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U.S. Scientists Create Drug to Fight Botulism

It could prove very valuable against biochemical weapons

MONDAY, Aug. 5, 2002 (HealthDayNews) -- American military and civilian scientists have produced the first drug that can be mass-produced to prevent or treat botulism, a potential biochemical weapon.

In scientific terms, the drug consists of "recombinant oligoclonal antibodies" -- three laboratory-manufactured molecules that bind to the deadly toxin created by the botulism bacterium, rendering it harmless. Current treatment for botulism poisoning requires weeks of intensive care, and prevention is possible only with a little-used vaccine.

"For 10 years, we've been trying to develop protection against botulism," says Leonard Smith, chief of immunology and molecular biology at the Army Medical Research Institute of Infectious Diseases, and a member of the team reporting the result in tomorow's Proceedings of the National Academy of Sciences.

"There are a number of countries out there that might use it [botulism]," Smith says. "Certainly, Iraq has developed botulinum toxin as a weapon. There were 19,000 liters of botulinum toxin actually deployed against U.S. forces in the Gulf War. It is the most toxic protein known, in fact the most toxic agent known."

The toxin is a protein that binds to nerve cells, rendering them inactive and causing paralysis. Death occurs when the breathing muscles are paralyzed. The body can fight back by producing antibodies that bind to the toxin, but they can't inactivate it completely.

The effort by Smith, with Dr. James D. Marks of the University of California, San Francisco and other scientists, produced a cocktail of three artificial antibodies that adhere to different parts of the toxin so it can't attack nerve cells.

"When we started we thought it would be simple to find a monoclonal antibody that would do the job," says Marks, who is professor of anesthesiology and pharmaceutical chemistry at UCSF.

"Despite looking at a hundred of them, we never found one that would work by itself. Then we decided to combine pairs of antibodies that would bind to different parts of the toxin. We were able to achieve a potency much greater than that of the human immunoglobulins that are now used. When we looked at a combination of three antibodies, we increased the potency more than a hundred-fold," Marks adds.

Smith's end of the work included screening of clones of antibodies to determine their effectiveness in animals, and development of molecular tools that Marks could use to pick out promising antibodies.

The job was difficult because there are seven serotypes, or variants, of the toxin. "We made synthetic genes for the three domains of all seven serotypes," Smith says. "We pulled out the monoclonal antibodies, and once those were picked out, they [Marks and his colleagues] did the binding studies. A lot of collaboration was required."

The final product includes one fully human antibody and two that are derived from mice and humans.

A shot of the newly developed drug will protect against the toxin within one to two hours, and the protection lasts for three to six months, Marks says. As a treatment, it is effective when given up to two days after exposure, he says.

Plans for using the drug for the nation's military haven't been finalized. But, Smith says, "I would doubt that we would vaccinate the complete force."

What To Do

You can learn the basics about botulism from the Centers for Disease Control and Prevention. For more on bioterrorism, see this Mayo Clinic site.

SOURCES: Leonard Smith, chief of immunology and molecular biology, Army Medical Research Institute of Infectious Diseases, Frederick, Md.; James D. Marks, M.D., Ph.D, professor of anesthesiology and pharmaceutical chemistry, University of California, San Francisco; Aug. 6, 2002, Proceedings of the National Academy of Sciences
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