Abstract 2649: Tumor endothelial cell and cancer cell targeting anti-PRND antibody-drug conjugate to treat hypervascular tumors such as glioblastoma and sarcomas

Abstract Antibody-drug conjugates (ADCs) have emerged as a major class of targeted therapeutics but remain limited by poor tumor penetration, antigen heterogeneity, and a narrow therapeutic window. To overcome these limitations, we developed an anti-PRND ADC targeting PRND (Doppel), a prion-like glycoprotein selectively expressed in tumor endothelial cells (TECs) and cancer cells but absent in normal tissues except in the testis. This localization enables direct vascular targeting without diffusion barriers and provides a unique opportunity for precise drug delivery to the tumor vasculature. The resulting antibody-drug conjugate, 3H9-KGDEVD-MMAE, is a homogeneous ADC (DAR = 8) free of soluble aggregates. It couples a high-affinity anti-PRND antibody (3H9) with a caspase/cathepsin B-cleavable KGDEVD linker that can be specifically cleaved by both cathepsin B and caspase-3/7. This dual activation allows MMAE release through lysosomal cathepsin B and induces apoptosis of PRND positive cells, and caspase-3/7 from the apoptosis of target cells induces the apoptosis of adjacent tumor tissues. The caspase-mediated cleavage establishes an in-situ feedback amplification loop that maintains continuous local drug release, sustained cytotoxicity, and producing a potent bystander effect that overcomes antigen heterogeneity. By combining TEC and cancer cell-specific targeting with a caspase/cathepsin-responsive linker, 3H9-KGDEVD-MMAE (anti-PRND ADC), achieves deep intratumoral penetration, robust vascular disruption, and durable antitumor efficacy. In preclinical models of glioblastoma, sarcoma, and renal cell carcinoma (RCC) - hypervascular malignancies with limited ADC options, anti-PRND ADC induced extensive and durable tumor regressions without systemic toxicity. Collectively, these findings establish anti-PRND ADC as a next-generation vascular-disrupting ADC, integrating endothelial docking with apoptosis-triggered drug amplification for potent and selective control of highly vascularized tumors. Acknowledgments: This research was supported by the Korea Drug Development Fund (HN21C0264) funded by the Ministry of Science and ICT and the National Research Foundation of Korea (NRF) grant (2020R1A2C2015026) funded by the Korea government (MSIT). Citation Format: Byoungmo Kim, Ha Kyeong Lee, So-Young Choi, Sera Lee, Sang Yoon Kim, Youngro Byun, Seong Who Kim. Tumor endothelial cell and cancer cell targeting anti-PRND antibody-drug conjugate to treat hypervascular tumors such as glioblastoma and sarcomas [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 2649.