Pepscan Case – Use of 3D-structured peptides mimicking monoclonal antibody binding site to develop VEGF targeting vaccine
Therapeutic targeting of the VEGF signaling axis by the VEGF neutralizing monoclonal antibody bevacizumab has clearly demonstrated clinical benefit in cancer patients. To improve this strategy using a polyclonal approach, a vaccine targeting VEGF was developed for medical oncology using 3D-structured peptides that mimic the bevacizumab binding site.
“Before the start of this RVO-funded project a small research group, including myself, had developed a general approach to protein-mimics using scaffold-technology. We wanted to apply this approach to the mimicry of the bevacizumab-binding site,” says Peter Timmerman, Chief Scientific Officer at Pepscan. “During the four years of research that followed, the research-team, including our project partners Prof. Griffioen (VUMC Amsterdam) and Prof. Hackeng (Maastricht University), learnt that reconstruction of the the native ‘cysteine-knot’ fold (3xSS bond) already present in the the VEGF-protein turned out to be the most effective strategy. This approach created our lead-candidate ‘VEGF-trunc’, a 79-mer peptide that starts with the 1st cysteine of the cys-knot fold and ends with the 6th cysteine. Upon native folding of this peptide (i.e. spontaneous formation of the 3 SS-bonds), the peptide starts to bind to bevacizumab with nanomolar affinity, just like the full VEGF-165 protein. Moreover, the peptide is able to elicit high titers of antibodies that bind and neutralize the VEGF-protein in its general setting. We were able to show in a B16F10 murine melanoma model that the generated antibodies have a very strong potency to block the growth of VEGF-dependent tumors.”
Study results were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).