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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2024-12-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Peter Jung |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c2908d372da44d1ba0185724032d1d65 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-c2908d372da44d1ba0185724032d1d652025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2438173A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancerPeter Jung0Stefan P. Glaser1Jing Han2Alexandra Popa3Laura Pisarsky4Ningping Feng5Antonia Geyer6Franziska Haderk7Donat Alpar8Christopher Bristow9Susanne Schmittner10Paula-Elena Traexler11Mikhila Mahendra12Birgit Poehn13Poojabahen Gandhi14Roberto Fiorelli15Sanket Awate16Nicole Budano17Florian Martin18Christoph Albrecht19Barbara Drobits-Handl20Sathanandam S. Anand21Srinath Kasturirangan22Francesca Trapani23Norbert Schweifer24Joseph R. Marszalek25Ulrike Tontsch-Grunt26Mark Pearson27Timothy P. Heffernan28Norbert Kraut29Christopher P. Vellano30Juan Manuel García-Martínez31Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USAGlobal Computational Biology and Digital Sciences, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USATranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USATranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, GermanyTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USATranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaBoehringer Ingelheim Pharmaceuticals, Inc., Nonclinical Drug Safety, Ridgefield, CT, USABoehringer Ingelheim Pharmaceuticals, Inc., Biotherapeutics Discovery, Ridgefield, CT, USATranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaCancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaTranslational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, AustriaExploitation 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.https://www.tandfonline.com/doi/10.1080/19420862.2024.2438173Apoptosisbispecific antibodyCDH3pancreatic cancertargeted therapyTRAILR2 |
| spellingShingle | 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 A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer mAbs Apoptosis bispecific antibody CDH3 pancreatic cancer targeted therapy TRAILR2 |
| title | A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer |
| title_full | A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer |
| title_fullStr | A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer |
| title_full_unstemmed | A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer |
| title_short | A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer |
| title_sort | trailr2 cdh3 bispecific antibody demonstrates selective apoptosis and tumor regression in cdh3 positive pancreatic cancer |
| topic | Apoptosis bispecific antibody CDH3 pancreatic cancer targeted therapy TRAILR2 |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2438173 |
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