Chemobiological intervention (Team G. Zuber/E. Weiss)
Antibodies are popular tools in biomedical research and they have become valuable for treatment of human pathologies by targeting extracellular ligands. However, their application for blocking disease-triggering intracellular factors or for studying molecular mechanisms inside living animal cells is restricted because proteins do not naturally cross the cell membrane and cannot reach by diffusion intracellular compartments. This limitation should not be minimized because the secreted or membrane-associated proteins account for only approximately 30% of the proteins in animal cells, leaving thus nearly 70% of putative protein targets unreachable.
In the last years, we set up several methodologies for effective intracellular protein delivery and we expended the applicability of antibodies for targeting intracellular effectors within living cells. We have successfully obtained antibodies that block the function of nuclear proteins, such as HPV E6 oncoprotein, PCNA and DNA polymerase alpha after intracellular delivery.
Our main objective is to pursue the development of the immuno-intervention technology. Our focus is on investigating intracellular signaling cascades and post-translational modifications inside living cells.
The immuno-intervention technology may be of particular interest for monitoring the efficiency of anticancer treatment at early stages. As a proof of concept, we are measuring the phosphorylation of the histone H2AX, an event marking DNA damage, using antibodies and alpaca-derived nanobodies. The nanobodies are generated in house by phage-display. In parallel, we develop high affinity probes for electron microscopy imaging by addition of synthetic functionality to the antibody fragments.