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Beyond Vaccination: A New Platform for Treating Infectious Disease November 2009
Influenza pandemics have struck three times—1918, 1957, and 1968—and each outbreak claimed the lives of millions of people around the world. Earlier this spring, the World Health Organization raised the threat of H1N1 (swine flu) to pandemic level. Another more lethal flu (H5N1 or avian flu) has also been identified in recent years as having the potential to cause a pandemic that could overwhelm healthcare systems, kill hundreds of millions of people, and result in widespread financial losses from ensuing quarantines. As a countermeasure against flu pandemics and other biological threats, a MITRE-sponsored research program ("Development of Human Monoclonal Antibodies for Neutralization of Avian Influenza Virus and for Use in Diagnosis") is working on therapies for flu victims. Juan Arroyo, a lead scientist in our Department of Defense federally funded research and development center, and his team—in collaboration with the Medical University of South Carolina (MUSC)—have developed an innovative method for the treatment of infectious diseases such as the flu. Vaccine Readiness? Existing vaccines help prevent a small percentage of the disease threats affecting humans. In the case of flu viruses, new vaccines are being developed and deployed every year to combat the continuously evolving flu pathogens. Current methods for producing flu vaccines rely on virus production in eggs. These methods are costly and time consuming and typically cannot generate a sufficient number of doses to protect a large population in situations where a disease threat occurs rapidly or unexpectedly. While vaccines are considered the best preventive measure, they usually do not work if administered subsequent to exposure to the pathogen. In the event of a pandemic, it's estimated that current rates of conventional vaccine production only allow for the vaccination of 20 percent of the population before the majority of the population has been exposed to infection.
Arroyo and his team devised a new approach to developing therapies for infectious diseases, such as flu, based on the production of human monoclonal antibodies. As explained by Fred Steinberg, a senior advisor to the program, "The method uses B cells obtained from human tonsils that are driven to differentiate into antibody forming cells." B cells are one of the cell types found in blood and lymphoid organs. They start as immature ("naïve") cells and must undergo several transformations before they can produce useful antibodies. MITRE research has demonstrated that naïve B cells of human origin can be manipulated to produce antibodies able to bind to specific pathogens. "In this process, we introduced B cells into a transformation course that turns them into immortalized cells that can grow indefinitely outside the body," says Arroyo. "We then selected from that population of cells those that are generating antibodies that bind to our target." From the total population of B cells in each individual, at least a few are able to recognize almost any given pathogenic agent. The method—known as antibody therapy—is a promising alternative to vaccination. "Not only do protective antibodies have preventive power, they also can inhibit the pathogen's ability to cause disease even when administered subsequent to exposure," says Arroyo. Therefore, a rapid method for producing protective antibodies would have an immediate impact on protection from infectious diseases. The successful isolation of B cell clones generating antibodies against H5N1 suggests we can generate antibodies against new pathogen threats as they appear. The speed of developing these antibody-based therapeutics represents a significant advantage over technologies currently employed to develop vaccines. Monoclonal antibodies have yielded dramatic therapeutic benefits in cancer treatment worldwide. This same power has been used to bind and neutralize toxins, viruses, and bacteria. Tonsil Tissue To obtain human B cells, the research team gets human tonsil tissue from children undergoing tonsillectomies. Tonsils are an excellent source because 109 white blood cells can be obtained from an average tonsil, about half of which are human B cells. "It's important to note that the antibodies produced with this technology are cost effective and 100 percent of human origin," says Arroyo. In the past, animal antibodies were given to people; however, recipients often developed "serum sickness" from the foreign proteins. These potentially dangerous side effects are avoided by using antibodies from human origins. Human antibodies are not seen as foreign substances by the human immune system. In October 2008, the technology was transferred from MUSC to the Biotechnology/Nanotechnology Laboratory at MITRE after methods to induce antibody production and selection of B cell clones were defined. This milestone not only established the bio/nano lab as a facility for antibody production, but also supports the transferability of MITRE's technology into other labs (including government-designated sites) for production. At MITRE, methods were developed to isolate B cells effective against other pathogenic viruses. Another milestone occurred in June when Arroyo's team had success in increasing the scale of production of antibodies against H5N1. The MITRE lab now can generate antibodies for efficacy testing of binding to flu viruses. "We plan to perform in-vitro neutralization testing within our MITRE-sponsored research budget, and testing in collaboration with the National Institute of Allergy and Infectious Disease of the National Institutes of Health beyond those funds," says Arroyo. National Security Stockpile In addition to potential widespread civilian uses for combating infectious disease, monoclonal antibody research is expected to have biodefense-related applications. Even though a vaccine for the avian flu H5N1 exists in emergency stockpiles, these therapeutic monoclonal antibodies would be of interest to the biodefense and public health communities. With cost-effective manufacturing, this technology can provide a fast and deployable countermeasure against avian flu and other biothreats. Since a new vaccine requires time for development, testing, and approval for use by the Food and Drug Administration, it can take years for a vaccine to reach market. However, a Department of Health and Human Services initiative known as Project Bioshield was implemented to expedite the process. Under its directive, the same mechanism may accelerate MITRE's technology-derived antibody drugs. With the research program in its third year, the team is shifting from the research stage to the process development stage. Shortly, they plan to test the stability of the B cell lines, large scale production of antibodies, and other aspects of development. They also can license this technology for use against toxins and infectious diseases. Although currently focusing on the avian influenza strain, the team expects this cost-effective concept can apply to other targets. "All you need to decide is what the source of the protein target will be," says Arroyo. "We've chosen avian flu strains, but down the road any specific target can be chosen, such as proteins from other viruses like Ebola, Marburg, or Hantaviruses." "Ultimately, it is hoped that this technology will enable large-scale production of therapeutic monoclonal antibodies from selected B cell lines," says Steinberg. "Such B cell lines could be developed so that antibodies would be produced against many select agents." According to Arroyo, the stable antibodies can then be frozen and become part of the national strategic stockpile to help protect against viruses, bacteria, or targets of interest to biodefense. —by Elvira Caruso Related Information Articles and News
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