Cited by 764Glycosylation and Glycoproteins ResearchViral Infectious Diseases and Gene Expression in InsectsMonoclonal and Polyclonal Antibodies Research

Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity

Umaña, Pablo, Jean–Mairet, Joël, Moudry, Radmila, Amstutz, Hanspeter, Bailey, James E.·1999·Nature Biotechnology

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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Crossref · 10.1038/6179

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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”
  • 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].”
  • 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].”

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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
OpenAlex
W1518819083
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
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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