The proteins of class I major histocompatibility complex, MHC-I, display epitopic peptides on the cell surface, providing the foundation for immune surveillance of intracellular threats. MHC-I folding and peptide loading are subject to intricate cellular quality control. The peptide loading complex, PLC, comprising the TAP transporter, the molecular chaperones tapasin, ERp57, and calreticulin, assemble peptide-MHC-I, pMHC-I, molecules with high-affinity peptides in the endoplasmic reticulum, ER, in a process termed peptide editing. However, the recapitulation of loaded MHC-1 complexes in vitro has been a long-standing challenge.

Here we report on the use of beta-peptides as conditional ligands for refolding of MHC and their facile exchange to desired peptide sequences via the use of molecular chaperones. This technology can be utilized in various cancer immunotherapeutic settings to narrow the peptide repertoire, thereby increasing neoepitope immunogenicity.