TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation

Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T-cells and call for alternative antigen receptor designs for effective T-cell-based cancer immunotherapy. Here we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousand-fold. TCC-based antigen recognition occurred without adverse non-specific signaling, which is typically observed in CAR-T-cells, and did not depend - unlike sensitized peptide/MHC detection by conventional T-cells - on CD4- or CD8-coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anti-cancer response., , , # TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation

[https://doi.org/10.5061/dryad.zpc866tgv](https://doi.org/10.5061/dryad.zpc866tgv)

Data underlying Fig.1-9 in the main text as well as Fig. S2-S9 of the supplementary material.

## Deposited data

DNA sequences are accessible on GenBank under the following accession numbers:

BankIt2823001 c58c61_1G4hi_TCR_T2A_copGFP: PP746584
BankIt2823001 T1_STARnat_T2A_copGFP: PP746585
BankIt2823001 T1_STARmir_T2A_copGFP: PP746586
BankIt2823001 T1_eTRuC_T2A_copGFP: PP746587
BankIt2823001 T1_BBz_CAR_T2A_copGFP: PP746588
BankIt2823001 1G4wt_TCR_CRISPR_construct: PP746589
BankIt2823001 c58c61_1G4hi_TCR_CRISPR_construct: PP746590
BankIt2823001 RA14_TCR_CRISPR_construct:  PP746591
BankIt2823001 T1_STARnat_T2A_copGFP_CRISPR_construct: PP746592
BankIt2823001 T1_STARmir_T2A_copGFP_CRISPR_construct: PP746593
BankIt2823001 T1_BBz_CAR_T2A_copGFP_CRISPR_construct: PP746594

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