Soluble trivalent engagers redirect cytolytic T cell activity toward tumor endothelial marker 1
| Autor: | Laureline Wetterwald, George Coukos, Vasileios Atsaves, Tatiana V. Petrova, Mariastella de Tiani, Julie K. Fierle, Steven M. Dunn, Johan Abram-Saliba, Matteo Brioschi |
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| Rok vydání: | 2021 |
| Předmět: |
T cell engager
sarcoma medicine.medical_treatment T cell TEM1 Article General Biochemistry Genetics and Molecular Biology BiTE CAR cancer immunotherapy endosialin/CD248 Mice Cancer immunotherapy Stroma Antigens CD Antigens Neoplasm Cell Line Tumor medicine Animals Humans Receptors Chimeric Antigen Chemistry Mesenchymal stem cell Cancer medicine.disease Xenograft Model Antitumor Assays Chimeric antigen receptor Clone Cells Cytolysis medicine.anatomical_structure Solubility Cancer research Female Sarcoma Protein Multimerization Protein Binding Single-Chain Antibodies T-Lymphocytes Cytotoxic |
| Zdroj: | Cell Reports Medicine Cell reports. Medicine, vol. 2, no. 8, pp. 100362 |
| ISSN: | 2666-3791 |
| DOI: | 10.1016/j.xcrm.2021.100362 |
| Popis: | Summary Tumor endothelial marker 1 (TEM1) is an emerging cancer target with a unique dual expression profile. First, TEM1 is expressed in the stroma and neo-vasculature of many human carcinomas but is largely absent from healthy adult tissues. Second, TEM1 is expressed by tumor cells of mesenchymal origin, notably sarcoma. Here, we present two fully human anti-TEM1 single-chain variable fragment (scFv) reagents, namely, 1C1m and 7G22, that recognize distinct regions of the extracellular domain and possess substantially different affinities. In contrast to other, well-described anti-TEM1 binders, these fragments confer cytolytic activity when expressed as 2nd generation chimeric antigen receptors (CARs). Moreover, both molecules selectively redirect human T cell effector functions toward TEM1+ tumor cells when incorporated into experimental soluble bispecific trivalent engagers that we term TriloBiTEs (tBs). Furthermore, systemic delivery of 1C1m-tB prevents the establishment of Ewing sarcoma tumors in a xenograft model. Our observations confirm TEM1 as a promising target for cancer immunotherapy and illustrate the prospective translational potential of certain scFv-based reagents. Graphical abstract Highlights Discovery and characterization of two fully human scFv binders targeting human TEM1 Specific killing of TEM1+ cancer cell lines Demonstration of a versatile soluble heterodimeric trivalent T cell engager format Fierle et al. describe the targeting of the human TEM1 (CD248/endosialin) tumor marker by redirecting the lytic activity of T cells. This study indicates that both cell-based CAR and soluble engager paradigms may have utility in this regard and suggests a potential immunotherapeutic approach for the treatment of soft-tissue sarcomas. |
| Databáze: | OpenAIRE |
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