New insights about experimental monoclonal antibody cocktails that recognize Ebola virus may soon help provide an effective treatment option. Ebola virus disease (EVD) is a highly lethal illness in humans that is sometimes associated with bleeding. It is caused by a family of viruses (Filoviridae, genus Ebolvirus) linked to hemorrhagic fever. No approved medications exist to prevent or treat EVD.
Investigators from The Scripps Research Institute (TSRI) and Mapp Biopharmaceuticals are developing 3 different monoclonal antibody (mAb) cocktails (or mixtures) that bind to Ebola virus and limit its spread to healthy cells.
In past outbreaks—affecting mainly small, isolated human populations in African countries—the mortality rates ranged from 30 to 90%1,2. Currently, the 2014 outbreak in Western Africa is the largest on record, with more than 15,000 confirmed infections and 5,400 deaths as of November 20143.
The experimental Ebola antibody cocktails, MB-003 and ZMAb have shown success in treating non-human primates. A small supply of ZMapp—the most effective of the 3 experimental therapies — was exhausted after treating 6 medical and religious workers (some of whom died) that contracted EVD1, 4. New information about the rationale for how the cocktails work may aid in developing a much needed treatment option; however, well-designed clinical trials must ultimately determine ZMapp efficacy.
Dr. Charles Murin of TSRI and co-authors reported their findings in the October 2014 issue of the Proceedings of the National Academy of Sciences. 1 The researchers used electron microscopy and other methods to compare structural features and Ebola-specific binding capabilities of the antibody cocktails MB-003, ZMAb, and ZMapp.1
The results showed the antibodies fall into 3 groups based on the vulnerable viral region they bind (specifically, the mucin-like domain, the glycan cap, or the core glycoprotein). Analyses also revealed that while each of the cocktails contain some unique components, redundancies exist, and in some cases, the cocktails contain antibodies that compete for overlapping regions of the virus. It is hopeful that the new study will help identify the components of the cocktails that most effectively target distinct regions of the virus and aid in developing enhanced drug formulations.
Fortunately, ebolavirus mutations thus far detected in Guinea and Sierra Leone have not altered the sites of the Ebola virus that are recognized by the ZMapp antibodies1—indicating that new supplies of ZMapp “would likely have efficacy against viral strains circulating in the ongoing 2014 outbreak.” The authors note, “This work provides clear next steps to determine if ZMapp can be honed for even greater potency, efficacy, or production.” This work by Murrin and colleagues provides direction for strategically selecting next-generation antibody cocktails that may be effective against existing ebolaviruses and mutated viral variants.1
1Murin, C.D., Fusco, M.L., Bornholdt, Z.A., et al. 2014. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proceedings of the National Academy of Sciences doi:10.1073/pnas.1414164111.
2World Health Organization. http://www.who.int/mediacentre/factsheets/fs103/en/. Accessed November 20, 2014.
32014 Ebola Outbreak in West Africa. http://www.cdc.gov/vhf/Ebola/outbreaks/2014-west-africa/index.html. Accessed November 20, 2014.
4Judging An Ebola Drug In The Middle Of A Crisis. http://www.kpbs.org/news/2014/aug/21/evaluating-san-diego-companys-ebola-drug-amidst-cr/. Accessed November 20, 2014.
5Detailed Picture Of ZMapp Shows Room For Improvement. http://www.kpbs.org/news/2014/nov/18/detailed-picture-zmapp-shows-room-improvement/. Accessed November 20, 2014.