Enhanced T cell receptor specificity through framework engineering.

ABSTRACT: Development of T cell receptors (TCRs) as immunotherapeutics is hindered by inherent TCR cross-reactivity. Engineering more specific TCRs has proven challenging, as unlike antibodies, improving TCR affinity does not usually improve specificity. Although various protein design approaches have been explored to surmount this, mutations in TCR binding interfaces risk broadening specificity or introducing new reactivities. Here we explored if TCR specificity could alternatively be tuned through framework mutations distant from the interface. Studying the 868 TCR specific for the HIV SL9 epitope presented by HLA-A2, we used deep mutational scanning to identify a framework mutation above the mobile CDR3β loop. This glycine to proline mutation had no discernable impact on binding affinity or funct

SUBMITTER: Rosenberg AM 

PROVIDER: S-EPMC10967027 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature