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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Enhancing activity of FcαRI-bispecific antibodies using glycoengineering
Céline A N Sewnath1,2,3, Timon Damelang4,5, Arthur E H Bentlage5
1Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Journal of Immunology (Baltimore, Md. : 1950)
|March 29, 2025
Summary
Glycoengineering bispecific antibodies (BsAb) enhanced NK cell tumor killing but did not improve neutrophil or macrophage activity. This research focuses on improving cancer immunotherapy through antibody modifications.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Monoclonal antibodies (mAbs) are crucial in cancer therapy, but their efficacy varies across immune cell types.
- Neutrophils are less effective than NK cells and macrophages in antibody-dependent cell-mediated cytotoxicity (ADCC).
- Bispecific antibodies (BsAb) targeting FcαRI (CD89) and tumor antigens show promise for neutrophil-mediated tumor killing.
Purpose of the Study:
- To enhance the efficacy of an anti-EGFR/FcαRI bispecific antibody (BsAb) through IgG-Fc glycoengineering.
- To investigate the impact of Fc afucosylation and galactosylation on immune cell recruitment and tumor cell killing.
- To assess improvements in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Main Methods:
- Glycoengineering of IgG-Fc domain, specifically Fc afucosylation and galactosylation.
- Development of an anti-EGFR (Cetuximab)/FcαRI-bispecific antibody.
- In vitro assessment of NK cell, macrophage, and neutrophil-mediated tumor cell killing and phagocytosis.
- Evaluation of complement-dependent cytotoxicity (CDC) activity.
Main Results:
- Fc afucosylation moderately increased NK cell-mediated tumor cell killing.
- Glycoengineering did not enhance neutrophil-mediated ADCC or macrophage phagocytosis.
- The engineered BsAbs did not acquire complement-dependent cytotoxicity (CDC) activity.
- Fc galactosylation did not significantly improve antibody hexamerization or CDC.
Conclusions:
- Glycoengineered FcαRI bispecific antibodies can enhance NK cell-mediated ADCC.
- Modifications did not improve neutrophil or macrophage anti-tumor functions.
- Further strategies are needed to optimize bispecific antibody efficacy across multiple immune cell types for cancer immunotherapy.
