Engineering T Cell Receptors for Optimal Affinities and Desired Specificities

T cells, via their T-cell receptors (TCRs), evolved to target intracellular antigenic peptides, as cell-surface complexes with MHC products. While the structural and biochemical characteristics of the TCR:pepMHC interaction have been well studied, there remains interest in understanding the molecular basis of peptide specificity exhibited by TCRs. Furthermore, understanding the binding properties of the TCR that can optimally mediate the activity of T cells is important, especially as adoptive T cell therapies have become more feasible. We have used various strategies to engineer the binding properties of TCRs for adoptive T-cell therapies, either as full-length heterodimeric TCRs or as CAR-like signaling receptors. TCR engineering has been performed using yeast display of single-chain TCRs in order to generate affinity-matured variants. In addition, we recently used synthetic TCR libraries in key CDR residues to convert the specificity of a TCR from a virus peptide to a cancer peptide. This approach allo...