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Virology. 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.

Author information

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.
5
IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United states; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, United states.
6
The Vanderbilt Vaccine Center, Departments of Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United states; The Vanderbilt Vaccine Center, Departments of Pediatrics, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United states. Electronic address: james.crowe@vanderbilt.edu.

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

PMID:
24725940
PMCID:
PMC4004766
DOI:
10.1016/j.virol.2014.02.010
[Indexed for MEDLINE]
Free PMC Article

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