Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

Immunity. 2020 Feb 18;52(2):388-403.e12. doi: 10.1016/j.immuni.2020.01.001. Epub 2020 Feb 4.


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.

Keywords: Ebolavirus; antibody synergy; antibody therapeutics; cooperative neutralization; ebolavirus infection; epitope mapping; glycoprotein; molecular mimicry; neutralizing antibodies; viral antibodies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / therapeutic use
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / therapeutic use
  • Cell Line
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Ebolavirus / immunology*
  • Epitopes
  • Female
  • Glycoproteins / chemistry
  • Glycoproteins / immunology*
  • Hemorrhagic Fever, Ebola / immunology*
  • Hemorrhagic Fever, Ebola / prevention & control
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Molecular Mimicry
  • Protein Conformation


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Glycoproteins
  • Immunoglobulin Fab Fragments