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
{"title":"A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer.","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","doi":"10.1080/19420862.2024.2438173","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>TRAILR2</i> or <i>CDH3</i> 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.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2438173"},"PeriodicalIF":5.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11633135/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"mAbs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2024.2438173","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.