Immunovo’s Immune Activation System “IAS” A Novel Approach to Angiogenesis Inhibition
Immunotherapy as a treatment modality in oncology has recently gained solid ground with the use of monoclonal antibodies (MAbs) responsible for significant therapeutic progress. These novel therapies have significantly increased patient survival and enhanced quality of life.This evolution creates a novel subset of patients that overcame their initial phase of disease, but are often confronted with recurrent symptoms that once again threaten their health and lives. The current available monoclonal therapies are limited when considered to use as chronic therapy. Cost and tolerability of these immunotherapy treatment modalities create potential barriers. For this emerging patient population Immunovo has been developing the “Immune Activation System”, IAS, consisting of 2 proprietary elements that effectively mobilize a patient’s immune system to interfere with signaling systems of malignant cells and tumors.
The most advanced application of Immunovo’s IAS targets VEGF, a well established way of inhibiting angiogenesis and has been applied in different tumor types in combination with chemotherapy. The equivalent humanized monoclonal antibody against VEGF, bevacizumab, is able to help reversing the immunosuppressive state in cancer patients. Recognizing the need as expressed clearly from EU based oncology key opinion leaders and in order to circumvent the potential long term specific drawbacks of bevacizumab treatment while making use of the hypothesized synergy of anti-angiogenic therapy and immunotherapy, a therapeutic IAS targeting VEGF has been developed.
The IAS consists of a synthetically truncated peptide mimic of the VEGF protein (hVEGF26-104) antigen emulsified with the immune stimulant Raffinose Fatty Acid Sulphate Ester (RFASE). Truncation of the sequence, combined with minor alterations in the primary amino acid structure to prevent dimerization, maintains the three dimensional cysteine knot structure of the full length VEGF proteins, transforming this peptide mimic into an immunogen.
To test efficacy and safety in a preclinical setting, active immunization studies had been conducted in mice and rats. In both species high anti-VEGF antibody titers had been induced as determined by ELISA. Furthermore, a VEGF-specific proliferation assay using Ba/F3-VEGFR2 cells showed that induced antibodies were able to block the functional binding of VEGF to VEGFR2.
A passive immunization study with rat antisera had been carried out in LS174 T human colon carcinoma-bearing nude mice. Treatment with antisera generated with the VEGF26-104 immunogen significantly inhibited tumor growth (93% reduction in tumor volume; p<0.0001) and tumor microvessel density (MVD) (54% reduction; p<0.0001) compared to saline treated mice. This was equally effective as treatment with bevacizumab. A final preclinical safety and immunogenicity study in Cynomolgus macaques showed that, besides a temporary increase in body temperature and mild to moderate injection site reactions, the immunization proved to be safe. In 31 out of 32 immunized macaques a strong anti-VEGF antibody response (titers up to 1:21,870) was induced. Moreover, for a period of 72 weeks, the antisera have been able to inhibit the binding of bevacizumab to VEGF in a competition ELISA, which illustrates the functional activity of the antisera generated. The preclinical work on the hVEGF26-104/RFASE IAS shows that it can be safely administered and will be able to induce polyclonal anti-VEGF antibodies neutralizing VEGF activity and will have potent tumor-inhibiting capacities. As of Q2 2014 the first-in-human phase I/II clinical trial is ongoing at VU Medical centre in Amsterdam to investigate the safety and tolerability of this IAS (NCT02237638).
- Date April 2, 2015
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