Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
B Cell Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Cell Rep. 2023 Nov 28;42(11):113330. doi: 10.1016/j.celrep.2023.113330. Epub 2023 Oct 28.
IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.
IGHV3-33 编码的抗体在人体针对疟原虫环子孢子蛋白（PfCSP）的体液免疫反应中普遍存在。在 VH3-33 抗体中，PfCSP 主要重复（NANP）、次要（NVDP）和连接（NPDP）基序之间的交叉反应性与高亲和力和强效寄生虫抑制作用相关。然而，抗体交叉反应性的分子基础及其与疗效的关系仍未解决。在这里，我们对 12 种具有不同程度交叉反应性的 VH3-33 抗 PfCSP 单克隆抗体（mAb）进行了广泛的结构-功能表征，这些 mAb 是通过免疫表达人免疫球蛋白基因库的小鼠诱导产生的。我们确定了抗体变区中介导交叉反应性结合的残基，并描绘了抗体结合诱导的四个不同的表位构象，其中一个与高保护效力一致，另一个赋予相当强效的寄生虫肝脏入侵抑制作用。我们的数据表明，PfCSP 上 VH3-33 mAb 交叉反应性结合的分子特征与 mAb 效力之间存在关联，这对于开发针对疟疾的基于抗体的干预措施具有重要意义。
