Development of small molecular "MHC-loading enhancers" (MLE) for applications in tumour immune therapies and vaccinations

Class I and class II MHC molecules are proteins encoded by the ‘Major histocompatibility gene Complex’ (MHC). They function as peptide receptors that display antigens on the cell surface for the surveillance by T cells. Upon recognition, these antigens can trigger the destruction of the cell, so that they had become a focal point for experimental tumour immune therapies. While, in principle, exogenously added peptides can activate tumour specific T cells very efficiently, their efficacy is severely reduced by the low number of MHC molecules actually accessible for loading. Most MHC molecules are either occupied by endogenous peptides or are functionally inactive by acquiring a conformation that is non-receptive for free peptides. We have recently discovered small molecules that are able to generate peptide-receptive MHC molecules. In a reversible reaction these compounds ‘open up’ the binding site of human class II MHC molecules by specific interactions with a defined pocket. By this mechanism these ‘MHC-loading enhancers’ (MLE) can recover inactive MHC molecules and provide additional free binding sites by triggering the release of endogenous ligands of low affinity. Preliminary experiments indicated that the increased loading efficiency translates directly into a dramatic enhancement of the T cell response. The primary objective of this project is therefore to develop MLE compounds into prototype drugs that can enter Phase I trials for tumour immune therapies .

This project is funded by the BMBF (Bundesministerium für Bildung und Forschung) http://www.bmbf.de. Project Management Agency: DLR, Dr. Ursula Hurtenbach; http://www.gesundheitsforschung-bmbf.de/en/169.php