Therapeutic high affinity T cell receptor targeting a KRAS^G12D cancer neoantigen.

ABSTRACT: Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRAS^G12D, presented in the context of HLA-A*11:01. The affinity of the engineered TCR is increased by over one million-fold yet fully able to distinguish KRAS^G12D over KRAS^WT. While crystal structures reveal few discernible differences in TCR interactions with KRAS^WT versus KRAS^G12D, thermodynamic analysis and molecular dynamics simulations reveal that TCR specificity

SUBMITTER: Poole A 

PROVIDER: S-EPMC9464187 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature