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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.<\/jats:p>","DOI":"10.7554\/elife.91181","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T11:45:07Z","timestamp":1701344707000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91181","source":"Crossref","is-referenced-by-count":6,"title":["A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus"],"prefix":"10.7554","volume":"12","author":[{"given":"Yuting","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/01mtxmr84","id-type":"ROR","asserted-by":"publisher"}],"name":"Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University","place":["Hohhot, 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