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Cited by 225Monoclonal and Polyclonal Antibodies ResearchGlycosylation and Glycoproteins ResearchProtein purification and stability

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

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Washburn, Nathaniel, Schwab, Inessa, Ortiz, Daniel, Bhatnagar, Naveen, Lansing, Jonathan C., Medeiros, Amy, Tyler, Steven, Mekala, Divya +13 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1422481112PMC PMC4371931
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Abstract

Significance: IgG fragment crystallizable domain (Fc) sialylation has emerged as an important but controversial concept for regulating anti-inflammatory activity of antibodies. Moreover, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for human use. We describe for the first time, to our knowledge, the development of a robust, scalable process to generate a sialylated intravenous immunoglobulin (IVIg) drug candidate with maximum Fc sialylation devoid of unwanted modifications. By using a wide panel of physicochemical analytics and in vivo models, we have validated the quality and potent anti-inflammatory activity of this clinical candidate. This report not only confirms the controversial anti-inflammatory activity of IgG-Fc sialylation, it also represents the first sialylated IVIg preparation, to our knowledge, with consistent anti-inflammatory potency suitable for clinical development.

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Crossref · 10.1073/pnas.1422481112

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  • Galactose is required for sialylation with NeuAc, which can improve solubility, anti-inflammatory activity, thermal stability and serum half-life of mAbs.

    “On the other hand, galactose is required for sialylation with N-acetylneuraminic acid (NeuAc), which in turn can improve the solubility, anti-inflammatory activity, thermal stability and serum half-life of mAbs [8,23–26].”

    From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [25]

    The Results describe galactose-containing reagents in Fc sialylation, and the paper reports enhanced anti-inflammatory activity for sialylated IVIg in animal models. It does not establish improved solubility or thermal stability of mAbs. The Results also report no significant pharmacokinetic difference between sialylated and parent IVIg, so they do not support an improved serum half-life for this product. Page numbers were not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Co-expression of ST6Gal1 and β4GalT1 in HEK293 also helped optimizing sialylation of human Fc-IVIg, therefore enhancing its therapeutic activity.

    “Co-expression of the same enzymes in HEK293 also helped optimizing sialylation of human Fc-IVIg (intravenous immunoglobulin), therefore enhancing its therapeutic activity (Washburn et al., 2015).”

    From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Washburn et al., 2015

    Materials and Methods says B4GalT1 and ST6Gal1 were produced by transient expression in HEK293 cells, but does not say they were co-expressed. The Results describe using the enzymes in an optimized sialylation reaction, and the Discussion reports enhanced anti-inflammatory activity of the resulting IVIg. The paper therefore supports the enzyme-based sialylation and activity, but not the claimed co-expression mechanism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Washburn, N., Schwab, I., Ortiz, D., Bhatnagar, N., Lansing, J. C., Medeiros, A., Tyler, S., Mekala, D., Cochran, E., Sarvaiya, H., Garofalo, K., Meccariello, R., Meador, J. W., Rutitzky, L., Schultes, B. C., Ling, L., Avery, W., Nimmerjahn, F., Manning, A. M., Kaundinya, G. V., & Bosques, C. J.
Affiliations
  • Momenta Pharmaceuticals (United States) (US)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-03-02
Volume
112
Issue
11
Pages
E1297-306
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1422481112
PMC
PMC4371931
OpenAlex
W1975345897
Cited by
225
References
5
Citations by year
2026: 6 · 2025: 8 · 2024: 25 · 2023: 17 · 2022: 21 · 2021: 27 · 2020: 21 · 2019: 18 · 2018: 22 · 2017: 22 · 2016: 24 · 2015: 14
FWCI
22.15
Type
journal article
Language
en
Update notices
correction (2015-07-13)
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Amgen
  • Genentech
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Keywords
intravenous immunoglobulin, anti-inflammatory activity, enzymatic glycosylation, pharmacokinetics, tissue distribution, animal models of inflammation
MeSH terms
Animals, Anti-Inflammatory Agents, Arthritis, Experimental, Blister, Disease Models, Animal, Glycosylation, Humans, Immunoglobulin Fab Fragments, Receptors, Fc, Tissue Distribution, Drug Design, Epidermolysis Bullosa Acquisita, Purpura, Thrombocytopenic, Idiopathic, Immunoglobulins, Intravenous, Treatment Outcome, N-Acetylneuraminic Acid, Mice, HEK293 Cells

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