Bispecific antibodies for cancer therapy: Targeting tumor connective tissue

A new approach could improve the effectiveness of immunotherapies for certain types of cancer. Instead of directly attacking cancer cells, this treatment targets the tumor microenvironment. A bispecific antibody developed at the University of Stuttgart was tested on tissue slices from patients with lung and ovarian cancer in collaboration with researchers from the Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology at the Bosch Health Campus and Jena University Hospital. The study, published in the journal Science Advances, shows how the antibody attacks the tumor's connective tissue and triggers an immune response against the tumor.

 About the publication

A tumor consists of much more than just cancer cells. Among other things, the tumor's immediate surroundings contain connective tissue cells that can promote tumor growth and make it more difficult to treat. The researchers investigated a novel approach that targets not the cancer cells themselves, but rather these connective tissue cells (fibroblasts). Preclinical results show that the antibody OMTX305 can eliminate tumor-supporting cells in connective tissue and even kill neighboring tumor cells.

The research focuses on the FAP x CD3 bispecific antibody OMTX305, which belongs to the class of so-called “T-cell engagers.” It was developed by the Institute of Cell Biology and Immunology at the University of Stuttgart in collaboration with the Spanish industry partner Oncomatryx.

The defining characteristic of bispecific antibodies is that they can bind to two different cell types at the same time. The molecule used here binds, on the one hand, to CD3 receptors on T cells – immune cells that can directly kill diseased cells – and, on the other hand, to the FAP protein on tumor-supporting fibroblasts. It acts as a bridge between T cells and their target, the fibroblasts. These often form a dense network around the tumor that acts as a protective barrier and makes it difficult for immune cells and drugs to penetrate.

“With OMTX305, we have developed a molecule that specifically binds to tumor-supporting fibroblasts while simultaneously mobilizing the immune system’s killer T cells to combat them,” explains Prof. Roland Kontermann, head of the Department of Biomedical Engineering at the IZI. “The study results show that this approach is effective even in complex human tumor tissue. The new antibody therefore has the potential to make immunotherapies more effective.”

The studies were conducted in collaboration with the Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology using tumor tissue from patients at the Robert Bosch Hospital who had lung or ovarian cancer. A key methodological feature of the study is the combination of the new immunotherapeutic approach with a preclinical yet patient-oriented test system, namely tumor tissue slices (Precision-Cut Tumor Slices). Unlike traditional cell cultures, these tissue slices preserve numerous cell types and structures from the original tumor. This made it possible to study how the therapy works in a complex tumor environment, rather than just on isolated tumor cells.

Using this method, the researchers investigated how cancer cells, fibroblasts, and immune cells interact with one another and how this complex environment responds to treatment. It was particularly noteworthy that not only were the targeted cells killed, but neighboring tumor cells were also eliminated. The study thus provides evidence that the targeted elimination of tumor-supporting fibroblasts actually promotes a more extensive immune response against the tumor.

“Developing innovative biotherapeutics and testing them in preclinical, patient-relevant models requires an interdisciplinary team,” says Prof. Monilola Olayioye, director of the Department of Molecular Tumor Cell Biology at the IZI and spokesperson for the 3R-US Network. The network establishes meaningful patient models for cancer research based on the 3R principle – “Replace, Reduce, Refine”: to avoid, reduce, and refine animal testing. Since animal models generally do not adequately reflect the complexity of tumors, alternative models are particularly relevant for testing new therapeutics. “As part of 3R-US, we are therefore collaborating with the Bosch Health Campus. Julia Thiel's doctoral project, which has now been published in the journal Science Advances, is an excellent example of successful collaboration.”

About the publication: Thiel, J., Schlegel, J.A., Liang, C., Mürdter, T.E., Kneer, A., Dreher, S., Schäfer, A., Seifert, O., Kühl, L., Preissler, G., Simon, L., Fabre, M., Egaña, I., Kurz, K.S., Ott, G., Kontermann, R.E., Aulitzky, W.E., Schwab, M., Olayioye, M.A. & Dong, M. The FAP × CD3 bispecific antibody OMTX305 induces T cell–mediated antitumor effects in patient-derived ex vivo models of solid tumors. Sci. Adv. 12, eaee2124(2026). DOI:10.1126/sciadv.aee2124

Participating institutions and funding
The project was funded by the Ministry of Science, Research, and the Arts (MWK) (3R-US Network), the German Research Foundation, the Federal Ministry of Research, Technology, and Space, the Leibinger Foundation, and the Robert Bosch Foundation. The participants included the University of Stuttgart, the Bosch Health Campus, and the Robert Bosch Hospital; the University Hospital of Jena (Comprehensive Cancer Center Central Germany); and the Spanish biotechnology company Oncomatryx.

Our "Publications compact" series presents further news about research findings from Stuttgart publications in a clear, concise, and accessible way for everyone.