Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, M5G 0A4, ON, Canada.
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands.
Nat Commun. 2018 Oct 26;9(1):4458. doi: 10.1038/s41467-018-06742-9.
Interventions that can block the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and Anopheles vector have the potential to reduce the incidence of malaria. Pfs48/45 is a gametocyte surface protein critical for parasite development and transmission, and its targeting by monoclonal antibody (mAb) 85RF45.1 leads to the potent reduction of parasite transmission. Here, we reveal how the Pfs48/45 6C domain adopts a (SAG1)-related-sequence (SRS) fold. We structurally delineate potent epitope I and show how mAb 85RF45.1 recognizes an electronegative surface with nanomolar affinity. Analysis of Pfs48/45 sequences reveals that polymorphisms are rare for residues involved at the binding interface. Humanization of rat-derived mAb 85RF45.1 conserved the mode of recognition and activity of the parental antibody, while also improving its thermostability. Our work has implications for the development of transmission-blocking interventions, both through improving vaccine designs and the testing of passive delivery of mAbs in humans.
干预措施可以阻断疟原虫（Pf）在人类宿主和疟蚊媒介之间的传播，从而有潜力降低疟疾的发病率。Pfs48/45 是一种配子体表面蛋白，对寄生虫的发育和传播至关重要，其单克隆抗体（mAb）85RF45.1 的靶向作用导致寄生虫传播的有效减少。在这里，我们揭示了 Pfs48/45 6C 结构域如何采用（SAG1）相关序列（SRS）折叠。我们对有效表位 I 进行了结构划分，并展示了 mAb 85RF45.1 如何识别具有纳摩尔亲和力的带负电荷表面。对 Pfs48/45 序列的分析表明，在结合界面上涉及的残基的多态性很少。鼠源性 mAb 85RF45.1 的人源化保留了亲本抗体的识别模式和活性，同时还提高了其热稳定性。我们的工作对开发传播阻断干预措施具有重要意义，既可以通过改进疫苗设计，也可以通过测试在人类中被动输送 mAbs。
