Abstract Antibody-drug conjugates (ADCs) enable the selective delivery of highly cytotoxic payloads to tumors and are emerging as new, promising therapeutic options for prostate cancer. Prostate stem cell antigen (PSCA) is a cell-surface antigen that is highly overexpressed in prostate cancer and upregulated in advanced disease states, while minimally expressed in normal tissues, making it an ideal target for ADC therapy. In this study, we identified and generated full-length human anti-PSCA antibodies, exhibiting high binding affinity and rapid internalization into PSCA-expressing cancer cells. Various cytotoxic drugs (e.g., monomethyl auristatin E (MMAE), DM1, etc.) were conjugated to the lead anti-human PSCA antibody (A2) using a chemically validated linker. Among the resulting ADC candidates, A2-MMAE demonstrated the most potent, concentration-dependent cytotoxicity against PSCA-positive human prostate cancer cell lines, with an IC50 range of 0.18-2.17 nM, while exhibiting no cytotoxicity in PSCA-negative cells. Hydrophobic interaction chromatography (HIC-HPLC) analysis revealed a heterogeneous distribution of drug-to-antibody ratios (DARs), with an average DAR of 4.84. Furthermore, A2-MMAE retained a high level of total ADC integrity following 10 days of incubation in mouse plasma, indicating a robust plasma stability. These findings suggest that the novel anti-PSCA ADC (anti-PSCA-VC-PAB-MMAE), characterized by its strong target specificity, high potency, and excellent stability, holds promise as a safer and more effective therapeutic for prostate cancer. Ongoing studies will evaluate its in vivo antitumor efficacy, tolerability, safety, and pharmacokinetic/pharmacodynamic (PK/PD) profiling in mouse models. Citation Format: Yanyang Cao, Evelyn A. Kono, Robert E. Reiter, . Development of a novel PSCA-targeting antibody-drug conjugate with high potency and stability for prostate cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1659.
Cao et al. (2026) studied this question.