Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics
Open accessAbstract
Significance: Therapeutic antibodies of the immunoglobulin G (IgG) isotype show a pharmacokinetic (PK) profile that is strongly mediated by the interaction with the neonatal Fc receptor (FcRn). Therefore, modulating the FcRn–IgG interaction allows altering PK characteristics of therapeutic antibodies. So far, engineering the crystallizable fragment (Fc) is known to affect PK, and, although the influence of the antigen binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism remains unknown. Here, we demonstrate that the charge distribution in the distal variable fragment (Fv) of IgGs is involved in excessive binding to the FcRn, thereby reducing FcRn-dependent terminal half-lives in vivo. These findings contribute to a better understanding of the FcRn–IgG interaction.
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The Fab portion of IgGs and subtle differences in complementarity-determining region sequence can impact interactions of IgG with FcRn.
“it has been demonstrated that the Fab portion of IgGs, and even subtle differences in complementarity-determining region sequence, can impact on interactions of IgG with this receptor [30–34].”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [30]
Many factors, such as antibody properties (hydrophobicity, charge, glycosylation patterns), intersubject variability (disease status, body size, genetic polymorphisms, concomitant medication, comorbidities), and immune-mediated response generated by mAbs administration, can also impact mAb clearance.
“Many other factors, such as antibody properties (hydrophobicity, charge,38 glycosylation patterns39), intersubject variability (disease status, body size, genetic polymorphisms, concomitant medication, comorbidities, etc.40), and immune‐mediated response generated by mAbs administration can also impact mAb clearance.”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [38]
Physicochemical properties including hydrated size, charge, hydrophobicity, electrophoretic mobility, isoelectric point, and glycosylation can potentially influence mAb PK.
“Physiochemical properties including hydrated size (Stokes radius), charge, hydrophobicity, electrophoretic mobility, isoelectric point (pI), and glycosylation can potentially influence mAb PK.38, 39”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [38]
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- Authors
- Schoch, A., Kettenberger, H., Mundigl, O., Winter, G., Engert, J., Heinrich, J., & Emrich, T.
- Affiliations
- Large Molecule Bioanalytical Research and Development, Pharmaceutical Sciences,
- Large Molecule Research Biochemical and Analytical Research, Large Molecule Research, and
- Large Molecule Research Discovery, Large Molecule Research, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Penzberg, 82377 Penzberg, Germany; and
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Emrich, Thomas
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-04-27
- Volume
- 112
- Issue
- 19
- Pages
- 5997-6002
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4434771
- OpenAlex
- W2034501477
- Cited by
- 202
- References
- 47
- Citations by year
- 2026: 18 · 2025: 13 · 2024: 20 · 2023: 24 · 2022: 21 · 2021: 17 · 2020: 13 · 2019: 21 · 2018: 21 · 2017: 15 · 2016: 10 · 2015: 7 · 2014: 2
- FWCI
- 14.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Keywords
- neonatal Fc receptor, IgG, FcRn binding, antibody pharmacokinetics, antibody half-life, charge distribution, ustekinumab, antibody engineering
- MeSH terms
- Ustekinumab, Animals, Antibodies, Antibodies, Monoclonal, Antigen-Antibody Reactions, beta 2-Microglobulin, Chromatography, Affinity, Female, Humans, Hydrogen-Ion Concentration, Immunoglobulin G, Immunoglobulin Fc Fragments, Mice, Transgenic, Protein Binding, Protein Conformation, Receptors, Fc, Protein Engineering, Histocompatibility Antigens Class I, Microscopy, Confocal, Surface Plasmon Resonance, Mice, Protein Multimerization, Static Electricity, Molecular Dynamics Simulation, Antibodies, Monoclonal, Humanized, Human Umbilical Vein Endothelial Cells
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