James Crowe
Faculty Member
Last active: 3/31/2019

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein.

Mousa JJ, Sauer MF, Sevy AM, Finn JA, Bates JT, Alvarado G, King HG, Loerinc LB, Fong RH, Doranz BJ, Correia BE, Kalyuzhniy O, Wen X, Jardetzky TS, Schief WR, Ohi MD, Meiler J, Crowe JE
Proc Natl Acad Sci U S A. 2016 113 (44): E6849-E6858

PMID: 27791117 · PMCID: PMC5098655 · DOI:10.1073/pnas.1609449113

Palivizumab was the first antiviral monoclonal antibody (mAb) approved for therapeutic use in humans, and remains a prophylactic treatment for infants at risk for severe disease because of respiratory syncytial virus (RSV). Palivizumab is an engineered humanized version of a murine mAb targeting antigenic site II of the RSV fusion (F) protein, a key target in vaccine development. There are limited reported naturally occurring human mAbs to site II; therefore, the structural basis for human antibody recognition of this major antigenic site is poorly understood. Here, we describe a nonneutralizing class of site II-specific mAbs that competed for binding with palivizumab to postfusion RSV F protein. We also describe two classes of site II-specific neutralizing mAbs, one of which escaped competition with nonneutralizing mAbs. An X-ray crystal structure of the neutralizing mAb 14N4 in complex with F protein showed that the binding angle at which human neutralizing mAbs interact with antigenic site II determines whether or not nonneutralizing antibodies compete with their binding. Fine-mapping studies determined that nonneutralizing mAbs that interfere with binding of neutralizing mAbs recognize site II with a pose that facilitates binding to an epitope containing F surface residues on a neighboring protomer. Neutralizing antibodies, like motavizumab and a new mAb designated 3J20 that escape interference by the inhibiting mAbs, avoid such contact by binding at an angle that is shifted away from the nonneutralizing site. Furthermore, binding to rationally and computationally designed site II helix-loop-helix epitope-scaffold vaccines distinguished neutralizing from nonneutralizing site II antibodies.

MeSH Terms (17)

Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antibodies, Neutralizing Antibodies, Viral Antiviral Agents Cell Line Crystallography, X-Ray Epitope Mapping Epitopes Humans Mice Mutagenesis Palivizumab Respiratory Syncytial Virus, Human Respiratory Syncytial Virus Vaccines Viral Fusion Proteins

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