Between 1970 and 1994, cancer claimed the lives of about 123 million Americans. According to the most recent statistics, it is estimated that 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Inhibitors of angiogenesis have received considerable attention because of their anti-cancer opportunities and the market for this therapeutic class is anticipated to reach $1.75 billion by 2006. Inhibition of angiogenesis has also been advanced as a treatment strategy for diabetic retinopathy and rheumatoid arthritis. The former affects more than 75 million people world-wide and has now become the leading cause of blindness in the United States in middle-aged adults. The latter affects about 1% of all populations, women two to three times more often than men. This translates to a total of 5 million sufferers in the major pharmaceutical markets. Despite the level of angiogenesis-related research, advance of new clinical entities into the market has yet to occur. A number of strategies designed to block the effects of vascular endothelial growth factor (VEGF), one of the key angiogenic growth factors, has however generated promising data. VEGF is a homodimeric protein that activates its receptor by binding two receptor molecules and inducing dimerization. By mixing two VEGF monomers each with different substitutions, heterodimers with only one active receptor binding site have previously been prepared. These heterodimers bind the receptor molecule but are unable to induce dimerization and activation. However, preparation of heterodimers is cumbersome, involving separate expression of different monomers, refolding the mixture and separating heterodimers from homodimers. Maxygen have however recently shown that a fully functional ligand can efficiently be expressed as a single protein-chain containing two monomers. Single-chain VEGF is functionally equivalent to the wildtype protein. By monomer specific mutagenesis, one receptor binding site was altered. This variant competitively and specifically antagonizes the mitogenic effect of the wildtype protein on endothelial cells suggesting a new approach to VEGF blockade.

Entry date September, 2002

Adapted from Boessen et al, J Biol Chem 2002 Jul 31

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