Author: Gilchuk, Pavlo; Murin, Charles D.; Milligan, Jacob C.; Cross, Robert W.; Mire, Chad E.; Ilinykh, Philipp A.; Huang, Kai; Kuzmina, Natalia; Altman, Pilar X.; Hui, Sean; Gunn, Bronwyn M.; Bryan, Aubrey L.; Davidson, Edgar; Doranz, Benjamin J.; Turner, Hannah L.; Alkutkar, Tanwee; Flinko, Robin; Orlandi, Chiara; Carnahan, Robert; Nargi, Rachel; Bombardi, Robin G.; Vodzak, Megan E.; Li, Sheng; Okoli, Adaora; Ibeawuchi, Morris; Ohiaeri, Benjamin; Lewis, George K.; Alter, Galit; Bukreyev, Alexander; Saphire, Erica Ollmann; Geisbert, Thomas W.; Ward, Andrew B.; Crowe, James E.
Title: Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization Cord-id: wb966r76 Document date: 2020_2_18
ID: wb966r76
Snippet: 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
Document: 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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