Display, engineering, and applications of antigen-specific T cell receptors

Engineering High-Affinity T Cell Receptor/ Cytokine Fusions for Therapeutic Targeting

“…The use of engineered scTv TCR fragments as targeting elements for soluble molecules is an increasingly attractive and viable option (Aggen et al 2011;Richman & Kranz 2007). T cells play a central role in many inflammatory diseases, and effective T cell responses can combat serious infections or cancer.…”

“…The goal of using a TCR as a targeting moiety for a soluble immunotherapeutic has become plausible due to advances in engineering and directed evolution (reviewed in (Richman & Kranz 2007)) using techniques such as yeast surface display, phage display, or more recently, T cell display (Chervin et al 2008). Engineered receptors with 1000-fold or more increased affinity compared to their original, wild-type TCRs have been isolated, and the soluble forms of these TCRs bind to the targeted peptide-MHC with a high level of specificity (Chervin et al 2008;Holler et al 2003;Holler et al 2000;Li et al 2005b;Weber et al 2005).…”

Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

“…Since identical epitopes are processed in humans and mice (114), possible side effects on somatic cells expressing the autochthonous mouse HER2 should be revealed in preclinical models, making them more relevant. The success of this approach depends on engineering a high-affinity TCR for the targeted epitope (115).…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…TCR with high avidity can be obtained not only by direct cloning, but also from different display technologies such as yeast, phage and mammalian cell surface display (98). Highaffinity, peptide-specific TCRs could be generated by mutations in CDR1, CDR2 or CDR3 (99): a single point mutation in the CDR3β loop of the 2C TCR (Gly95Arg) increased its affinity by a factor of 1000 to the QL9/Ld pMHC, most likely due to direct electrostatic interaction of the TCR arginine side chain with an aspartate residue at P8.…”