On April 7, 2014 ImmuNovo and VUmc reproted that they have received CCMO approval for Phase I with hVEGF26-104 vaccine in combination with the RFASE based adjuvant in the Department of Medical Oncology of VUmc Amsterdam headed by Professor Dr Henk Verheul (Press release Immunovo, APR 7, 2014, View Source [SID:1234500781]).
ImmuNovo’s CEO Joost van Bree PhD: ‘We are delighted to make this important step forward.’
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More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF). The VEGF family and their receptors (VEGFR) are receiving increasingly more attention in the field of neoplastic vascularization. VEGF is a powerful angiogenic agent in neoplastic tissues, as well as in normal tissues. Under the influence of certain cytokines and other growth factors, the VEGF family appears in cancerous tissue and the adjacent stroma, and plays an important role in neovascularization.
ImmuNovo and VUmc’s Medical Oncology are working on the development of hVEGF-trunc vaccine in combination with the RFASE based adjuvant for the treatment of cancer. A pro-angiogenic phenotype can be triggered by hypoxia resulting from the increasing distance between the growing tumor cells and the capillaries or from the inefficiency of new vessels. Hypoxia induces the expression of VEGF and its receptor via hypoxia-inducible factor-1α (HIF-1α). Tumor cells feed on the new blood vessels by producing VEGF and then secreting it into the surrounding tissue. Secreted VEGF binds its receptors (VEGFR1 and VEGFR2) on the outer surface of the endothelial cell. Once VEGF binds its receptor, a sequence of events follows that lead to angiogenesis. First, activated vascular endothelial cells produce matrix metalloproteinases (MMPs). MMPs cause degradation of the extracellular matrix (ECM). Next, the endothelial cells migrate into the surrounding tissues and begin to divide. Finally, the endothelial cells differentiate in order to form a functional blood vessel. ImmuNovo is working on the development of hVEGF26-104 vaccine in combination with the RFASE based adjuvant for the treatment of cancer.
The vaccine hVEGF26-104/RFASE consists of a truncated synthetic mimic of the human VEGF protein (hVEGF26-104) emulsified in the adjuvant RFASE. hVEGF26-104 is a new chemical entity based on Pepscan’s and ImmuNovo’s joint proprietary peptide technology. hVEGF26-104 consists of a continuous sequence out of the VEGF protein (residue 26-104) that covers the β1 to β6 and α2 region of the full protein sequence. Correct formation of the cys-knot fold gives both the β1/2/α2/β3 loop (first loop) and the β5/β6 loop (second loop) the correct 3D conformation that is required for a correct mimicry of the VEGF protein surface. In its oxidized form it is used as an antigen for VEGF directing the body’s subsequent polyclonal antibody response towards the active site of the VEGF molecule. The important issue is that antibodies raised against the synthetic molecule hVEGF26-104 strongly cross-react with endogenous VEGF and after binding of the antibodies to endogenous VEGF this hormone will no longer be able to bind to its receptors (VEGFR1 and VEGFR2) and consequently will no longer exert its angiogenic effect.
To enhance the immune response, RFASE will be used as an adjuvant. RFASE belongs to the adjuvant group of sulpholipopolysaccharides.
Preclinical data has already demonstrated the feasibility of this approach.