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. 2014 Apr:454-455:139-44.
doi: 10.1016/j.virol.2014.02.010. Epub 2014 Mar 3.

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

John T Bates  1 , Christopher J Keefer  2 , James C Slaughter  3 , Daniel W Kulp  4 , William R Schief  5 , James E Crowe Jr  6
Affiliations

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

John T Bates et al. Virology. 2014 Apr.

Abstract

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.

Keywords: Antibodies; Human; Monoclonal; Neutralizing; Palivizumab; Respiratory Syncytial Virus; Viral.

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Figures

Figure 1
Figure 1
The structure of RSV F and mutations that confer resistance to palivizumab. (A) Antigenic Site A is shown in gold on the previously published structure of post-fusion RSV F (PDBid: 3rrr). (B) The amino acid sequence of antigenic Site A is shown in the context of the linearized, uncleaved RSV F. (C) Specific amino acid changes within antigenic Site A which confer resistance to palivizumab are bolded and underlined.
Figure 2
Figure 2
Relationship between association rate (A), dissociation rate (B), and steady-state affinity (C) of palivizumab binding to variant RSV F proteins with neutralizing activity of palivizumab against viruses bearing the same mutations. The RSV F wild type sequence is shown in red. P values indicate Spearman’s Rank Correlation.
See this image and copyright information in PMC

References

    1. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics. 1998;102:531–537. - PubMed
    1. Adams O, Bonzel L, Kovacevic A, Mayatepek E, Hoehn T, Vogel M. Palivizumab-resistant human respiratory syncytial virus infection in infancy. Clin Infect Dis. 2010;51:185–188. - PubMed
    1. Aiyegbo MS, Sapparapu G, Spiller BW, Eli IM, Williams DR, Kim R, Lee DE, Liu T, Li S, Woods VL, Jr, Nannemann DP, Meiler J, Stewart PL, Crowe JE., Jr Human rotavirus VP6-specific antibodies mediate intracellular neutralization by binding to a quaternary structure in the transcriptional pore. PLoS One. 2013;8:e61101. - PMC - PubMed
    1. Bates JT, Keefer CJ, Utley TJ, Correia BE, Schief WR, Crowe JE., Jr Reversion of Somatic Mutations of the Respiratory Syncytial Virus-Specific Human Monoclonal Antibody Fab19 Reveal a Direct Relationship between Association Rate and Neutralizing Potency. J Immunol. 2013;190:3732–3739. - PMC - PubMed
    1. Beeler JA, van Wyke Coelingh K. Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol. 1989;63:2941–2950. - PMC - PubMed

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