The FAP × CD3 bispecific antibody OMTX305 induces T cell–mediated antitumor effects in patient-derived ex vivo models of solid tumors
Within solid tumors, stromal barriers and immune exclusion limit the success of immunotherapies. Thus, novel therapeutic approaches are required to remodel the tumor-supportive microenvironment and enhance therapeutic responses. We developed a bispecific, trivalent Fab-eIg T cell engager (OMTX305) targeting fibroblast activation protein (FAP), a marker of tumor-promoting cancer-associated fibroblasts. The translational potential of OMTX305 was investigated in 2D and 3D patient-derived preclinical models, with a focus on precision-cut tumor slices (PCTSs) of lung and ovarian cancer cocultured with autologous PBMCs. By combining spatial biology with cytokine and transcriptomic analysis, we show that OMTX305 treatment eliminated FAP-expressing fibroblasts, induced interferon responses and extracellular matrix remodeling, ultimately triggering bystander killing of adjacent tumor cells. Distinct immune phenotypes and PD-L1 expression patterns appeared to be associated with differential treatment responses, suggesting their potential as biomarkers for patient stratification. Our findings highlight the clinical potential of targeting stromal elements as a cancer therapy and establish PCTS as a powerful preclinical platform for personalized immunotherapy assessment.
Authors
- Katrin S. Kurz (ORCID: https://orcid.org/0000-0002-1361-8729)
- Laureano Simón
- Oliver Seifert (ORCID: https://orcid.org/0000-0003-1876-4212)
- Lennart Kühl (ORCID: https://orcid.org/0000-0002-6887-8923)
- Chunguang Liang (ORCID: https://orcid.org/0000-0002-0305-2522)
- Adrian Kneer
- Annelie K. Schäfer (ORCID: https://orcid.org/0000-0001-8869-8690)
- Jan Schlegel (ORCID: https://orcid.org/0000-0003-3159-8079)
- Gerhard Preißler
- Monilola A. Olayioye (ORCID: https://orcid.org/0000-0003-1093-263X)
- Thomas E. Mürdter (ORCID: https://orcid.org/0000-0002-8786-8122)
- Walter E. Aulitzky (ORCID: https://orcid.org/0000-0003-2165-0187)
- Matthias Schwab (ORCID: https://orcid.org/0000-0002-9984-075X)
- Isabel Egaña
- Roland E. Kontermann (ORCID: https://orcid.org/0000-0001-7139-1350)
- Julia Thiel (ORCID: https://orcid.org/0009-0003-5437-8498)
- Meng Dong (ORCID: https://orcid.org/0000-0002-6434-1678)
- Myriam Fabre
- German Ott
- Sascha Dreher
Institutions
- University of Stuttgart (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- Robert Bosch Hospital (DE)
- Oncomatryx (Spain) (ES)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- Research Institute for Work, Technology and Culture (DE)
- Jena University Hospital (DE)
- University Hospital Ulm (DE)
- Friedrich Schiller University Jena (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-11
- DOI
- https://doi.org/10.1126/sciadv.aee2124
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Berthold Leibinger Stiftung
- Robert Bosch Stiftung
- Deutsche Forschungsgemeinschaft
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
- Bundesministerium für Forschung und Technologie