美国国立卫生研究院Robert A. Seder及其研究小组发现，有效抗疟疾人类单克隆抗体（mAb）靶向环子孢子蛋白次要重复序列并中和肝脏中的子孢子。该项研究成果在线发表在2020年9月17日的《免疫》上。

研究人员分离了一种中和型人类单克隆抗体L9，该抗体优先以高亲和力与恶性疟原虫环子孢子蛋白（PfCSP）的NVDP次要重复序列结合，同时与NANP主要重复序列交叉反应。在介导小鼠蚊虫叮咬保护作用方面，L9比六种已发表的中和人PfCSP mAb更有效。等温滴定量热法和多光子显微术显示，L9和其它结合PfCSP的最具保护性mAb具有两个结合位点，并通过杀死肝脏中的子孢子（SPZ）防止它们从血窦和肝细胞横穿而发挥保护作用。

这项研究把主要PfCSP的次要重复序列作为中和表位，确定了中和SPZ的体外生物物理相关性，并证明肝脏是抗体预防疟疾的重要部位。

据了解，研发针对SPZ PfCSP的有效mAb并阐明它们的中和机制将有助于转变被动预防，并有利于下一代疫苗的研发。

附：英文原文

Title: A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver

Author: Lawrence T. Wang, Lais S. Pereira, Yevel Flores-Garcia, James O’Connor, Barbara J. Flynn, Arne Schn, Nicholas K. Hurlburt, Marlon Dillon, Annie S.P. Yang, Amanda Fabra-García, Azza H. Idris, Bryan T. Mayer, Monica W. Gerber, Raphael Gottardo, Rosemarie D. Mason, Nicole Cavett, Reid B. Ballard, Neville K. Kisalu, Alvaro Molina-Cruz, Jorgen Nelson, Rachel Vistein, Carolina Barillas-Mury, Rogerio Amino, David Baker, Neil P. King, Robert W. Sauerwein, Marie Pancera, Ian A. Cockburn, Fidel Zavala, Joseph R. Francica, Robert A. Seder

Issue&Volume: 2020-09-17

Abstract: Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanismsof neutralization will facilitate translation for passive prophylaxis and aid next-generationvaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentiallybound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANPmajor repeats. L9 was more potent than six published neutralizing human PfCSP mAbsat mediating protection against mosquito bite challenge in mice. Isothermal titrationcalorimetry and multiphoton microscopy showed that L9 and the other most protectivemAbs bound PfCSP with two binding events and mediated protection by killing SPZ inthe liver and by preventing their egress from sinusoids and traversal of hepatocytes.This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifiesan in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is animportant site for antibodies to prevent malaria.

DOI: 10.1016/j.immuni.2020.08.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30371-X