Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus
Katie A. Howell,
Jennifer M. Brannan,
Christopher Bryan,
Andrew McNeal,
Edgar Davidson,
Hannah L. Turner,
Hong Vu,
Sergey Shulenin,
Shihua He,
Ana Kuehne,
Andrew S. Herbert,
Xiangguo Qiu,
Benjamin J. Doranz,
Frederick W. Holtsberg,
Andrew B. Ward,
John M. Dye,
M. Javad Aman
Affiliations
Katie A. Howell
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA
Jennifer M. Brannan
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA
Christopher Bryan
Integral Molecular, Philadelphia, PA 19104, USA
Andrew McNeal
Integral Molecular, Philadelphia, PA 19104, USA
Edgar Davidson
Integral Molecular, Philadelphia, PA 19104, USA
Hannah L. Turner
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Hong Vu
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA
Sergey Shulenin
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA
Shihua He
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
Ana Kuehne
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA
Andrew S. Herbert
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA
Xiangguo Qiu
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
Benjamin J. Doranz
Integral Molecular, Philadelphia, PA 19104, USA
Frederick W. Holtsberg
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA
Andrew B. Ward
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
John M. Dye
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA
Summary: 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 (IC50 1–10 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. : Howell et al. describe the phenomenon of “enabling, cooperative neutralization” where weakly neutralizing and/or non-neutralizing ebolavirus monoclonal antibodies exhibit potent neutralization when combined. The previously identified antibodies m8C4 and FVM09, which are non-protective alone, offer 100% protection against Ebola and Sudan virus challenge in mice when combined. Keywords: Ebola virus, vaccine, filovirus, monoclonal antibody, antibody therapeutics, antibody synergy, cooperative neutralization, synergistic neutralization
