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 .

Computational core facility: Compound library optimization, structure based ligand design, NMR-supported mechanistic modelling of MHC.

Major aim of this project is the development of potent MLE compounds that can amplify antigen-specific T cell responses. Within this project the function of the Computational Core Facility (CCF) is to support the other subprojects with computational expertise and to develop a self-consistent model describing the MHC, antigen and MLE interactions on a molecular level.

The CCF will participate on all major steps required for the development of MLE. By using in silico screening tools that have been developed in a pilot project and by utilizing refined docking models the CCF will design compound libraries for the High Throughput Screen and will advice the Combinatorial Chemistry group on compound optimization.

The CCF will also be involved in the Biophysical Analysis (NMR). The data that the NMR measurements are expected to yield are direct as well as indirect structural data by nature. The full impact of the NMR measurements can only be exploited when applied to a atomic structure model of the MHC.

The Project in the WWW

Please kontact :

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)