靶向恶性疟原虫PfRH5的全人源新结构抗体开发及机制研究

Malaria caused by Plasmodium falciparum (P. falciparum) continues to be a serious threat to global public health. Currently, the occurrence of multidrug-resistant P. falciparum worldwide have rendered antimalarial drugs ineffective, which call for the development of new and effective therapeutics to treat P. falciparum infections. P. falciparum reticulocyte binding-like homologue protein (PfRH5), which was found to be highly conserved in all P. falciparum merozoites, mediates erythrocyte invasion, and serves as an ideal target for the development of broadly neutralizing and highly effective antibodies. Here, we intend to identify PfRH5-specific and broadly P. falciparum neutralizing human nanobodies (HsdAb) by using an extraordinarily large human nanobody phage-display library we previously established. On the other hand, we intend to engineer novel single-chain Fc (sFc) with effector functions including ADCC and CDC based on the previously reported monomeric IgG1 Fc. Next, we will construct the fusion protein HsdAb-sFc with good specificity, long in vivo half-life, potent biological activity and low production cost, which is expected to be novel and effective therapeutics to treat malaria infections. This study may also have direct implications for the design of P. falciparum subunit vaccines, and for the development of next-generation antibody-based therapeutics for the treatment of infectious diseases.

由恶性疟原虫感染引起的恶性疟疾一直严重威胁着人类健康。近年来，全球范围内均出现了对青蒿素等抗疟药物多重耐药的恶性疟原虫，显示了疟疾再次大规模暴发和流行传播的危险。因此，开发广谱高效的新型特效抗疟药物意义重大。恶性疟原虫裂殖子表面的网状细胞结合蛋白同源物5（PfRH5）是裂殖子入侵的关键蛋白，在所有种类恶性疟原虫中高度保守，是研发广谱高效抗体的理想靶点。因此，本项目将利用大容量全人源纳米抗体库进行抗PfRH5全人源纳米抗体（HsdAb）的筛选，期望获得具有广谱抗疟活性的HsdAb。另一方面，我们还将基于人IgG单体Fc构建一类具有效应功能的新型Fc单体，并与HsdAb进行融合，构建一类靶向性好、半衰期长、活性高、成本低的新型抗体，并对其作用机制进行深入研究，期望作为一种新型抗疟药物应用于恶性疟的治疗及疫情防控，也为疫苗研制提供新思路，同时为突破抗体药物的发展瓶颈提供重要的理论依据和解决方案。

由恶性疟原虫感染引起的恶性疟疾一直严重威胁人类健康，尤其是一些恶性疟原虫对青蒿素等抗疟药物出现多重耐药，显示了疟疾再次大规模暴发和流行传播的危险。但目前仍缺乏广谱高效的特效抗疟药物。本项目利用合成生物学理论和技术，通过优化重构，研发了小尺寸、高安全性、强活性的新结构抗体——全人源纳米抗体。基于全人源纳米抗体研发平台，针对恶性疟原虫裂殖子表面的网状细胞结合蛋白同源物5（PfRH5）研发高活性的新型抗疟药物。其中，项目负责人以通讯作者发表的14篇SCI论文获得本项目资助，并申请5项发明专利，获得2项专利授权，完成1项成果转化。因此，本项目建立了更快速、经济、安全的防治传染病的技术平台，研发的新型抗疟全人源纳米抗体药物有望作为治疗恶性疟的候选药物，同时有望指导广谱疫苗的设计。