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

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

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 bispec...

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Main Authors: Peter Jung, Stefan P. Glaser, Jing Han, Alexandra Popa, Laura Pisarsky, Ningping Feng, Antonia Geyer, Franziska Haderk, Donat Alpar, Christopher Bristow, Susanne Schmittner, Paula-Elena Traexler, Mikhila Mahendra, Birgit Poehn, Poojabahen Gandhi, Roberto Fiorelli, Sanket Awate, Nicole Budano, Florian Martin, Christoph Albrecht, Barbara Drobits-Handl, 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
Format: Article
Language:English
Published: Taylor & Francis Group 2024-12-01
Series:mAbs
Subjects:
Apoptosis
bispecific antibody
CDH3
pancreatic cancer
targeted therapy
TRAILR2
Online Access:https://www.tandfonline.com/doi/10.1080/19420862.2024.2438173
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Summary: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 monotherapy. Together with the potential to deliver a favorable safety profile, these data support clinical testing of TR2/CDH3 BAB in patients with PDAC.
ISSN:1942-0862
1942-0870

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