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Cell Rep. 2017 Apr 11;19(2):413-424. doi: 10.1016/j.celrep.2017.03.049.

Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.

Author information

1
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA.
2
US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA.
3
Integral Molecular, Philadelphia, PA 19104, USA.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
5
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.
6
Integrated BioTherapeutics, Inc., Rockville, MD 20850, USA. Electronic address: javad@integratedbiotherapeutics.com.

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 (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.

KEYWORDS:

Ebola virus; antibody synergy; antibody therapeutics; cooperative neutralization; filovirus; monoclonal antibody; synergistic neutralization; vaccine

PMID:
28402862
PMCID:
PMC6082427
DOI:
10.1016/j.celrep.2017.03.049
[Indexed for MEDLINE]
Free PMC Article

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