Peptide-MHC complexes (pMHCs) are central to essential immune decisions, including recognition of infection, autoimmune and tumor eradication. After thymic selection, T cell receptors (TCRs) are the natural receptors that can achieve pMHC recognition, but TCR or other antibody-based TCR mimetic engineering for an arbitrary pMHC remains a challenge. Here we create a novel platform to recognize pMHC. The novel scaffold will simplify the process of creating specific pMHC binders, as the designs will have only one variable loop and no longer require the involvement of six loops like TCRs. We combine computational protein design with experimental high throughput screen techniques to achieve highly specific pMHC recognition of tumor, viral and autoimmune antigens to single-residue mutation sensitivity. This novel platform can potentially be a game changer for new theranogstics development.

• Novel platform for pMHC recognition
• Computational Protein Design combined with high-throughput screening for target specificity