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.

Global epidemiology of non-influenza RNA respiratory viruses: data gaps and a growing need for surveillance

“…Despite relatively rare usage of the antibody and the highly conserved nature of its viral protein target, resistance has been reported due to variations in the fusion protein binding site. [64][65][66][67][68] One study 69 investigated the human monoclonal antibody MPE8, which cross-neutralises respiratory syncytial virus and human metapneumovirus by binding to two highly conserved anti-parallel β-strands on the pre-fusion viral fusion protein. The investigators found naturally occurring antibodies with this same target specificity in some patient serum samples, and therefore proposed this pre-fusion viral fusion protein as a potential vaccine candidate.…”

Drug Development of Therapeutic Monoclonal Antibodies

“…As an example, Bates et al [30] used this methodology to explore the role of binding kinetics on the neutralizing potency of the MAb palivizumab against respiratory syncytial virus (RSV). Investigating naturally occurring mutations of the RSV F protein, the target of palivizumab, indicated that while reduction of k on resulted in increased escape from MAb-mediated neutralization of RSV, changes in k off did not significantly affect neutralizing activity.…”

Molecular evolution of the fusion protein gene in human respiratory syncytial virus subgroup A

“…One of these substitutions, Asn268Ile, may affect the neutralization of HRSV (Bates et al, 2014), whereas other substitutions may not have such an effect (Bates et al, 2014;Schickli et al, 2015).…”

“…Thus, nonsynonymous mutations, such as Asn268Ile, that map to the Palivizumab epitope may influence the effectiveness of this drug (Bates et al, 2014). However, this mutant, which occurs in GA5, has rarely been detected globally (Trento et al, 2015) and additional surveillance may be needed to detect this mutant in the future.…”