The high-affinity antibody, an anthrax antitoxin, successfully eliminated both anthrax bacteria and its deadly toxins in animal tests. If future tests concur, this could be the first successful treatment for late-stage anthrax infection, even for an anthrax strain that has been designed to resist antibiotics.
The new antibody treatment, reported in the December issue of Infection and Immunity, is the result of collaboration between the labs of Dr. Brent Iverson and Dr. George Georgiou at The University of Texas at Austin and a research team led by Dr. Jean Patterson at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio.
"What we have found is that you may not even need the antibiotics to beat anthrax," says Iverson, professor of chemistry. He says that the new treatment "looks promising" and that it could lead to a simpler and cheaper way to treat anthrax. The new antibody is produced in bacterial cells, rather than the more expensive mammalian cell culture now used to produce anthrax antibodies.
Patterson, chair of the Department of Virology and Immunology at SFBR, adds, "A concern to national defense is that terrorists might design a strain of anthrax that is resistant to antibiotics, but this antitoxin could eliminate those concerns by providing an effective treatment that doesn't require antibiotics."
Anthrax infection is successfully treatable only in its early stages, when antibiotics can be used to kill anthrax bacteria. Before 2002, nothing was available to treat the large amounts of deadly toxin released by those bacteria, which is what leads to death in patients with late-stage anthrax infection.
In 2002, Iverson and Georgiou, a biomedical and chemical engineer, reported that their labs had developed a high-affinity, "sticky" antibody designed to bind with anthrax toxin and remove it from the body. This antibody was licensed to Elusys Theraputics, a New Jersey-based biopharmaceutical company, who turned it into a full immunoglobulin G (IgG). In trials, Elusys has found that the IgG protects test animals from anthrax when administered both before and after exposure to the disease.
Since those findings, Dr. Robert Mabry of the Iverson and Georgiou laboratory has reformulated the antitoxin to make it last longer in the bloodstream. Dr. Mabry also produced the antibody in bacterial culture, which could eliminate the need for complicated and expensive IgG production in mammalian cell culture. Drs. Jean Patterson and Ricardo Carrión at SFBR, along with veterinary staff from the SFBR Department of Comparative Medicine, have tested the re-engineered antibody with guinea pigs to determine if the antitoxin could protect against a true infection with anthrax spores.
"We expected the antitoxin to extend the lifespan of the infected animals," says Patterson, "but since we did not couple it with antibiotics, we thought that the bacteria would continue to replicate, and the increasing amount of toxins would eventually overpower the treatment."
In fact, results differed from the scientists' expectations, leading to the serendipitous discovery that the antibody effectively eliminates both the toxin and the anthrax bacteria.
In two separate experiments conducted in SFBR's biosafety level 4, maximum containment laboratory, researchers placed anthrax spores in the nasal passages of guinea pigs, mimicking exposure to inhalation anthrax. The doses were 250 to 625 times what would ordinarily be lethal to 50 percent of the animals. After 72 hours, the animals not treated with the antitoxin succumbed to the infection, but those that received the treatment were still healthy two and three weeks later.
"Day after day, we came into the lab to find the animals still healthy and happy," Patterson said.
Upon examination of all the animals at the end of both experiments, scientists found no evidence of disease, with no or only trace amounts of anthrax residing in typical reservoirs for the bacteria, the lungs and spleen.
Iverson cautions it's not yet clear that this antibody treatment is as effective as the IgG antibody produced by Elusys, and that he and his collaborators are doing more studies to confirm that.
The researchers also plan to conduct additional tests to determine how the antitoxin eliminates anthrax bacteria, which is still unknown. They have two hypotheses, which might both be part of the full story. One hypothesis is that the antitoxin somehow neutralizes anthrax bacteria and prevents it from replicating. The other looks to innate immunity, theorizing that since the high-affinity antibody clears the body of the deadly toxin, it allows the body's initial immune response to successfully kill the anthrax bacteria on its own.
This research was sponsored by the National Institute for Allergy and Infectious Diseases and the U.S. Department of Defense.
Infection and Immunity