Rare human antibodies protect mice from lethal strains of influenza

Scientists have identified a new, highly conserved molecular target on the influenza A virus and demonstrated that human antibodies against this target are protective in animal models of seasonal and highly-pathogenic avian influenza. The work was conducted by researchers at Theraclone Sciences, with collaborators at University of Wisconsin-Madison, University of Tokyo and Johns Hopkins University; and is reported this week in the online Early Edition of the Proceedings of the National Academy of Sciences.

“The ability of these antibodies to protect mice from highly lethal strains of influenza is encouraging”

Each year in the United States, 5% to 20% of the population is infected with influenza virus, and over 200,000 people are hospitalized as a result of influenza-related complications. Of the different types of influenza virus, influenza A viruses typically cause more serious infections and also pandemics, with potentially severe impacts on global health. Current preventative and therapeutic approaches are only partially effective due to the ability of influenza viruses to multiply and mutate rapidly, making it difficult to identify a universal target for an anti-viral agent.

The newly identified influenza target is on the outer tip of the external portion, or "ectodomain," of the influenza matrix 2 protein (M2e). Using Theraclone's I-STAR™ technology, the researchers found rare, naturally occurring, human antibodies in healthy volunteers that targeted this highly conserved part of the influenza virus. When they mass produced the human anti-M2e antibodies and administered them to infected mice, they showed 60-80% recovery in the treated animals, compared with 10% or less survival of the untreated animals. Notably, the antibodies protected against two structurally distinct influenza strains - a highly pathogenic avian (H5N1) strain and a seasonal human (H1N1) strain.

"The ability of these antibodies to protect mice from highly lethal strains of influenza is encouraging," said Yoshihiro Kawaoka, Professor of Virology at University of Wisconsin-Madison and University of Tokyo, and a co-author on the study. "Such antibodies may be especially useful during outbreaks of newly emerging, highly pathogenic influenza viruses."

M2 is known to be essential for the normal function of the influenza virus; in fact, one class of existing influenza drugs - adamantanes - are M2 inhibitors, and researchers have previously studied the therapeutic potential of antibodies specific for other regions of the M2 protein. Unfortunately, in most cases, M2 mutations have evolved that evade these therapeutic approaches. The fact that the M2 target discovered in this new research study comprises a region where very few changes have been observed means that antibodies that target it have the potential to be successful against multiple types of influenza A, and suggests that viral escape from such antibodies could be minimal.

Last year, Theraclone scientists identified two novel antibodies that potently neutralize a broad range of HIV-1 viruses, described in a paper published in the journal Science. "We have now found human antibodies that identify novel viral targets for two completely different viral pathogens for which development of effective therapeutic agents has proven to be challenging," noted Matthew Moyle, Theraclone's Chief Scientific Officer. "Unlike other antibody technologies, our approach enables rapid functional screening of human antibody repertoires which captures the work that the human immune system has already invested in pathogen defense." The company is currently pursuing the development of therapeutic antibodies against influenza as its lead program.

Papers published in the PNAS Early Edition are available online at: http://www.pnas.org/content/early/recent. Because PNAS publishes daily online, this article may appear later in the week.

This paper is dedicated to the memory of David J. Fanning.

SOURCE Theraclone Sciences