Cell Reports (May 2016)
Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site
- Katie A. Howell,
- Xiangguo Qiu,
- Jennifer M. Brannan,
- Christopher Bryan,
- Edgar Davidson,
- Frederick W. Holtsberg,
- Anna Z. Wec,
- Sergey Shulenin,
- Julia E. Biggins,
- Robin Douglas,
- Sven G. Enterlein,
- Hannah L. Turner,
- Jesper Pallesen,
- Charles D. Murin,
- Shihua He,
- Andrea Kroeker,
- Hong Vu,
- Andrew S. Herbert,
- Marnie L. Fusco,
- Elisabeth K. Nyakatura,
- Jonathan R. Lai,
- Zhen-Yong Keck,
- Steven K.H. Foung,
- Erica Ollmann Saphire,
- Larry Zeitlin,
- Andrew B. Ward,
- Kartik Chandran,
- Benjamin J. Doranz,
- Gary P. Kobinger,
- John M. Dye,
- M. Javad Aman
Affiliations
- Katie A. Howell
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Xiangguo Qiu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Jennifer M. Brannan
- U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
- Christopher Bryan
- Integral Molecular, Philadelphia, PA 19104, USA
- Edgar Davidson
- Integral Molecular, Philadelphia, PA 19104, USA
- Frederick W. Holtsberg
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Anna Z. Wec
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Sergey Shulenin
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Julia E. Biggins
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Robin Douglas
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Sven G. Enterlein
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Hannah L. Turner
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Jesper Pallesen
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Charles D. Murin
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
- Shihua He
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Andrea Kroeker
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Hong Vu
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA
- Andrew S. Herbert
- U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
- Marnie L. Fusco
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
- Elisabeth K. Nyakatura
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Jonathan R. Lai
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Zhen-Yong Keck
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA
- Steven K.H. Foung
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA
- Erica Ollmann Saphire
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Larry Zeitlin
- Mapp Biopharmaceutical, San Diego, CA 92121, USA
- Andrew B. Ward
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Kartik Chandran
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Benjamin J. Doranz
- Integral Molecular, Philadelphia, PA 19104, USA
- Gary P. Kobinger
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Deparment of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- John M. Dye
- U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
- M. Javad Aman
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20878, USA; Corresponding author
- Journal volume & issue
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Vol. 15,
no. 7
pp. 1514 – 1526
Abstract
Summary: Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails. : Howell et al. examine a mAb, FVM04, that binds the ebolavirus receptor-binding site and find that FVM04 protects against EBOV and SUDV. When combined with two ZMapp™ components, the antibody cocktail retains EBOV protection similar to that of ZMapp™ and extends protection against SUDV. Specific glycoprotein mutations that enhance the exposure of cross-neutralizing epitopes are described.
