Chimeric “icon” finds another target

A versatile molecule developed at Yale, already shown to destroy blood vessels in tumors, now shows promise for arresting macular degeneration, a leading cause of vision loss in the United States.

Known as an icon—short for immunoconjugate—the chimeric molecule is made, using recombinant DNA technology, from part of an antibody and a molecule that targets abnormal blood vessels. “We describe it as a synthetic antibody, because it really functions as an antibody, but its targeting mechanism is different,” said Alan Garen, Ph.D., professor of molecular biophysics and biochemistry. Garen used as a model an antibody found in camels, because it is more suitable for manipulation by recombinant technology than human antibodies. The targeting portion, fVII, draws the molecule tightly and specifically to the abnormal vessel; then the antibody portion activates an immune attack, destroying the vessel. An important feature of the icon is its flexible design that can generate an all-human molecule for clinical use.

The icon’s targeting mechanism ignores normal blood vessels and zeroes in on tissue factor (TF), a protein produced on the inner wall of abnormal but not of normal vessels. The same search-and-destroy strategy works against tumors by destroying the blood vessels that nourish them, while leaving normal tissue unharmed.

“The pleasing result is that the same mechanism can apply to two very different medical problems: cancer and macular degeneration. What links them are the unique properties of the blood vessels that are involved in both diseases,” said Garen, who collaborated on the work with Research Scientist Zhiwei Hu, Ph.D., M.D. Ophthalmologist Henry J. Kaplan, M.D., and associates at the University of Louisville performed the macular-degeneration studies, which were published in the March 4 issue of the Proceedings of the National Academy of Sciences.

Macular degeneration is the deterioration of the macula—a tiny spot at the center of the retina—resulting in blurs and blank spots in the field of vision. Abnormal blood vessels are the culprit in the wet form of the disease; they leak fluid onto the macula, damaging the cells. The Yale molecule destroys those leaky vessels without harming normal ones.

So far, the icon has been tested in mouse models of both diseases, and studies are under way at Louisville on a model of macular degeneration in pigs, whose eyes are similar to those of humans. The researchers plan to apply to the U.S. Food and Drug Administration for permission to begin clinical trials of the icon for patients with cancer and macular degeneration.

An icon could be administered in either of two ways, said Garen. “One way would be to produce it externally and administer it by injection,” either into the bloodstream or directly into the affected area. A second method, which the researchers are proposing to use in the cancer trial, involves the insertion of a gene for the molecule into an adenoviral vector that has been rendered harmless. “Then you inject the vector directly into the tumor,” said Garen. “It infects the tumor cells, and this sets up what you might call in vivo factories for producing the molecule in the body. With this method, you get continual synthesis, and it seems to be more effective.”