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Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization.
- Source :
-
Immunity [Immunity] 2020 Feb 18; Vol. 52 (2), pp. 388-403.e12. Date of Electronic Publication: 2020 Feb 04. - Publication Year :
- 2020
-
Abstract
- 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 />Competing Interests: Declaration of Interests A.L.B., E.D., and B.J.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular. J.E.C. has served as a consultant for Sanofi and is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines, is a recipient of previous unrelated research grants from Moderna and Sanofi, and is founder of IDBiologics. Vanderbilt University has applied for a patent that is related to this work. All other authors declare no competing interests.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antibodies, Monoclonal therapeutic use
Antibodies, Neutralizing therapeutic use
Antibodies, Viral therapeutic use
Cell Line
Disease Models, Animal
Drug Therapy, Combination
Epitopes
Female
Glycoproteins chemistry
Hemorrhagic Fever, Ebola prevention & control
Humans
Immunoglobulin Fab Fragments immunology
Macaca mulatta
Male
Mice
Mice, Inbred BALB C
Molecular Mimicry
Protein Conformation
Antibodies, Monoclonal immunology
Antibodies, Neutralizing immunology
Antibodies, Viral immunology
Ebolavirus immunology
Glycoproteins immunology
Hemorrhagic Fever, Ebola immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 52
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 32023489
- Full Text :
- https://doi.org/10.1016/j.immuni.2020.01.001