From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells in vitro and in vivo
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Susann Albert1,*, Claudia Arndt2,*, Stefanie Koristka2, Nicole Berndt3, Ralf Bergmann2, Anja Feldmann2, Marc Schmitz3,4,5, Jens Pietzsch2,6, Jörg Steinbach2,5,6 and Michael Bachmann1,2,3,5
1UniversityCancerCenter (UCC) Dresden, Tumor Immunology, ‘Carl Gustav Carus’ Technische Universität Dresden, Dresden, Germany
2Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
3German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
4Institute of Immunology, Medical Faculty, ‘Carl Gustav Carus’ Technische Universität Dresden, Dresden, Germany
5National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany
6Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany
*These authors contributed equally to this work
Michael Bachmann, email: [email protected]
Keywords: CAR T cell immunotherapy; solid epithelial tumor; nanobody; affinity; PET imaging
Received: January 22, 2018 Accepted: April 28, 2018 Published: May 22, 2018
CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and “on-target, off-tumor” reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR+ epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments in vivo, the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.
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