Journal
ACS SYNTHETIC BIOLOGY
Volume 11, Issue 6, Pages 2029-2035Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.1c00397
Keywords
E3 ligase; allogeneic; CAR-T; GRAIL; claudin 18.2; CD3 zeta
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Funding
- Boan Boston LLC, Woburn, MA
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The study demonstrates a synthetic E3 fusion protein called ReceptorTAC, which can regulate gene expression by targeting T cell antigen receptor degradation, achieving specific degradation of TCR.
Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3 zeta transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.
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