A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer

作者：Peter Jung, Stefan Glaser, Jing Han, Alexandra Popa, Laura Pisarsky, Ningping Feng, Antonia Geyer, Franziska Haderk, Donát Alpár, Christopher A. Bristow, Susanne Schmittner, Paula-Elena Traexler, Mikhila Mahendra, Birgit Poehn, Poojabahen Gandhi, Roberto Fiorelli, Sanket Awate, Nicole Budano, Florian Martin, Christoph Albrecht, Barbara Drobits, Sathanandam S. Anand, Srinath Kasturirangan, Francesca Trapani, Norbert Schweifer, Joseph R. Marszalek, Ulrike Tontsch-Grunt, Mark Pearson, Timothy P. Heffernan, Norbert Kraut, Christopher P. Vellano, Juan Manuel García‐Martínez · 发表于：mAbs · 年份：2024 · DOI：10.1080/19420862.2024.2438173 · 被引用次数：3 · 研究领域：Endoplasmic Reticulum Stress and Disease、Neuroblastoma Research and Treatments、Phagocytosis and Immune Regulation

Exploitation of extrinsic apoptosis signaling via TRAILR2 activation represents a promising therapeutic concept in cancer treatment. The limited clinical success of previous TRAILR2 agonistic agents, to date, has been ascribed to either poor efficacy or hepatotoxicity. TR2/CDH3 BAB is a human bispecific antibody that relies on binding both CDH3 and TRAILR2 on cell surfaces to achieve TRAILR2 hyperclustering and efficient apoptosis induction by TRAILR2 signaling selectively in CDH3-expressing tumor cells. We demonstrate target-dependent TR2/CDH3 BAB anti-tumor activity in CRISPR/Cas9-engineered TRAILR2 or CDH3 knock-out cells. By utilizing the cell line screening platform PRISM, we found selective TR2/CDH3 BAB efficacy in various cancer types, such as pancreatic, gastric, colorectal, and triple negative breast cancer. The efficacy of TR2/CDH3 BAB correlated with caspase activation in cancer cell lines and in xenograft tumor tissues. In pancreatic ductal adenocarcinoma (PDAC), where patient benefit from current cytotoxic therapy options is unsatisfactory, a close to uniform cell surface expression of CDH3 and TRAILR2 was observed, which will qualify the majority of PDAC patients for TR2/CDH3 BAB-based treatment. TR2/CDH3 BAB demonstrated anti-tumor activity in a panel of PDAC patient-derived xenograft models, including tumor regressions. By combining TR2/CDH3 BAB with chemotherapeutic agents, deeper and more sustained anti-tumor responses were observed when compared to monother...