m396 neutralizes all strains tested and could neutralize all strains with known sequences.
An international team of investigators identified the first human antibodies that can neutralize different strains of the virus responsible for outbreaks of SARS.
“This study is important because the viral strain that caused the outbreak in people in 2002 probably no longer exists in nature,” explains Kanta Subbarao, M.D., NIAID, whose laboratory verified the efficacy of the anti-SARS antibodies in animal models. “What we need to prove for any vaccine, therapeutic antibody, or drug is that it is effective not only against the strain of SARS virus isolated from people but also against a variety of animal strains, because animals will be a likely source for re-emergence of the SARS virus.”
The team led by scientists from the NCI and the NIAID, with collaborators from the U.S. Army and academic institutions in the U.S., Switzerland, and Australia used a mouse model and in vitro assays to test the neutralizing activity of the antibodies.
Dimiter S. Dimitrov, Ph.D., head of the protein interaction group at NCI’s Frederick, MD campus and his colleagues identified two human antibodies that bind to a region on the SARS virus’ spike glycoprotein that is called the receptor binding domain (RBD). One of the antibodies, called S230.15, was found in the blood of a patient who had been infected with SARS and later recovered. The second antibody, m396, was taken from a library of human antibodies the researchers developed from the blood of 10 healthy volunteers.
Dr. Dimitrov’s team next determined the structure of m396 and its complex interaction with the SARS RBD and showed that the antibody binds to the region on the RBD that allows the virus to attach to host cells. If the antibodies were successful in binding to the SARS RBD, they would prevent the virus from attaching to the SARS coronavirus receptor, ACE2, on the outside of human cells, effectively neutralizing it.
When tested in cells, both antibodies potently neutralized samples of the virus from both outbreaks, according to the investigators. The antibodies also neutralized samples of the virus taken from wild civets, though with somewhat lower potency.
The scientists next tested the antibodies in a mouse model of SARS virus infection. Mice were given an injection of one of the two antibodies and 24 hours later, were exposed either to samples of the SARS virus from one of the two outbreaks or to virus isolated from civets. Mice that received m396 or S230.15 were fully protected from infection by SARS from humans, the researchers found. Also, the mice were also protected against infection by SARS from civets, though not completely.
Further analysis of the structure of m396 and its interactions with experimental mutations in the SARS virus receptor binding area suggested that the antibody can successfully neutralize all known forms of the virus, according to the researchers. “This antibody neutralizes all strains of SARS we tested and is likely to neutralize all strains of the virus with known sequences,” says Dr. Dimitrov. “There are no other reports for such antibodies available.”
The findings will appear after the July 2 early online edition of the Proceedings of the National Academy of Sciences.
