title: Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses.
abstract: The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species.
  
  
  OBJECTIVE
  Filoviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross-protective immunotherapeutics are urgently needed. Here, we describe monoclonal antibodies with cross-reactivity to several filoviruses, including the first report of a cross-neutralizing antibody that exhibits protection against Ebola virus and Sudan virus in mice. Our results further describe a novel combination of antibodies with enhanced protective efficacy. These results form a basis for further development of effective immunotherapeutics against filoviruses for human use. Understanding the cross-protective epitopes are also important for rational design of pan-ebolavirus and pan-filovirus vaccines.
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Shulenin
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Vu
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Howell
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Sonal J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, Massachusetts, USA.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Gunn
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, Massachusetts, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karim
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lai
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Frei
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Nyakatura
authors.affiliation: Mapp Biopharmaceutical, San Diego, California, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Zeitlin
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Douglas
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Fusco
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Froude
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Herbert
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Ariel S
authors.initials: AS
authors.lastname: Wirchnianski
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Calli M
authors.initials: CM
authors.lastname: Lear-Rooney
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, Massachusetts, USA.
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Glass
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: Integrated BioTherapeutics, Inc., Gaithersburg, Maryland, USA javad@integratedbiotherapeutics.com.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification*; D056738:Cross Protection; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D016563:Filoviridae / Q000276:immunology*; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control*; D007116:Immunization, Passive; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes