Puligedda Rama Devudu, Kouiavskaia Diana, Al-Saleem Fetweh H, Kattala Chandana Devi, Nabi Usman, Yaqoob Hamid, Bhagavathula V Sandeep, Sharma Rashmi, Chumakov Konstantin, Dessain Scott K
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Vaccine. 2017 Oct 4;35(41):5455-5462. doi: 10.1016/j.vaccine.2017.03.038. Epub 2017 Mar 24.
Following the eradication of wild poliovirus (PV), achieving and maintaining a polio-free status will require eliminating potentially pathogenic PV strains derived from the oral attenuated vaccine. For this purpose, a combination of non-cross-resistant drugs, such as small molecules and neutralizing monoclonal antibodies (mAbs), may be ideal. We previously isolated chimpanzee and human mAbs capable of neutralizing multiple PV types (cross-neutralization). Here, we describe three additional human mAbs that neutralize types 1 and 2 PV and one mAb that neutralizes all three types. Most bind conformational epitopes and have unusually long heavy chain complementarity determining 3 domains (HC CDR3). We assessed the ability of the mAbs to neutralize A12 escape mutant PV strains, and found that the neutralizing activities of the mAbs were disrupted by different amino acid substitutions. Competitive binding studies further suggested that the specific mAb:PV interactions that enable cross-neutralization differ among mAbs and serotypes. All of the cloned mAbs bind PV in the vicinity of the "canyon", a circular depression around the 5-fold axis of symmetry through which PV recognizes its cellular receptor. We were unable to generate escape mutants to two of the mAbs, suggesting that their epitopes are important for the PV life cycle. These data indicate that PV cross-neutralization involves binding to highly conserved structures within the canyon that binds to the cellular receptor. These may be facilitated by the long HC CDR3 domains, which may adopt alternative binding configurations. We propose that the human and chimpanzee mAbs described here could have potential as anti-PV therapeutics.
在根除野生脊髓灰质炎病毒（PV）之后，要实现并维持无脊髓灰质炎状态，就需要消除源自口服减毒疫苗的潜在致病PV毒株。为此，小分子和中和性单克隆抗体（mAb）等非交叉耐药药物的组合可能是理想选择。我们之前分离出了能够中和多种PV类型（交叉中和）的黑猩猩和人类mAb。在此，我们描述了另外三种中和1型和2型PV的人类mAb以及一种中和所有三种类型的mAb。大多数抗体结合构象表位，并且具有异常长的重链互补决定区3（HC CDR3）。我们评估了这些mAb中和A12逃逸突变PV毒株的能力，发现mAb的中和活性因不同的氨基酸取代而受到破坏。竞争性结合研究进一步表明，能够实现交叉中和的特定mAb与PV的相互作用在不同mAb和血清型之间存在差异。所有克隆的mAb都在“峡谷”附近结合PV，“峡谷”是围绕5重对称轴的圆形凹陷，PV通过它识别其细胞受体。我们无法针对其中两种mAb产生逃逸突变体，这表明它们的表位对PV生命周期很重要。这些数据表明，PV交叉中和涉及与峡谷内与细胞受体结合的高度保守结构的结合。这可能由长的HC CDR3结构域促进，其可能采用替代的结合构型。我们提出，此处描述的人类和黑猩猩mAb可能具有作为抗PV治疗剂的潜力。
