A Safety and Immunogenicity Study of Immunization with Hvegf26-104/Rfase in Cynomolgus Monkeys

Introduction: Vascular endothelial growth factor (VEGF) is pivotal in tumor angiogenesis and therapies targeting the VEGF axis are widely used in the clinic for the treatment of cancer. We have developed a therapeutic vaccine targeting human (h)VEGF(165) . hVEGF(26).(104)/RFASE is based on the truncated protein hVEGF(26).(104) as antigen formulated in an oil-in-water emulsion containing the sulpholipopolysaccharide RFASE as adjuvant. Here we describe the toxicity and immunogenicity of this therapeutic vaccine in cynomolgus monkeys. Methods: In total 54 cynomolgus monkeys were used and divided in 7 groups. Groups 1-3 were control groups, either receiving PBS alone (group 1), RFASE alone (group 2) or hVEGF (26).(404) alone (group 3). Animals allocated to groups 4-7 received hVEGF(26-104) together with RFASE, but with varying doses of the antigen or the adjuvant. All animals were immunized four times with 2-week intervals and safety and immunogenicity were monitored until 3 days after the final immunization. Results: Immunization induced an RFASE adjuvant dependent acute phase response. High titers of antibodies against hVEGF(26-104) and cross-reactive with hVEGF(165) , were found in monkey sera, 28 days after primer immunization. These antibodies were able to inhibit the binding of the monoclonal antibody bevacizumab with hVEGF(165) in a competition ELISA. Moreover, the biological activity of hVEGF(165) could be inhibited by the addition of immunized monkey serum in a VEGF specific bioassay. Importantly, no adverse events commonly observed with VEGF neutralization were observed throughout the study. Conclusion: These data show that hVEGF(26).(104)/RFASE can be safely administered in cynomolgus monkeys, induces the desired immune response and therefore support the clinical development of this vaccine. (C) 2018 The Authors. Published by Elsevier Ltd.