Immunovo has today reported on the successful development of a peptide-based vaccine enabling a successful active anti-tumor immunization therapy targeting the growth hormone Vascular Endothelial Growth Factor (VEGF). An academic research team, in collaboration with Immunovo, has established that treatment with vaccine caused suppression of tumor growth in mice. These encouraging preclinical results were published last week in the leading international journal “Proceedings of the National Academy of Sciences of the USA” (PNAS). An exploratory Phase I/II studie in patients is now well underway at VU Medical Center (Amsterdam, The Netherlands).
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 demonstrated 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.
Joost van Bree, CEO of Immunovo explains: “At Immunovo, we think that clinical benefit could be enhanced by inducing a humoral immune response against VEGF through active immunization with VEGF-based peptides. In this study we demonstrated the successful development of a unique synthetic vaccine with potent in vitro and in vivo VEGF-neutralizing activities, as shown in passive and active immunization tumor models. We strongly believe that this strategy has the exciting potential to outperform the current clinical anti-VEGF treatment strategies”
The research team included Professor Peter Timmerman of Pepscan Systems BV and the University of Amsterdam’s Van’t Hoff Institute for Molecular Sciences (HIMS) and Madelon Wentink and Professor Arjan Griffioen, both of VU Medical Center Amsterdam.
Representation of the folded peptide, including the intact cysteine-knot fold. Image taken from the PNAS publication.
Full bibliographic information
Madelon Q. Wentink, Tilman M. Hackeng, Sebastien P. Tabruyn, Wouter C. Puijk, Klaus Schwamborn, Daniele Altschuh, Rob H. Meloen, Teun Schuurman, Arjan W. Griffioen, and Peter Timmerman: Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity. PNAS Early Edition, published online 17 October 2016. DOI:10.1073/pnas.1610258113