title: 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.
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.
authors.affiliation: The Vanderbilt Vaccine Center, Departments of Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United states.
authors.forename: John T
authors.initials: JT
authors.lastname: Bates
authors.affiliation: The Vanderbilt Vaccine Center, Departments of Pediatrics, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United states.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Keefer
authors.affiliation: The Vanderbilt Vaccine Center, Departments of Biostatistics and Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United states.
authors.forename: James C
authors.initials: JC
authors.lastname: Slaughter
authors.affiliation: IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United states.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kulp
authors.affiliation: 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.
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.affiliation: 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.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D024882:Drug Resistance, Viral; D006801:Humans; D007700:Kinetics; D009154:Mutation; D000069455:Palivizumab; D011485:Protein Binding; D012136:Respiratory Syncytial Viruses / Q000235:genetics* / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C526850:F protein, human respiratory syncytial virus; D014760:Viral Fusion Proteins; D000069455:Palivizumab
keywords: Antibodies; Human; Monoclonal; Neutralizing; Palivizumab; Respiratory Syncytial Virus; Viral
references.citation: J Virol. 2011 Aug;85(15):7788-96
references.pmid: 21613394
references.citation: Virology. 2004 Jan 20;318(2):608-12
references.pmid: 14972528
references.citation: J Infect Dis. 2011 Mar 1;203(5):674-82
references.pmid: 21208913
references.citation: Methods Enzymol. 2011;487:545-74
references.pmid: 21187238
references.citation: J Infect Dis. 2012 Feb 15;205(4):635-8
references.pmid: 22184728
references.citation: J Mol Biol. 2007 May 4;368(3):652-65
references.pmid: 17362988
references.citation: J Virol. 2005 Oct;79(19):12528-35
references.pmid: 16160180
references.citation: Virology. 1998 Dec 20;252(2):373-5
references.pmid: 9878616
references.citation: Lancet. 2010 May 1;375(9725):1545-55
references.pmid: 20399493
references.citation: N Engl J Med. 1979 Mar 8;300(10):530-4
references.pmid: 763253
references.citation: Pediatrics. 1998 Sep;102(3 Pt 1):531-7
references.pmid: 9738173
references.citation: N Engl J Med. 2005 Apr 28;352(17):1749-59
references.pmid: 15858184
references.citation: J Infect Dis. 2004 Sep 1;190(5):975-8
references.pmid: 15295704
references.citation: J Virol. 2005 Oct;79(19):12311-20
references.pmid: 16160158
references.citation: J Immunol. 2008 Mar 15;180(6):3980-9
references.pmid: 18322207
references.citation: J Immunol. 1994 Jul 1;153(1):449-59
references.pmid: 7515931
references.citation: Lancet. 2000 Mar 18;355(9208):1014
references.pmid: 10768456
references.citation: J Virol. 1989 Jul;63(7):2941-50
references.pmid: 2470922
references.citation: Virol J. 2007 Jul 10;4:71
references.pmid: 17623075
references.citation: Pediatr Int. 2002 Jun;44(3):235-41
references.pmid: 11982888
references.citation: J Virol. 2006 Dec;80(23):11651-7
references.pmid: 17005645
references.citation: Nat Struct Mol Biol. 2010 Feb;17(2):248-50
references.pmid: 20098425
references.citation: J Infect Dis. 2004 Dec 1;190(11):1941-6
references.pmid: 15529258
references.citation: PLoS One. 2013 May 09;8(5):e61101
references.pmid: 23671563
references.citation: J Immunol. 2013 Apr 1;190(7):3732-9
references.pmid: 23455501
references.citation: J Mol Biol. 2005 Jul 1;350(1):126-44
references.pmid: 15907931
references.citation: Vaccine. 1990 Oct;8(5):497-502
references.pmid: 2251875
references.citation: Clin Infect Dis. 2010 Jul 15;51(2):185-8
references.pmid: 20528472