Blocking or inhibiting tumor blood vessel growth (angiogenesis) remains a critical focal point for anticancer drug development. Studies on Vascular Endothelial Growth Inhibitor (VEGI; TNFSF-15) secreted from human endothelial cells have demonstrated that it is a potent negative regulator of angiogenesis that induces growth arrest and apoptosis in endothelial cells. Unfortunately, because of a limitation in the quantity of VEGI obtained in this manner and the difficulty encountered in the production of the recombinant form of this protein, preclinical studies using therapeutically administered VEGI to assess its potential as an anti-cancer or anti-angiogenesis drug have not been possible. In addition, no academic or commercial laboratory has succeeded in producing large quantities of this valuable molecule. In Phase 1 funding, our company, Proteomtech, has demonstrated proof of concept in successfully refolding 3 of 4 isoforms of h-VEGI from E.coil inclusion bodies into potent biologically active forms using novel refolding technology and then went on to demonstrate our ability to produce large quantities of the active forms for preclinical animal testing. In preliminary animal studies using rodent tumor models, our university collaborator demonstrated that one isoform of VEGI tested was capable of dramatically slowing tumor growth and prolonging animal survival when compared to controls. During Phase 2 funding, we intend to focus on VEGI-192A, the most potent isoform in cellular and animal studies. We propose to (i) advance to process scale development of a robust expression and refolding strategy, (ii) develop multiple candidate drug formulations of the refolded VEGI that will become the foundation for later clinical studies, and (iii) to test the candidate formulations in pre-clinical animal studies to assess potency, efficacy, and pharmacokinetic parameters using various forms of injection. The long term objective of this study is to develop VEGI-192A into an effective drug in diseases involving angiogenesis--particularly cancer, but also blindess(macular degeneration), psoriasis, and rheumatoid arthritis. It may be useful as an individual drug treatment or in combination with other therapeutics.
