With many flu strains developing resistance to traditional small molecule treatments like Tamiflu and Rimantadine, antibodies could represent a new strategy in the war on influenza. The use of antibodies in treatment has thus far been limited by their cost, since culturing cells is a much more involved process than synthesizing compounds. But their ability to act on multiple strains lends hope for a universal treatment.
In a paper published in PLoS Pathogens, researchers from Sea Lane Biotechnologies, in collaboration with other institutions, relate their latest success with a particular antibody named A06. In both mouse models and cell cultures, this antibody was able to effectively treat the recent pandemic ‘swine flu’ strain of H1N1. A06, which was previously shown to be successful against both H5N1 (avian flu) and seasonal H1N1, was isolated from a library of antibodies culled from the survivors of a 2006 epidemic of especially virulent bird flu in Turkey.
“These antibodies came from the battlefield, so to speak,” says Richard Lerner, president of the Scripps Research Institute, one of the authors of the PLoS paper.
A06 binds to the stem portion of hemaggluttinin, a surface protein on the influenza virus. Normally, when influenza infects a host cell, its stem springs open, revealing a fusion peptide which it uses to bind to the cell. The antibody blocks that ability to bind, rendering the virus unable to infect host cells. Most other antibodies target the prominent globular head of hemaggluttinin, but Lerner says that targeting the stem means it’s harder for the virus to develop resistance. Influenza can easily change the structure of the protein loops on the head of the protein (for example, a single amino acid substitution can result in Tamiflu resistance in seasonal H1N1), but the stem, being much more essential, proves more difficult for the virus to change significantly without damaging reproductive function.
“If you make a hole in the rear window of a car, you can still drive around. Not so if you get a hole in the carburetor,” says Lerner.
And A06 is only one implement in the antibody toolkit. Other scientists are investigating antibodies that target M2, an ion channel protein. Researchers from Theraclone Sciences and other institutions published a paper in PNAS last month that highlighted an antibody binding region on the portion of M2 that protrudes outside the viral envelope. A particular sequence of five amino acids, they write, is present in “nearly all strains” of influenza A viruses detected to date, including the 2009 swine flu.
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