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Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density
Abstract
Purpose: Recent studies have revealed that fucose removal from the oligosaccharides of human IgG1 antibodies results in a significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) via improved IgG1 binding to FcγRIIIa. In this report, we investigated the relationship between enhanced ADCC and antigen density on target cells using IgG1 antibodies with reduced fucose. Experimental Design: Using EL4 cell-derived transfectants with differential expression levels of exogenous human CC chemokine receptor 4 or human CD20 as target cells, ADCC of fucose variants of chimeric IgG1 antibodies specific for these antigens were measured. We further investigated IgG1 binding to natural killer (NK) cells and NK cell activation during ADCC induction to elucidate the mechanism by which low-fucose IgG1 induces ADCC upon target cells with low antigen expression. Results: Low-fucose IgG1s showed potent ADCC at low antigen densities at which their corresponding high-fucose counterparts could not induce measurable ADCC. The quantitative analysis revealed that fucose depletion could reduce the antigen amount on target cells required for constant degrees of ADCC induction by 10-fold for CC chemokine receptor 4 and 3-fold for CD20. IgG1 binding to NK cells was increased by ligating IgG1 with clustered antigen, especially for low-fucose IgG1. Up-regulation of an activation marker, CD69, on NK cells, particularly the CD56dim subset, in the presence of both the antibody and target cells was much greater for the low-fucose antibodies. Conclusions: Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells.
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“This increased affinity allows better therapeutic activity of Mabs used in cancer therapy, by triggering the antibody-dependent-cell-mediated cytotoxicity (ADCC) pathway (Niwa et al., 2005;Iida et al., 2006;Chung et al., 2012).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Niwa et al., 2005
In the citing paper
“It was reported that afucosylated Fc domain glycans of human IgG1 could enhance the binding to FcγRIIIa subtype receptors of natural killer cells (Shields et al., 2002;Shinkawa et al., 2003;Niwa et al., 2005;Iida et al., 2006;Subedi and Barb, 2016).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Niwa et al., 2005
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Ishida, T., Joh, T., Uike, N., Yamamoto, K., Utsunomiya, A., Yoshida, S., Saburi, Y., Miyamoto, T., Takemoto, S., Suzushima, H., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.37.3472 · Cited by 657
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Self-citationTherapeutic glycoprotein production in mammalian cells
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Glycosylation profile and biological activity of Remicade® compared with Flixabi® and Remsima®
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Metadata
- Authors
- Niwa, R., Sakurada, M., Kobayashi, Y., Uehara, A., Matsushima, K., Ueda, R., Nakamura, K., & Shitara, K.
- Affiliations
- 1Tokyo Research Laboratories, Kyowa Hakko Kogyo, Co., Ltd.;
- The University of Tokyo (JP)
- Nagoya City University (JP)
- Venue
- Clinical Cancer Research
- Published
- 2005-03-15
- Volume
- 11
- Issue
- 6
- Pages
- 2327-2336
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2160798258
- Cited by
- 187
- References
- 7
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 9 · 2018: 12 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 16 · 2013: 8 · 2012: 13
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- antibody-dependent cellular cytotoxicity, natural killer cells, NK cell activation, FCGR2A, antigen density, CD20, CD69, CD56dim NK cells, oligosaccharide modification
- MeSH terms
- Antibody-Dependent Cell Cytotoxicity, Fucose, Humans, Immunoglobulin G, Killer Cells, Natural, Lymphoma, Protein Binding, Tumor Cells, Cultured, Antigens, CD20, CD56 Antigen, Receptors, Chemokine, Receptors, CCR4
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