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
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Pages (from-to) | 25597-25616 |
Number of pages | 20 |
Journal | Oncotarget |
Volume | 9 |
Issue number | 39 |
Publication status | Published - 22 May 2018 |
Peer-reviewed | Yes |
External IDs
PubMed | 29876011 |
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Keywords
ASJC Scopus subject areas
Keywords
- Affinity, CAR T cell immunotherapy, Nanobody, PET imaging, Solid epithelial tumor