Peptide-based vaccination against vascular endothelial growth factor results in efficient antitumor activity

The vascular endothelial growth factor (VEGF) is a pivotal growth factor for angiogenesis (blood vessel formation) in tumor tissue. Therefore, it has been frequently investigated as a target in anticancer therapy. Its inhibition by the monoclonal anti-VEGF antibody bevacizumab (Avastin) has already improved survival in patients with several types of cancer.

There are, however, limitations to the effectiveness of this passive immunotherapy strategy since it does not stimulate a patient's immune system to actively respond to a disease in the way a vaccine does. The starting point of the research now reported in PNAS is that a VEGF vaccination has the potential to outperform the current clinical anti-VEGF treatment strategies.

Vaccination will not only provide durable VEGF suppression, it is also expected that the induced antibodies will have superior VEGF-neutralizing ability in comparison to bevacizumab. Furthermore, vaccination requires only a few intramuscular injections and reduces the number of hospital visits in comparison to treatment with bevacizumab.

However, vaccination with intact VEGF has major drawbacks such as unwanted biological activity and weak immunogenicity. The strategy pursued in the current research therefore is to use a VEGF mimicking peptide as a vaccine. The major challenge here was to identify the minimal peptide able to generate antisera with potent VEGF-neutralizing capacity and tumor-reducing capabilities.

A total of 33 peptide mimics of VEGF with varying levels of structural complexity (linear, conformational, and discontinuous) were designed, synthesized, and tested for the ability to generate potent antisera. It was established that induction of neutralizing antibodies with tumor-growth-inhibiting power was only successful for a 3D-structured 79-mer peptide with a fully intact cysteine-knot fold (covering the complete discontinuous binding site of bevacizumab).

Eradication of tumor growth using this peptide was demonstrated in two different tumor models (mice). It thus became clear that enforcing a native-like, secondary structure in the peptide is the key to success for inducing neutralizing anti-VEGF antibodies with tumor-inhibiting power.