Jun 30, 2010 (CIDRAP News) Researchers say they have identified human antibodies that bind to a molecular target found in a wide range of influenza A viruses, and they report that mice treated with these antibodies were protected against lethal H5N1 avian influenza and seasonal H1N1 virus challenges.
The new findings are expected to appear this week in en early online edition of the Proceedings of the National Academy of Sciences (PNAS), according to a press release from Theraclone Sciences, a Seattle-based biotechnology company that has developed a technology that allows scientists to rapidly screen thousands of human antibodies to find ones that have activities that might be developed for disease treatment.
Researchers from the University of Wisconsin, Madison, Johns Hopkins University, and Japan were also involved in the study.
They isolated a panel of monoclonal antibodies (mAbs) from the IgG memory B cells of humans that recognized a previously unknown target on the outer tip of the external part, or "ectodomain," of the influenza matrix 2 protein (M2e).They observed that the antibody-binding region is highly conserved across many influenza A viruses, including highly pathogenic strains that infect animals as well as the current pandemic H1N1 virus.
The researchers wrote that of three antibody targets on the surface of the flu virus, M2e is much more highly conserved than hemagglutinin or neuraminidase, "which makes it an attractive target for broadly protective mAbs."
Scientists have been intrigued by the promise of using human antibodies to fight flu since nearly a century ago, when doctors had some success treating 1918 pandemic flu patients with the serum of recovered patients. Last year, two different research groups reported on mAbs that target the stem or neck of the hemagglutinin protein. Both blocked the virus from fusing with cells.
Global health experts are eager for vaccines and treatments against a broad range of flu viruses, given the difficulties and delays pharmaceutical companies encounter when trying to produce vaccines against drifted and novel viruses and how quickly and unpredictably antiviral resistance can develop.
In the new study, scientists screened 140 healthy adults for IgG reactivity to M2e and found that 23 were seropositive. They isolated anti-M2e mAbs from five of these volunteers.
The researchers then treated mice with the human anti-M2e mAbs a day after lethal challenge with a highly pathogenic H1N1 virus. Survival in mice treated with the mAb was 70% to 80%, compared to 20% in those that received a control mAb and 0% in those receiving no treatment or treatment with a control vehicle, according to the study.
The animals that survived lost weight 4 to 8 days after infection, then gradually gained weight through the end of the study on day 14, the group reported. They observed that the anti-M2e mAbs protected the mice by reducing the severity of the infection rather than preventing it.
When mice were treated and then challenged with a seasonal H1N1 virus, 60% of treated mice survived, compared to none of those that received the control mAb. The investigators found evidence that the protective effect of anti-M2e mAb treatment involved a cell-mediated or complement-dependent toxic effect on infected host cells.
Yoshihiro Kawaoka, PhD, coauthor of the study and virologist at the University of Wisconsin, Madison, and the University of Tokyo, said in the Theraclone statement that protective effect in mice is encouraging. "Such antibodies may be especially useful during outbreaks of newly emerging, highly pathogenic influenza viruses."
To test the ability of the anti-M2e mAbs to recognize the pandemic H1N1 virus, they used mAbs from blood samples obtained in 2007, before the new virus emerged. The group found that the mAbs bound to Madin-Darby canine kidney cells that were infected with the pandemic virus.
The researchers said it is remarkable that a previously undescribed class of antibodies that seems to exist at suboptimal levelsfewer than 20% of individuals they sampled had detectable serum levelsmight be used to provide broad protection against influenza.
Jun 30 Theraclone press release
Feb 27, 2009, CIDRAP News story "Another antibody against diverse flu strains found"