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.
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 (Kon) for binding to RSV F protein, while alteration of dissociation rate (Koff) did not significantly affect neutralizing activity. Interestingly, linkage of reduced Kon with reduced potency mirrored the effect of increased Kon 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.
['Bates|John T|JT|', 'Keefer|Christopher J|CJ|', 'Slaughter|James C|JC|', 'Kulp|Daniel W|DW|', 'Schief|William R|WR|', 'Crowe|James E|JE|']
D000911:Antibodies, Monoclonal D061067:Antibodies, Monoclonal, Humanized D057134:Antibodies, Neutralizing D024882:Drug Resistance, Viral D006801:Humans D007700:Kinetics D009154:Mutation D000069455:Palivizumab D011485:Protein Binding D012136:Respiratory Syncytial Viruses D014760:Viral Fusion Proteins
Neutralizing Monoclonal Antibodies Palivizumab Viral Human Respiratory Syncytial Virus