Progress Towards a Pan-Ebolavirus Treatment

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 May 5 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.”

Publications

A "Trojan Horse" Bispecific Antibody Strategy for Broad Protection against Ebolaviruses. Wec, A.Z. Nyakatura, E.K. Herbert, A.S. Howell, K.A. Holtsberg, F.W. Bakken, R.R. Mittler, E. Christin, J.R. Shulenin, S. Jangra, R.K. Bharrhan, S. Kuehne, A.I. Bornholdt, Z.A. Flyak, A.I. Saphire, E. Crowe Jr., J.E. Aman, M.J. Dye, J.M. Lai, J.R. Chandran, K. (2016) Science 8(2016). doi: 10.1126/science.aag3267

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Feverish Quest for Ebola Immunotherapy: Straight or Cocktail?  Aman, M.J. Saphire, EO. (2016) Trends Microbiol 10(1016). pii: SD966-842X(16)30049-X

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Zika Virus: A New Animal Model for an Arbovirus.  Aman, M.J. Kashanchi, F. (2016) PLoS Negl Trop Dis 10(5): e0004702. doi:10.1371/journal.pntd.0004702

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Virus-Like Particle Vaccination Protects Nonhuman Primates from Lethal Aerosol Exposure with Marburgvirus (VLP Vaccination Protects Macaques against Aerosol Challenges).  Dye JM, Warfield KL, Wells JB, Unfer RC, Shulenin S, Vu H, Nichols DK, Aman MJ, Bavari S. Viruses. 2016 Apr 8;8(4). pii: E94. doi: 10.3390/v8040094

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Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.  Howell KA, Qiu X, Brannan JM, Bryan C, Davidson E, Holtsberg FW, Wec AZ, Shulenin S, Biggins JE, Douglas R, Enterlein SG, Turner HL, Pallesen J, Murin CD, He S, Kroeker K, Vu H, Herbert AS, Fusco ML, Nyakatura EK, Lai JR, Keck ZY, Foung SKH, Saphire EO, Zeitlin L, Ward AB, Chandran K, Doranz BJ, Kobinger GP, Dye JM, Aman MJ. (2016) Cell Reports 15, 1–13.

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Monoclonal antibody therapy for Junin virus infection.  Zeitlin L, Geisbert JB, Deer DJ, Fenton KA, Bohorov O, Bohorova N, Goodman C, Kim D, Hiatt A, Pauly MH, Velasco J, Whaley KJ, Altmann F, Gruber C, Steinkellner H, Honko AN, Kuehne AI, Aman MJ, Sahandi S, Enterlein S, Zhan X, Enria D, Geisbert TW. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4458-63.

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Aman MJ, Chasing Ebola through the Endosomal Labyrinth:, MBio, 2016, 7(2):e00346-16

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Holtsberg et al., Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses, J Virol, 2014

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Keck et al., Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein, J Virol, 2014

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Adhikari et al., Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs, PLoS One, 2015

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Fusco et al., Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs, PLoS Pathog, 2015

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Warfield et al., Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles, PLoS One, 2015

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Sully et al., A tripartite cocktail of chimeric monoclonal antibodies passively protects mice against ricin, staphylococcal enterotoxin B and Clostridium perfringens epsilon toxin, Toxicon, 2014

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Warfield et al., Vaccinating captive chimpanzees to save wild chimpanzees, Proc Natl Acad Sci USA, 2014

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Aman and Adhikari, Staphylococcal bicomponent pore-forming toxins: targets for prophylaxis and immunotherapy, Toxins, 2014

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Karauzum et al., Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model, PLoS One, 2013

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Adhikari et al., Lower antibody levels to Staphylococcus aureus exotoxins are associated with sepsis in hospitalized adults with invasive S. aureus infections, J Infect Dis, 2012

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Adhikari et al., Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia, PLoS One, 2012.

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