June 3, 2002
A long-term collaboration between Dr. George Georgiou, professor of biomedical engineering and chemical engineering, and Dr. Brent Iverson, professor of chemistry, developed the potential anthrax cure in research supported by the U.S. Department of Defense since 1997.
Further trials are necessary to determine the antibodies' effectiveness in humans and the best treatment methods. The antibodies theoretically would be administered by injection to persons exposed to anthrax, and would block the toxin's deadly effects. This new antibody treatment, possibly coupled with a concurrent regimen of antibiotics, would disable both the anthrax toxin and its related bacteria.
Anthrax, the disease now synonymous with bioterrorism, is caused by a bacterium whose dormant airborne spores can enter the body by breathing or through a cut on the skin. Once inside the human system, the spores begin to actively reproduce. In the case of deadly inhalation anthrax, rapidly multiplying, toxin-laden bacteria soon make their way from the lungs to the bloodstream, and throughout the entire body. When flu-like symptoms appear a week or so after exposure, they're often disregarded at first. By the time the sufferer develops full-blown respiratory distress, it's usually too late.
"By that time, it's not enough just to kill the bacteria," Georgiou said. "You have to do something about the toxin."
Anthrax microbes possess an arsenal of three toxins. The first, called PA, binds to the body's own immune cells. Working together in groups of seven, the PA molecules carry out a complex process that eventually punches a hole through the immune cell and "injects" two other toxins, Edema Factor, which causes swelling, and the deadly Lethal Factor. The triple assault seriously disrupts the body's natural defenses and can lead to death.
The University of Texas at Austin team's approach interrupts the lethal process at the toxin delivery stage. Their strategy is to genetically engineer "sticky" antibodies that derail PA by providing an alternative, more attractive surface for the destructive antigen to adhere to. Once bonded to such substitutes, the PA is rendered inert and innocuous.
Using modern laboratory techniques-Georgiou, Iverson, and Jennifer Maynard, a then-doctoral candidate in chemical engineering, isolated thousands of potentially useful protein fragments. The researchers then isolated the best antibody in the mixture, an approach known as laboratory directed evolution. The best protein, called "1H", was found to bind 50 times more tightly to PA than any antibody previously known.
"Having the antibody bind 50 times better means that it can hold onto the PA toxin long enough to have the entire complex cleared from the body, eliminating the toxin before it has a chance to do any damage." Iverson said. "Combined with antibiotics, this could represent an effective treatment."
"Our cells that make the 1H antibody can be grown in large quantities quickly and inexpensively, providing a ready source of the new agent," said Maynard, now a Stanford University post-doc in infectious diseases, who will join the University of Minnesota chemical engineering and materials science faculty next year.
In a series of laboratory tests conducted last summer, rats given the antibody survived 10 times a normally lethal dosage of anthrax toxin.
No anthrax spores were used during any phase of the experiments. The investigators worked with laboratory-synthesized toxin provided by Dr. Stephen Leppla of the National Institutes of Health in Bethesda, Md.
The rat trials were carried out at the Southwest Foundation for Biomedical Research in San Antonio under the direction of Dr. Jean Patterson. The next phase of research, also to be performed at Southwest Foundation for Biomedical Research, in conjunction with EluSys Therapeutics, Inc. will involve reformulation of the antibody to last longer in the body. "We are very encouraged by the first trials we conducted with this new anthrax antibody" said Patterson, chair of Virology and Immunology at Southwest Foundation for Biomedical Research, "we look forward to taking this vital research to the next level in hopes of developing a possible cure for this deadly pathogen."
The researchers indicated that further tests need to be conducted on primates, under conditions more closely emulating the way anthrax is contracted, before a therapeutic drug can be formulated. After that, it must be submitted to the U.S. Food and Drug Administration for approval. That process could take several years, but the researchers hope current concerns about bioterrorism will expedite the research.
"Although there is a long way to go, our current data make us very optimistic at this point." Iverson said.
Georgiou added that, in addition to anthrax, "engineered antibodies are likely to prove useful for the treatment of many other infectious diseases."
Most recently, funding for the project has come from the U.S. Army Soldier and Biological Chemical Command, administered through Dr. Steven Kornguth of the Institute for Advanced Technology at The University of Texas at Austin.
About the Cockrell School of Engineering:
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