March 3, 2010

New Weapon in Fight against Deadly Toxins

Research findings might have implications for treatment of poisonous substances

Using the world’s deadliest substance, researchers have devised a new strategy to clear toxins from the body. Those efforts might lead to more efficient ways to combat toxins that could be used in bioterrorist attacks, as well as snake bites, scorpion stings and even some chronic gastrointestinal diseases.

The Tufts-led team developed the strategy, in which antibodies are administered with specific binding agents that seek out Botulinum toxin molecules and attach to them at several points. Once the toxin molecule is surrounded by bound antibodies, it is flushed out of the system through the liver before it can poison the body.

Botulinum toxin, which causes botulism, is the most acutely poisonous substance known and is considered among the most dangerous bioterrorist threats. Studies have shown that one gram of the toxin, which is produced by a bacterium that lives in soil, could kill upwards of a million people. Although currently available antitoxins can be mass produced and administered in the event of an outbreak, they are costly to develop, store and deliver—and have a short shelf-life.

“We’ve proven this approach protects against Botulinum intoxication in mice, and we hope this will lead to rapid development and deployment of many new anti-toxin therapies—for botulism and beyond,” says Charles B. Shoemaker, a professor of biomedical sciences at the Cummings School of Veterinary Medicine. The study was done in collaboration with researchers at Thomas Jefferson University in Philadelphia.

The findings, published in February in the journal Infection and Immunity, expand on a 2002 breakthrough at the University of California at San Francisco, where scientists combined three monoclonal antibodies (made by one type of immune cell) to attack the Botulinum toxin by attaching to different parts of the toxin molecule. Using three different antibodies dramatically increased the potency of the attack on the toxin compared to fewer antibodies and prevented intoxication even following high-dose exposure. But developing, producing and stockpiling three different monoclonal antibodies against each known toxin would be prohibitively expensive.

Instead of using three antibodies, the Tufts approach uses three small binding agents to direct a single monoclonal antibody to multiple sites on the toxin biomolecule being targeted. What’s more, the binding agents can be produced with more than one tag, which enables them to direct more antibodies to the toxin—and speed its elimination from the body.

This approach, the researchers say, would only require the creation of new binding agents, not new antibodies, to clear a toxin from the body—paving the way for new therapies to fight toxins ranging from animal venom to bioterrorist agents such as ricin, a deadly poison found naturally in castor beans.

Treatment for botulism usually requires many weeks of intensive-care hospitalization, and exposure of even a small number of people to the deadly bacterium would seriously disrupt health-care delivery in any major city, experts have said. A vaccine has been developed, but widespread use is not being considered, the researchers say, since the likelihood of large numbers of people being exposed to the bug is uncertain.

Continuing the research, Tufts scientists are exploring whether the binding-agent strategy will disarm Shiga toxin and C. difficile, both of which cause gastrointestinal diseases, along with other types of Botulinum toxin. They hypothesize that this method could also be used to eliminate pathogenic cytokines, which cause inflammation and autoimmune diseases, from the body.

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