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.
Virology. 2014 Apr;454-455:139-44. doi: 10.1016/j.virol.2014.02.010. Epub 2014 Mar 3.
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.
结合动力学在确定抗病毒抗体的中和效价中的作用尚未被充分理解。虽然人们认为，稳态亲和力的增加与病毒中和活性的增加呈正相关，但结合速率或解离速率与中和效价之间的关系尚不清楚。我们研究了 RSV F 蛋白中天然存在的抗体耐药性突变对帕利珠单抗结合动力学的影响。与 RSV F 蛋白结合的结合速率（Kon）降低导致 RSV 逃避帕利珠单抗介导的中和作用，而解离速率（Koff）的改变并不显著影响中和活性。有趣的是，Kon 的降低与效力的降低与在高亲和力增强效力的帕利珠单抗变体（motavizumab）中发现的 Kon 增加的影响相吻合。这些数据表明，结合速率是决定 RSV F 蛋白抗原位点 A 抗体中和效价的主要因素，并决定了抗体体细胞变异体的效力或病毒糖蛋白变异体逃避的效率。
