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Single Molecule Force Spectroscopy Reveals Distinctions in Key Biophysical Parameters of αβ T‐Cell Receptors Compared with Chimeric Antigen Receptors Directed at the Same Ligand


Banik D. , Hamidinia M. , Brzostek J. , Wu L. , Stephens H.M. , MacAry P.A. , Reinherz E.L. , Gascoigne N.R.J. , Lang M.J. . The Journal of Physical Chemistry Letters. 2021 ; 12(31). 7566–7573


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Chimeric antigen receptor (CAR) T-cell therapies exploit facile antibody-mediated targeting to elicit useful immune responses in patients. This work directly compares binding profiles of CAR and αβ T-cell receptors (TCR) with single cell and single molecule optical trap measurements against a shared ligand. DNA-tethered measurements of peptide-major histocompatibility complex (pMHC) ligand interaction in both CAR and TCR exhibit catch bonds with specific peptide agonist peaking at 25 and 14 pN, respectively. While a conformational transition is regularly seen in TCR–pMHC systems, that of CAR–pMHC systems is dissimilar, being infrequent, of lower magnitude, and irreversible. Slip bonds are observed with CD19-specific CAR T-cells and with a monoclonal antibody mapping to the MHC α2 helix but indifferent to the bound peptide. Collectively, these findings suggest that the CAR–pMHC interface underpins the CAR catch bond response to pMHC ligands in contradistinction to slip bonds for CARs targeting canonical ligands.