A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

Zachary A Bornholdt; Andrew S Herbert; Chad E Mire; Shihua He; Robert W Cross; Anna Z Wec; Dafna M Abelson; Joan B Geisbert; Rebekah M James; Md Niaz Rahim; Wenjun Zhu; Viktoriya Borisevich; Logan Banadyga; Bronwyn M Gunn; Krystle N Agans; Ariel S Wirchnianski; Eileen Goodwin; Kevin Tierney; William S Shestowsky; Ognian Bohorov; Natasha Bohorova; Jesus Velasco; Eric Ailor; Do Kim; Michael H Pauly; Kevin J Whaley; Galit Alter; Laura M Walker; Kartik Chandran; Larry Zeitlin; Xiangguo Qiu; Thomas W Geisbert; John M Dye

doi:10.1016/j.chom.2018.12.005

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

Cell Host Microbe. 2019 Jan 9;25(1):49-58.e5. doi: 10.1016/j.chom.2018.12.005.

Authors

Zachary A Bornholdt¹, Andrew S Herbert², Chad E Mire³, Shihua He⁴, Robert W Cross³, Anna Z Wec⁵, Dafna M Abelson¹, Joan B Geisbert³, Rebekah M James², Md Niaz Rahim⁶, Wenjun Zhu⁴, Viktoriya Borisevich³, Logan Banadyga⁴, Bronwyn M Gunn⁷, Krystle N Agans³, Ariel S Wirchnianski⁵, Eileen Goodwin⁸, Kevin Tierney⁴, William S Shestowsky¹, Ognian Bohorov¹, Natasha Bohorova¹, Jesus Velasco¹, Eric Ailor¹, Do Kim¹, Michael H Pauly¹, Kevin J Whaley¹, Galit Alter⁷, Laura M Walker⁸, Kartik Chandran⁵, Larry Zeitlin⁹, Xiangguo Qiu¹⁰, Thomas W Geisbert¹¹, John M Dye¹²

Affiliations

¹ Mapp Biopharmaceutical, Inc., San Diego, CA, USA.
² United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA.
³ Department of Microbiology and Immunology, Galveston National Laboratory, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
⁴ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
⁵ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
⁶ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
⁷ The Ragon Institute, Cambridge, MA, USA.
⁸ Adimab LLC, Lebanon, NH, USA.
⁹ Mapp Biopharmaceutical, Inc., San Diego, CA, USA. Electronic address: larry.zeitlin@mappbio.com.
¹⁰ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada. Electronic address: xiangguo.qiu@canada.ca.
¹¹ Department of Microbiology and Immunology, Galveston National Laboratory, University of Texas Medical Branch at Galveston, Galveston, TX, USA. Electronic address: twgeisbe@utmb.edu.
¹² United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA. Electronic address: john.m.dye1.civ@mail.mil.

Abstract

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134^AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134^AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134^AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.

Keywords: ADI-15878; ADI-23774; BDBV; Bundibugyo; EBOV; MBP134; SUDV; Sudan; ebolavirus; pan-ebolavirus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animal Welfare
Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / isolation & purification
Antibodies, Monoclonal / therapeutic use*
Antibodies, Neutralizing / administration & dosage
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / isolation & purification
Antibodies, Neutralizing / therapeutic use
Antibodies, Viral / administration & dosage
Antibodies, Viral / immunology*
Antibodies, Viral / therapeutic use*
Cell Line
Chlorocebus aethiops
Disease Models, Animal
Ebolavirus / pathogenicity*
Female
Ferrets / virology*
Filoviridae / immunology
Filoviridae Infections / immunology
Filoviridae Infections / prevention & control
Filoviridae Infections / virology
Glycoproteins / immunology
Guinea Pigs
HEK293 Cells
Hemorrhagic Fever, Ebola / immunology*
Hemorrhagic Fever, Ebola / prevention & control*
Hemorrhagic Fever, Ebola / virology
Humans
Killer Cells, Natural
Macaca
Macaca fascicularis
Male
Primates
Survival Analysis
Treatment Outcome
Viral Proteins / immunology

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Glycoproteins
Viral Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding