2. Academic Validation
  3. 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

  • MAbs. 2024 Jan-Dec;16(1):2438173. doi: 10.1080/19420862.2024.2438173.
Peter Jung 1,  Stefan P Glaser 1,  Jing Han 2,  Alexandra Popa 3,  Laura Pisarsky 1,  Ningping Feng 2,  Antonia Geyer 4,  Franziska Haderk 5,  Donat Alpar 4,  Christopher Bristow 2,  Susanne Schmittner 1,  Paula-Elena Traexler 1,  Mikhila Mahendra 2,  Birgit Poehn 1,  Poojabahen Gandhi 2,  Roberto Fiorelli 5,  Sanket Awate 2,  Nicole Budano 4,  Florian Martin 4,  Christoph Albrecht 1,  Barbara Drobits-Handl 1,  Sathanandam S Anand 6,  Srinath Kasturirangan 7,  Francesca Trapani 4,  Norbert Schweifer 4,  Joseph R Marszalek 2,  Ulrike Tontsch-Grunt 1,  Mark Pearson 1,  Timothy P Heffernan 2,  Norbert Kraut 1,  Christopher P Vellano 2,  Juan Manuel García-Martínez 1
Affiliations

Affiliations

  • 1 Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 2 Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Global Computational Biology and Digital Sciences, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 4 Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 5 Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
  • 6 Boehringer Ingelheim Pharmaceuticals, Inc., Nonclinical Drug Safety, Ridgefield, CT, USA.
  • 7 Boehringer Ingelheim Pharmaceuticals, Inc., Biotherapeutics Discovery, Ridgefield, CT, USA.
PMID: 39654063 DOI: 10.1080/19420862.2024.2438173
Abstract

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.

Keywords

Apoptosis; CDH3; TRAILR2; bispecific antibody; pancreatic cancer; targeted therapy.

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