Journal
IMMUNITY
Volume 52, Issue 2, Pages 388-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2020.01.001
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Funding
- US NIH [U19 AI109711, U19 AI142785, R01 AI067927, U19 AI109762]
- U.S. Department of Health and Human Services (HHS) [HHSN272201400058C]
- Defense Threat Reduction Agency (DTRA) grant [HDTRA1-13-1-0034]
- Defense Advanced Reseach Projects Agency (DARPA) [W31P4Q-14-1-0010]
- Fogarty International Center of the NIH [D43TW009343]
- University of California Global Health Institute (UCGHI)
- Bill and Melinda Gates Foundation
- Atreca, Inc.
- NCRR grant [UL1 RR024975-01]
- National Center for Advancing Translational Sciences [2 UL1 TR000445-06]
- NIH [5UC7AI094660-07]
- Animal Resource Center of the Galveston National Laboratory
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Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.
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