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Oncotarget. 2018 May 22;9(39):25597-25616. doi: 10.18632/oncotarget.25390. eCollection 2018 May 22.

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.

Author information

1
UniversityCancerCenter (UCC) Dresden, Tumor Immunology, 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.
2
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
3
German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Institute of Immunology, Medical Faculty, 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.
5
National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany.
6
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany.

Abstract

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.

KEYWORDS:

CAR T cell immunotherapy; PET imaging; affinity; nanobody; solid epithelial tumor

Conflict of interest statement

CONFLICTS OF INTEREST MB has filed patent applications related to the UniCAR platform.

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