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Cited by 51Monoclonal and Polyclonal Antibodies ResearchProtein purification and stabilityDrug Transport and Resistance Mechanisms

Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life

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Grevys, Algirdas, Frick, Rahel, Mester, Simone, Flem-Karlsen, Karine, Nilsen, Jeannette, Foss, Stian, Sand, Kine Marita Knudsen, Emrich, Thomas +5 more·2022·iScience
DOI 10.1016/j.isci.2022.103746PMC PMC8800109
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Abstract

Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma half-life. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding.

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Authors
Grevys, A., Frick, R., Mester, S., Flem-Karlsen, K., Nilsen, J., Foss, S., Sand, K. M. K., Emrich, T., Fischer, J. A. A., Greiff, V., Sandlie, I., Schlothauer, T., & Andersen, J. T.
Affiliations
  • Oslo University Hospital (NO)
  • Roche Pharma AG (Germany) (DE)
  • University of Oslo (NO)
Corresponding author
  • Grevys, Algirdas
  • Andersen, Jan Terje
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2022-02
Volume
25
Issue
2
Pages
103746
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2022.103746
PMC
PMC8800109
OpenAlex
W4205117348
Cited by
51
References
5
Citations by year
2026: 6 · 2025: 8 · 2024: 16 · 2023: 17 · 2022: 4
FWCI
6.40
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
Funders
  • Helse Sør-Øst RHF (2018052)
  • Roche
  • Harvard Medical School
  • F. Hoffmann-La Roche
  • University of South-Eastern Norway
  • Norges Forskningsråd (179573, 230526, 274993, 287927)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
immunoglobulin variable region, plasma half-life, pharmacokinetics, cellular uptake, antibody recycling, intracellular degradation, endothelial cells, neonatal Fc receptor, FcRn binding, Fc engineering

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