In 2014, the alarm for the Zaire Ebola virus was sounded around the world - but there are other deadly ebolaviruses that cause identical symptoms, and they have even fewer treatment options. In a study publishing in Cell Reports, researchers from Integrated BioTherapeutics (IBT) describe and test an antibody cocktail, created with components from ZMappTM and a new antibody called FVM04, that brings researchers a step closer to an effective and efficient pan-ebolavirus treatment. This was a large collaborative project between IBT and researchers at the US Army Medical Research Institute of Infectious Diseases, Stanford University, Mapp Biopharmaceutical Inc, Public Health Agency of Canada, Albert Einstein College of Medicine, Integral Molecular Inc., and The Scripps Research Institute.
The new cocktail targeted and protected against infection caused by both the Zaire and Sudan ebolavirus strains in mice and guinea pigs.
"We don't know which type of ebolavirus might cause a future outbreak," says M. Javad Aman, President and CSO at Integrated BioTherapeutics and senior author on the study. "My immediate reaction in 2014 was that whatever we'd been doing so far, we needed to speed it up. We want to have a treatment that is broadly useful. If you have to stockpile three different drugs to be prepared for all kinds of ebolaviruses, it would take three times the resources."
Aman's team had previously identified a series of antibodies in monkeys that could fight different ebolaviruses, and have now plucked out the most effective: FVM04. The antibody targets a region, shared among all ebolaviruses, on top of the virus's outer shell. When FVM04 binds to this region, it prevents the virus from entering cells.
In experiments with mice infected with the Zaire or Sudan ebolaviruses, FVM04 protected against the virus when injected up to two days post-infection. In guinea pigs, FVM04 protected fully against Sudan ebolavirus, but only a third of the Zaire-infected animals survived. To create a more potent treatment, the researchers had to combine FVM04 with other antibodies.
Working with Mapp Biopharmaceutical, the team pulled apart the ZMappTM cocktail, which is made up of three antibodies - one targeting the cap of the viral package and two others that target the base. The researchers removed one of the base-targeting antibodies and replaced it with FVM04.
"We sort of developed ZMappTM 2.0," says Katie Howell, a postdoc at Integrated BioTherapeutics and first author on the study. "It was really exciting." The new cocktail retained FVM04's efficiency in protecting against the Sudan ebolavirus, while also protecting guinea pigs infected with the Zaire strain at levels comparable to ZMappTM in similar studies.
This study is the team's first step to demonstrating that ZMappTM can be modified and moved towards a broad reactivity. Going forward, Integrated BioTherapeutics and its collaborators are reviewing a range of antibodies to nail down the most effective cocktail, with an eye towards further development and clinical testing.
"In 2014, experimental drugs like ZMappTM were made available for clinical evaluation," says Aman. "But what if it had been a Sudan outbreak? Then we would have had absolutely nothing. It's motivated us to focus on other types of ebolaviruses and on a broad treatment that would be effective against all of them. We want to make sure we've turned over every rock."
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