may be effective across a spectrum of PSMA expression in mCRPC tumors. Pharmacokinetic studies in rats revealed that SDV2102 has a favorable profile, closely mirroring that of the unconjugated D10 antibody, suggesting maintained antibody-like characteristics in circulation. Dose-response studies in the C4-2 model identified a minimum effective dose of 2.5 mg/kg. Toxicology studies in non-human primates showed no major toxicities at doses up to 24 mg/kg, with the maximum tolerated dose (MTD) not reached, indicating a wide therapeutic window. SDV2102 achieved a therapeutic index of 38, representing a substantial safety margin. These preclinical results support the advancement of SDV2102 into clinical trials as a promising therapeutic candidate for the treatment of mCRPC. Citation Format: Damien Dattler, Fabian Schlimpen, Constantin Semenchenko, Oleksandr Koniev, Sergii Kolodych. Preclinical evaluation of SDV2102, a novel PSMA-targeting DAR1 ADC for mCRPC treatment [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 323.