Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity
Abstract
The glycosylation pattern of chCE7, an antineuroblastoma chimeric IgG1, was engineered in Chinese hamster ovary cells with tetracycline-regulated expression of beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase catalyzing formation of bisected oligosaccharides that have been implicated in antibody-dependent cellular cytotoxicity (ADCC). Measurement of the ADCC activity of chCE7 produced at different tetracycline levels showed an optimal range of GnTIII expression for maximal chCE7 in vitro ADCC activity, and this activity correlated with the level of constant region-associated, bisected complex oligosaccharides determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The new optimized variants of chCE7 exhibit substantial ADCC activity and, hence, may be useful for treatment of neuroblastoma. The strategy presented here should be applicable to optimize the ADCC activity of other therapeutic IgGs.
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Increases in fucosylation have been correlated with decreased ADCC activity and decreased FcγRIIIa and FcγRIIb binding affinity.
“This is ideal as increases in fucosylation have been correlated with decreased ADCC activity and decreased FcγRIIIa and FcγRIIb binding affinity. 40 , 41 , 42 , 43”
From Dynamic <scp>pH</scp> profiles drive higher cell‐specific and volumetric productivity (2026) · cites this paper as [40]
Antibody fucosylation is reduced by GnT-III overexpression because oligosaccharides with bisecting GlcNAc no longer act as FUT8 substrates.
“Antibody fucosylation is reduced by GnT-III overexpression because oligosaccharides with bisecting GlcNAc no longer act as FUT8 substrates [15].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [15]
Addition of bisecting β1,4-linked GlcNAc by GnT-III or in vitro glycan remodelling is linked to increased ADCC in IgGs, albeit to a lesser extent than afucosylation.
“The addition of bisecting β1,4-linked N-acetylglucosamine (GlcNAc) by endogenous or recombinant N-acetylglucosaminyltransferase III (GnT-III in YB2/0 and CHO cells respectively) or via in vitro glycan remodelling has also been linked to increased ADCC in IgGs, albeit to a lesser extent than afucosylation [15–17].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [15]
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- Authors
- Umaña, P., Jean–Mairet, J., Moudry, R., Amstutz, H., & Bailey, J. E.
- Affiliations
- ETH Zurich (CH)
- Swiss Red Cross (CH)
- Corresponding author
- Bailey, James E.
- Venue
- Nature Biotechnology
- Published
- 1999-02
- Volume
- 17
- Issue
- 2
- Pages
- 176-180
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- DOI
- 10.1038/6179
- OpenAlex
- W1518819083
- Semantic Scholar
- 91b684d5d7b8cdc532055ffbfcb872089efff9a2
- Cited by
- 764
- References
- 26
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 14 · 2023: 17 · 2022: 13 · 2021: 28 · 2020: 28 · 2019: 29 · 2018: 39 · 2017: 31 · 2016: 40 · 2015: 43 · 2014: 40 · 2013: 35 · 2012: 38
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- antibody glycosylation, glycoforms, antibody-dependent cellular cytotoxicity, neuroblastoma, tetracycline-regulated expression, CHO cells, therapeutic antibodies, glycosylation engineering
- MeSH terms
- Animals, Antibody-Dependent Cell Cytotoxicity, Carbohydrate Sequence, Cricetinae, Humans, Immunoglobulin G, Molecular Sequence Data, Neuroblastoma, Tetracycline, Gene Expression Regulation, Enzymologic, CHO Cells, N-Acetylglucosaminyltransferases
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