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"Trojan Horse" Strategy Uses Bispecific Antibodies to Block Ebola from Invading Cells

SEP 20, 2016 | KRISTI ROSA
Due to the fact that the virus can typically be found in lysosomes that are so far within the cell that they tend to remain undetected by the host’s immune system, the researchers found that targeting the viral protein that binds to NCP1 or neutralizing NCP1 itself would prove difficult, so Kartik Chandran, PhD, professor of microbiology and immunology at the Albert Einstein School of Medicine, John M. Dye, PhD, chief of viral immunology at USAMRIID, and author Jonathan R. Lai, PhD, associate professor of biochemistry at Einstein developed what they refer to as a “Trojan Horse” strategy, where the filoviruses would carry virus-destructive bispecific antibodies with them into the host cell.

Dr. Dye said, “Our team of scientists took the ‘Trojan Horse’ concept from the chalkboard to a product that has the capacity to provide a viable treatment for all filoviruses, both known and emerging. This work highlights the power of governmental, academic and industrial researchers collaborating together to solve a complex and important public health concern.”

Dr. Lai, experienced in engineering antibodies, assisted in the development of the two different bispecific antibodies: one would target NCP1 and the other would target the viral protein that binds to it, according to the press release.

Through the use of an antibody called FVM09, developed by M. Javad Aman, PhD, both bispecific antibodies were able to travel with the virus into the lysosome. When the “glycoprotein caps” are severed from the lysosome, the bispecific antibodies are then freed from the virus and are able to carry out their respective duties. A combination of the FVM09 with an antibody called MR72 (which is an isolate taken from an individual who had survived the Marburg virus by James E. Crowe Jr., MD, director of the Vanderbilt Vaccine Center), the MR72 antibody targets the viral protein that binds to NPC1. The other bispecific antibody, created at the Albert Einstein College of Medicine, combines FVM09 with an antibody called mAb-548, which specifically targets NPC1, according to the press release. Both of the bispecific antibodies could potentially prevent the filovirus from breaking free from the lysosome, and thus, could prevent the replication of the virus throughout the host cell.

In order to test their hypothesis, researchers created a “harmless” virus that would “display glycoproteins from all five ebolaviruses on its surface,” according to the press release. They found that both of the bispecific antibodies were successful in their intended purpose, in all five of the ebolaviruses. The USAMRIID found that in addition, the antibodies were also successful in blocking infection by three of the real Ebola virus strains (specifically Sudan, Zaire, and Bundibugyo), according to the press release.

Lastly, researchers at USAMRIID took the research a step further by administering the bispecific antibodies to mice, two days after being given with a deadly dose of Zaire and Sudan ebolaviruses to measure the amount of protection, if any, that the antibodies would offer. They found that the MR72 antibody offered protection from both viruses but the mAb-548 one did not. “It was designed to bind specifically to human NPC1, which differs slightly in structure from the NPC1 found in mice,” according to the press release.

Dr. Lai, said, “It’s impossible to predict where the next ebolavirus outbreak will occur or which virus will cause it. So the best therapy would be a monoclonal antibody that is active against the glycoproteins of all five ebolaviruses—and until our study, no such antibody had demonstrated the ability to do that. We hope that further testing in nonhuman primates will establish our antibodies are safe and effective for treating those exposed to any ebolavirus.”
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