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Updated: Jul 10, 2025
Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
Functional characterization of AF-04, an afucosylated anti-MARV GP antibody
Min Zhang1, Yuting Zhang2, Haiyan Wu1
1State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing 100089, China.
Abstract:
Marburg virus (MARV), one member of the Filoviridae family, cause sporadic outbreaks of hemorrhagic fever with high mortality rates. No countermeasures are currently available for the prevention or treatment of MARV infection. Monoclonal antibodies (mAbs) are promising candidates to display high neutralizing activity against MARV infection in vitro and in vivo. Recently, growing evidence has shown that immune effector function including antibody-dependent cell-mediated cytotoxicity (ADCC) is also required for in vivo efficacy of a panel of antibodies. Glyco-engineered methods are widely utilized to augment ADCC function of mAbs. In this study, we generated a fucose-knockout MARV GP-specific mAb named AF-04 and showed that afucosylation dramatically increased its binding affinity to polymorphic FcγRIIIa (F176/V176) compared with the parental AF-03. Accordingly, AF-04-mediated NK cell activation and NFAT expression downstream of FcγRIIIa in effector cells were also augmented. In conclusion, this work demonstrates that AF-04 represents a novel avenue for the treatment of MARV-caused disease.
Insights
A novel glyco-engineered monoclonal antibody, AF-04, shows enhanced Marburg virus (MARV) neutralization. Afucosylation boosts antibody-dependent cell-mediated cytotoxicity (ADCC), offering a promising new treatment for MARV infections.
Area of Science:
- Virology
- Immunology
- Biotechnology
Background:
- Marburg virus (MARV) causes severe hemorrhagic fever with high mortality.
- No effective treatments or preventative measures currently exist for MARV infection.
- Monoclonal antibodies (mAbs) show potential for MARV treatment, with immune effector functions like ADCC being crucial for in vivo efficacy.
Purpose of the Study:
- To develop and evaluate a glyco-engineered mAb with enhanced Marburg virus GP-specific activity.
- To investigate the impact of afucosylation on mAb binding affinity and effector functions.
Main Methods:
- Generation of a fucose-knockout MARV GP-specific mAb (AF-04) using glyco-engineering.
- Comparison of AF-04's binding affinity to FcγRIIIa with its parental mAb (AF-03).
- Assessment of NK cell activation and NFAT signaling downstream of FcγRIIIa.
Main Results:
- Afucosylation of AF-04 significantly increased its binding affinity to polymorphic FcγRIIIa (F176/V176) compared to AF-03.
- AF-04 demonstrated augmented NK cell activation and NFAT expression in effector cells.
- The enhanced binding and effector function suggest improved therapeutic potential.
Conclusions:
- AF-04, a glyco-engineered mAb, exhibits potent MARV-specific activity.
- Afucosylation is a viable strategy to enhance mAb-mediated ADCC against MARV.
- AF-04 represents a promising novel therapeutic candidate for Marburg virus disease.
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