SU5416 and SU6668, small synthetic molecules developed by Sugen Inc., of South San Francisco, Calif. By way of explanation, tumors larger than pinhead-size secrete vascular endothelial growth factors (VEGFs) that signal the endothelial cells lining nearby blood vessels to grow new ones for them. To accomplish their mission, however, VEGFs have to become attached to endothelial cell surface receptors where there are enzymescalled tyrosine kinasesthat convey their instructions into the cells interiors to be carried out. By blocking that transmission, the SU compounds also block angiogenesis. Both compounds are in clinical trials; SU5416 is in multi-center phase III trials.
IMC-1C11, developed by ImClone Systems Inc., New York City. A humanized monoclonal antibody (MAB), it prevents VEGFs from binding to endothelial cell surface receptors, thus precluding angiogenesis by denying the growth factors access to tyrosine kinases. ImClone will launch a phase I trial of this MAB if its investigational new drug application for it, filed with the FDA in December, is approved.
Vitaxin, developed by MedImmune of Gaithersburg, Md., and also a humanized MAB, is already in phase I trials. Its target is alphaVbeta3, a molecule that is found in particularly large amounts on endothelial cells during angiogenesis.
aaAT111, being developed by the molecular oncology division of Genzyme Corp., Cambridge, Mass. Discovered in Boston at the Childrens Hospital Medical Center by researchers Michael OReilly, M.D., and Judah Folkman, M.D., aaAT111 is a modified form of a blood plasma protein (antithrombin III). In announcing how they found the novel molecule (Science, Sept. 17, 1999), the two scientists and their colleagues reported that it had blocked angiogenesis that had been followed by tumor regression in mice, and in neither the mice nor cell culture studies had any dose of it resulted in toxicity.
Genzyme is doing further preclinical studies and scaling up production in anticipation of seeking FDA approval for a phase I clinical trial perhaps as early as this year.
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