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New Study Shows How ZMapp Binds to Ebola, Ways to Boost Potency

Xconomy San Diego — 

Scientists at The Scripps Research Institute have produced the first 3-D image of how the ZMapp drug developed by San Diego’s Mapp Biopharmaceutical binds to the Ebola virus, providing new insights about how the drug works and how it might be improved.

ZMapp is an experimental drug that combines three “humanized” monoclonal antibodies. Mapp Bio had produced only a limited amount for research purposes as the Ebola epidemic in West Africa mushroomed into a full-blown crisis this summer.

ZMapp was given to seven Ebola-infected patients under an emergency authorization, and five survived—including American caregivers Kent Brantley and Nancy Writebol. But there’s no way to scientifically validate the survivors’ outcomes, or to say whether ZMapp made a difference in their recoveries.

Structural biologists Andrew Ward and Erica Ollmann Saphire of the Scripps campus in San Diego released the results of their study online today, ahead of the publication of their paper in Proceedings of the National Academy of Sciences.

Using an imaging technique called electron microscopy, the study shows that two of the ZMapp antibodies bind to the same site near the base of the Ebola virus, and appear to prevent the virus from penetrating the surface of cells in the body. A third antibody binds to the virus in a more exposed site, and may act as a beacon calling for an immune response to the infection.

ZMapp antibodies (in color) binding to Ebola (courtesy TSRI)

ZMapp antibodies (in color) binding to Ebola (courtesy TSRI)

In an e-mail this morning, Saphire says a computer-generated image produced from the data represents the first structural picture of how ZMapp interacts with Ebola. She writes, “This is the first time we have done single particle electron microscopy instead of X-ray crystallography, and the first foray of the Ward lab into Ebola virus research.”

Saphire explains that the two antibodies that bind to the same site of Ebola may be redundant or even competing with each other. “If the two are truly redundant, then this could represent an opportunity for improvement,” Saphire writes. “The weaker or more poorly-producing one of the two could be replaced with more of the stronger, or with a third antibody against a distinct site for added potency.”

Understanding the binding sites and structure of the virus would be useful to many labs developing other antibody therapeutics and vaccines, Saphire added.
The new study also shows that the sites where the ZMapp antibodies bind to Ebola have so far been unaffected by the more than 300 genetic changes identified in the current strain of the virus by research published in August.

“The mutations known thus far do not prevent ZMapp binding, but more sequencing needs to be done to determine if the virus has evolved further,” Saphire writes.

“One reason we are doing the single particle electron microscopy as part of our global Ebola antibody consortium is to rapidly map where antibodies attach to the Ebola virus surface protein. By having the maps of all the known antibodies available, we could rapidly select replacement antibodies in case the virus mutates away from current therapies.”

Bruce V. Bigelow is the editor of Xconomy San Diego. You can e-mail him at bbigelow@xconomy.com or call (619) 669-8788 Follow @bvbigelow

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