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PLANTIBODIES Scientific American Nov 97

Human antibodies produced by field crops enter clinical trials

Down a country road in southern Wisconsin lies a cornfield with ears of gold. The kernels growing on these few acres could be worth millions-not to grocers or ranchers but to drug companies. This corn is no Silver Queen, bred for sweetness, but a strain genetically engineered by Agracetus in Middleton, Wis., to secrete human antibodies. This autumn a pharmaceutical partner of Agracetus's plans to begin injecting cancer patients with doses of up to 250 milligrams of antibodies purified from mutant corn seeds. If the treatment works as intended, the antibodies will stick to tumor cells and deliver radioisotopes to kill them. Using antibodies as drugs is not new, but manufacturing them in plants is, and the technique could be a real boon to the many biotechnology firms that have spent years and hundreds of millions of dollars trying to bring these promising medicines to market. So far most have failed, for two reasons. First, many early antibody drugs either did not work or provoked severe allergic reactions. They were not human but mouse antibodies produced in vats of cloned mouse cells. In recent years, geneticists have bred cell lines that churn out antibodies that are mostly or completely human. These chimeras seem to work better: this past July one made by IDEC Pharmaceuticals passed scientific review by the Food and Drug Administration. The compound, a treatment for non-Hodgkin's lymphoma, will be only the third therapeutic antibody to go on sale in the U.S. The new drug may be effective, but it will not be cheap; cost is the second barrier these medicines face. Cloned animal cells make inefficient factories: 10,000 liters of them eke out only a kilogram or two of usable antibodies. So some antibody therapies, which typically require a gram or more of drug for each patient, may cost more than insurance companies will cover. Low yields also raise the expense and risk of developing antibody drugs. This, Agracetus scientist Vikram M. Paradkar says, is where "plantibodies" come in. By transplanting a human gene into corn reproductive cells and adding other DNA that cranks up the cells' production of the foreign protein, Agracetus has created a strain that it claims yields about 1.5 kilograms of pharmaceutical-quality antibodies per acre of corn. "We could grow enough antibodies to supply the entire U.S. market for our cancer drug-tens of thousands of patients-on just 30 acres," Paradkar predicts. The development process takes about a year longer in plants than in mammal cells, he concedes. "But startup costs are far lower, and in full-scale production we can make proteins for orders of magnitude less cost," he adds. Plantibodies might reduce another risk as well. The billions of cells in fermentation tanks can catch human diseases; plants don't. So although Agracetus must ensure that its plantibodies are free from pesticides and other kinds of contaminants, it can forgo expensive screening for viruses and bacterial toxins.

Corn is not the only crop that can mimic human cells. Agracetus is also cultivating soybeans that contain human antibodies against herpes simplex virus 2, a culprit in venereal disease, in the hope of producing a drug cheap enough to add to contraceptives. Planet Biotechnology in Mountain View, Calif., is testing an anti-tooth-decay mouthwash made with antibodies extracted from transgenic tobacco plants. CropTech in Blacksburg, Va., lias modified tobacco to manufacture an enzyme called glucocerebrosidase in its leaves. People with Gaucher's disease pay up. to $160,000 a year for a supply of this crucial protein, which their bodies cannot make. "It's rather astounding how accurately transgenic plants can translate the subtle signals that control human protein processing," says CropTech founder Carole L. Cramer. But, she cautions, there are important differences as well. Human cells adorn some antibodies with special carbohydrate molecules. Plant cells can stick the [email protected],rarbohydrates onto a human antibody. If that happens, says Douglas A. Russell a molecular biologist at Agracettis, the maladjusted antibodies cannot stimulate the body into producing its own immune response, and they are rapidly filtered from the bloodstream. Until that discrepancy is solved, Russell says, Agracetus will focus on plantibodies that don't need the carbohydrates. Next spring the company's clinical trial results may reveal other differences as well. -W Wayt Gibbs in San Francisco