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Detection of Neutralization-sensitive Epitopes in Antigens Displayed on Virus-Like Particle VLP-Based Vaccines Using a Capture Assay
Published on: February 10, 2022
A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus
Yuting Zhang1,2, Min Zhang1, Haiyan Wu1
1State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China.
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.
Insights
A novel human antibody, AF-03, effectively neutralizes Marburg virus (MARV) and other filoviruses. This antibody targets the MARV glycoprotein, showing significant potential for treating deadly hemorrhagic fevers.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Marburg virus (MARV) causes severe hemorrhagic fever with high mortality rates.
- Effective antibody therapies for MARV are currently lacking.
- MARV's glycoprotein (GP) is a key target for neutralizing antibodies.
Purpose of the Study:
- To identify and characterize a novel human antibody targeting MARV GP.
- To evaluate the in vitro and in vivo efficacy of the identified antibody.
- To determine the epitope and mechanism of action of the antibody.
Main Methods:
- Identification and characterization of a novel human antibody (AF-03) against MARV GP.
- In vitro and in vivo neutralization assays using pseudotyped MARV.
- Epitope mapping via molecular docking and analysis of mutated viral species.
- Assessment of antibody activity against other filoviruses and Ebola virus variants.
Main Results:
- AF-03 demonstrated high binding affinity to MARV GP and potent neutralizing activity.
- The antibody recognized the Niemann-Pick C1 (NPC1) binding domain within GP1.
- AF-03 showed neutralizing activity against pseudotyped Ebola viruses with cleaved GP.
- An NPC2-fused version of AF-03 neutralized multiple filoviruses by binding to CI-MPR.
Conclusions:
- AF-03 is a promising therapeutic candidate for Marburg virus and other filovirus infections.
- The antibody's mechanism involves targeting the NPC1 binding site on the viral GP.
- Further development of AF-03 could lead to a novel treatment for filovirus diseases.
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