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Wednesday, April 30, 2008
Researchers Find Quick Way to Make Human Monoclonal Antibodies against Flu
Human monoclonal antibodies (mAbs) — highly specific, identical, infection-fighting proteins produced in large quantities in the lab in cell lines that are derived from a single antibody-producing cell — against influenza can be rapidly produced in the lab, according to a new report from scientists supported by the National Institutes of Health (NIH). Using cells drawn from volunteers inoculated with seasonal influenza vaccine, the investigators made influenza-specific mAbs in just a few weeks rather than the typical two to three months. The new technique could potentially be used to rapidly create mAbs for a range of uses, the team says.
Rafi Ahmed, Ph.D., and Jens Wrammert, Ph.D., of Emory Vaccine Center of the School of Medicine, Atlanta, and their coworkers collaborated with Patrick Wilson, Ph.D., and J. Donald Capra, M.D., and others from the Oklahoma Medical Research Foundation, Oklahoma City. They describe their new method in an advance online publication in Nature. The research was supported by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Center for Research Resources (NCRR).
The first therapeutic mAb was approved for human use in 1986 and there are now more than 20 Food and Drug Administration-approved mAbs, including two human mAbs, most of which are used to treat certain cancers or immunological diseases. Human mAbs have long been envisioned as possible treatments for acute or chronic infections, but various technical barriers have slowed their development.
"With this new technique for making human monoclonal antibodies efficiently and quickly, Drs. Wilson and Ahmed and their colleagues have made a significant advance," says NIAID Director Anthony S. Fauci, M.D. "Their accomplishment opens the way to producing mAbs that potentially could be used diagnostically or therapeutically not only for influenza but for other infectious diseases as well."
In addition to being relatively quick to make, the influenza mAbs also bound tightly to virus strains in the seasonal influenza vaccine, the scientists determined. Such high affinity for the vaccine’s viruses suggests that the mAbs would also bind well to the circulating viruses targeted by the vaccine and thus could be used either as a therapy or as a way to diagnose the strain of influenza virus an individual is infected with, say the investigators.
The mAbs made in this study were not tested on influenza virus strains with pandemic potential, such as the H5N1 subtype that causes so-called bird flu. Nevertheless, notes Dr. Ahmed, the ability to make high-affinity influenza mAbs quickly raises the possibility of deploying them in combination with other disease control strategies in the event of a global influenza pandemic. According to Dr. Ahmed, the group is now planning to use their technique to generate mAbs against H5N1.
To make the new influenza mAbs, the researchers first inoculated volunteers with seasonal influenza vaccine. The scientists wanted to know if a subset of immune system cells called antibody-secreting plasma cells (ASCs) could serve as a source of mAbs. ASCs are the body’s first responders, churning out a surge of antibodies as part of the initial reaction to infection or vaccination. ASC activity is swift but brief. In this study, ASC responses peaked at one week after vaccination, then dropped sharply and were barely detectable after two weeks. The Emory University researchers found a way to capture the fleeting ASCs that produce the initial wave of influenza-specific antibodies. Importantly, says Dr. Ahmed, as many as 80 percent of the purified ASCs produced influenza-specific antibodies.
Dr. Wilson and his coworkers at the Oklahoma Medical Research Foundation used the vaccine-generated, influenza-specific ASCs to create the mAbs. Only a few weeks elapsed between vaccination of the volunteers and purification of human mAbs with a high affinity for influenza virus. "With just a few tablespoons of blood, we can now rapidly generate human monoclonal antibodies that potentially could be used for diagnosis and treatment of newly emerging strains of influenza," says Dr. Wilson. "In the face of a disease outbreak, the ability to produce infection-fighting human mAbs swiftly would be invaluable."
The technique developed by the Emory University and Oklahoma Medical Research Foundation scientists is not limited to the production of mAbs for influenza, and the team is currently working to make mAbs for other disease agents. "This research holds clinical potential for a host of infectious diseases including anthrax, respiratory syncytial virus and pneumococcal pneumonia," says Dr. Capra.
For more information on information about influenza, visit http://www3.niaid.nih.gov/healthscience/healthtopics/Flu/default.htm.
NIAID is a component of the NIH. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
NCRR, also a component of NIH, provides laboratory scientists and clinical researchers with resources, tools and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR also supports basic, translational and applied research on variety of diseases through resource building. The research highlighted here was supported, in part, by NCRR’s Institutional Development Awards Program, which helps build research infrastructure to enhance institutions’ research capacity and competitiveness for NIH grants.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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J Wrammert et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature DOI: 10.1038/nature06890 (2008).