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Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization
- Source :
- Immunity
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Summary 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.<br />Graphical Abstract<br />Highlights • Human mAbs of two epitope specificities bind cooperatively to the ebolavirus GP • Cooperativity is mediated by a mAb that enhances binding to a vulnerable GP epitope • A two-mAb cocktail exhibits enhanced potency against heterologous ebolaviruses • Two 30 mg/kg doses of the cocktail fully protected non-human primates (NHPs) challenged with EBOV<br />Cooperative interactions of monoclonal antibodies (mAbs) with viral antigens are poorly understood. Gilchuk et al. perform structural and functional analysis of cooperativity in a cocktail of two human mAbs, recognizing major epitopes of ebolavirus glycoprotein (GP), and define cooperative binding of the GP as a mechanism for enhanced ebolavirus neutralization.
- Subjects :
- glycoprotein
Male
0301 basic medicine
Protein Conformation
cooperative neutralization
antibody synergy
Antibodies, Viral
medicine.disease_cause
Epitope
Neutralization
Epitopes
Mice
0302 clinical medicine
Immunology and Allergy
antibody therapeutics
Mice, Inbred BALB C
Antibodies, Monoclonal
Ebolavirus
3. Good health
Molecular mimicry
Infectious Diseases
030220 oncology & carcinogenesis
Drug Therapy, Combination
Female
Immunology
Biology
ebolavirus infection
Article
Virus
Cell Line
Immunoglobulin Fab Fragments
03 medical and health sciences
Antibody Repertoire
medicine
Animals
Humans
neutralizing antibodies
Glycoproteins
Ebola virus
Molecular Mimicry
Hemorrhagic Fever, Ebola
Antibodies, Neutralizing
Macaca mulatta
Virology
epitope mapping
Disease Models, Animal
030104 developmental biology
Epitope mapping
viral antibodies
Subjects
Details
- ISSN :
- 10747613
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....92b316e1574d5db753fb12341546212c