针对间日疟原虫前体红细胞期和血液期的强效AMA1特异性人单克隆抗体。

Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages.

作者信息

Winnicki Anna C, Dietrich Melanie H, Yeoh Lee M, Carias Lenore L, Roobsoong Wanlapa, Drago Chiara L, Malachin Alyssa N, Redinger Karli R, Feufack-Donfack Lionel Brice, Baldor Lea, Jung Nicolai C, McLaine Olivia S, Skomorovska-Prokvolit Yelenna, Orban Agnes, Opi D Herbert, Kirtley Payton, Nielson Kiersey, Aleshnick Maya, Zanghi Gigliola, Rezakhani Nastaran, Vaughan Ashley M, Wilder Brandon K, Sattabongkot Jetsumon, Tham Wai-Hong, Popovici Jean, Beeson James G, Bosch Jürgen, King Christopher L

机构信息

Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, USA.

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

出版信息

Nat Commun. 2024 Dec 4;15(1):10556. doi: 10.1038/s41467-024-53848-4.

DOI:10.1038/s41467-024-53848-4

PMID:39632799

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11618605/

Abstract

New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC of 0.3 - 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.

摘要

由于间日疟原虫易于传播且在肝脏中存在休眠现象，导致复发增加临床负担，因此需要新的治疗方法来预防间日疟原虫疟疾。在本论文中，我们从一名接触过间日疟原虫的个体的外周血单个核细胞中鉴定出12种间日疟原虫顶端膜抗原1（PvAMA1）特异性人单克隆抗体。PvAMA1对于子孢子和裂殖子的入侵至关重要，使其成为一个独特的治疗靶点。我们表明，单克隆抗体826827使用间日疟原虫临床分离株阻断人网织红细胞的入侵，并在体外抑制子孢子对人肝细胞的入侵（IC为0.3 - 3.7µg/mL）。用人单克隆抗体826827接种人肝脏转基因（FRG-humHep）雌性小鼠可显著降低体内肝脏感染。与826827结合的重组PvAMA1的晶体结构表明，826827部分占据了PvAMA1中与已知受体RON2结合的高度保守疏水凹槽。我们分离出了一种强效单克隆抗体，它具有分离株超越性，可阻断红细胞前期和血液阶段感染，可能是治疗间日疟原虫的潜在疗法。