Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein

Journal Article · Tue Apr 15 04:00:00 EDT 2014 · Virology

DOI:https://doi.org/10.1016/J.VIROL.2014.02.010· OSTI ID:22435022

Bates, John T. ^[1]; Keefer, Christopher J. ^[2]; Slaughter, James C. ^[3]; Kulp, Daniel W. ^[4]; Schief, William R. ^[4]

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1. The Vanderbilt Vaccine Center, Departments of Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States)
2. The Vanderbilt Vaccine Center, Departments of Pediatrics, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States)
3. The Vanderbilt Vaccine Center, Departments of Biostatistics and Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN (United States)
4. IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (United States)

The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (K{sub on}) for binding to RSV F protein, while alteration of dissociation rate (K{sub off}) did not significantly affect neutralizing activity. Interestingly, linkage of reduced K{sub on} with reduced potency mirrored the effect of increased K{sub on} found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants. - Highlights: • The relationship of affinity to neutralization for virus antibodies is uncertain. • Palivizumab binds to RSV escape mutant fusion proteins, but with reduced affinity. • Association rate (K{sub on}) correlated well with the potency of neutralization.

• OSTI ID: 22435022
• Journal Information: Virology, Journal Name: Virology Vol. 454-455; ISSN VIRLAX; ISSN 0042-6822
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AFFINITY
DISSOCIATION
EFFICIENCY
GLYCOPROTEINS
KINETICS
MONOCLONAL ANTIBODIES
MUTATIONS
STEADY-STATE CONDITIONS
VIRUSES