title: Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.
abstract: Drug combinations are synergistic when their combined efficacy exceeds the sum of the individual actions, but they rarely include ineffective drugs that become effective only in combination. We identified several "enabling pairs" of neutralizing and non-neutralizing anti-ebolavirus monoclonal antibodies, whose combination exhibited new functional profiles, including transforming a non-neutralizing antibody to a neutralizer. Sub-neutralizing concentrations of antibodies 2G4 or m8C4 enabled non-neutralizing antibody FVM09 (IC50>1 μM) to exhibit potent neutralization (IC501-10 nM). While FVM09 or m8C4 alone failed to protect Ebola-virus-infected mice, a combination of the two antibodies provided 100% protection. Furthermore, non-neutralizers FVM09 and FVM02 exponentially enhanced the potency of two neutralizing antibodies against both Ebola and Sudan viruses. We identified a hotspot for the binding of these enabling antibody pairs near the interface of the glycan cap and GP2. Enabling cooperativity may be an underappreciated phenomenon for viruses, with implications for the design and development of immunotherapeutics and vaccines.
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Howell
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Brannan
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bryan
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McNeal
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Davidson
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Turner
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Vu
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Shulenin
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Shihua
authors.initials: S
authors.lastname: He
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Kuehne
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Herbert
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA. Electronic address: javad@integratedbiotherapeutics.com.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000276:immunology* / Q000627:therapeutic use; D004357:Drug Synergism; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000628:therapy / Q000821:virology; D006801:Humans; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral
keywords: Ebola virus; antibody synergy; antibody therapeutics; cooperative neutralization; filovirus; monoclonal antibody; synergistic neutralization; vaccine