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一种新型 MARV 糖蛋白特异性抗体，具有广谱中和丝状病毒的潜力。

A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus.

机构信息

State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China.

Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China.

出版信息

Elife. 2024 Mar 25;12:RP91181. doi: 10.7554/eLife.91181.

DOI:10.7554/eLife.91181
PMID:38526940
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10963030/
Abstract

Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed a high binding affinity to MARV GP and showed neutralizing and protective activities against the pseudotyped MARV in vitro and in vivo. Epitope identification, including molecular docking and experiment-based analysis of mutated species, revealed that AF-03 recognized the Niemann-Pick C1 (NPC1) binding domain within GP1. Interestingly, we found the neutralizing activity of AF-03 to pseudotyped Ebola viruses (EBOV, SUDV, and BDBV) harboring cleaved GP instead of full-length GP. Furthermore, NPC2-fused AF-03 exhibited neutralizing activity to several filovirus species and EBOV mutants via binding to CI-MPR. In conclusion, this work demonstrates that AF-03 represents a promising therapeutic cargo for filovirus-caused disease.

摘要

马尔堡病毒（MARV）是引起人类致命性出血热的丝状病毒之一，死亡率高达 90%。中和抗体是预防或治疗病毒病的理想候选物。然而，迄今为止，尚无抗体被批准用于 MARV 治疗。在这项研究中，我们鉴定了一种针对 MARV 糖蛋白（GP）的新型人源抗体，命名为 AF-03。AF-03 对 MARV GP 具有高亲和力，并表现出针对体外和体内假型 MARV 的中和和保护活性。表位鉴定，包括分子对接和基于突变体的实验分析，表明 AF-03 识别 GP1 内的尼曼-匹克 C1（NPC1）结合域。有趣的是，我们发现 AF-03 对含有裂解 GP 而不是全长 GP 的假型埃博拉病毒（EBOV、SUDV 和 BDBV）具有中和活性。此外，通过与 CI-MPR 结合，融合 NPC2 的 AF-03 对几种丝状病毒和 EBOV 突变体表现出中和活性。总之，这项工作表明 AF-03 代表了一种有前途的丝状病毒病治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/dbebf324e1a1/elife-91181-fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/dbebf324e1a1/elife-91181-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/3319f62e780d/elife-91181-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/09669a5b5747/elife-91181-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/2b28decef550/elife-91181-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/c47155149cc2/elife-91181-fig3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/1b7b64834dea/elife-91181-fig4-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/16bfa599417d/elife-91181-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/1a332b455103/elife-91181-fig5-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5662/10963030/c7dcfb4ca58d/elife-91181-fig6.jpg
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