ArticleProceedings of the National Academy of Sciences of the United States of America2015
Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers.
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Who cites it
125 citing papers in PubMed, 198 citations in OpenAlex.
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- Near UV and Visible Light-Induced Degradation of IgG2: Photo-Fenton Reaction in Citrate Buffer.Pharmaceutical research · 2026Article
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- Integrative structural insights into the IgG-FcRn interactions revealed by engineered FcRn-immobilized affinity chromatography.Communications biology · 2026Article
- Impact of Neonatal Fc Receptor on Transferrin Receptor Antibody Fusion Protein Pharmacokinetics.Pharmaceutics · 2026Article
- Characterizing pH-Dependent Interactions Between Immunoglobulin and the Neonatal Fc Receptor Using Surface Plasmon Resonance.Methods in molecular biology (Clifton, N.J.) · 2026Article
- scFv-based biologics in diabetes: from therapeutic potential to clinical prospects.Frontiers in immunology · 2026Review
- The Impact of Cognate Antigen Binding on the FcRn-mediated Transcytosis and Recycling of Monoclonal Antibodies.The AAPS journal · 2025Article
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- Novel antibodies for identification, selection, and manipulation of T cells expressing Whitlow linker-containing CARs.Journal for immunotherapy of cancer · 2025Article
- Regulation of immune responses to therapeutic factor VIII by transplacental delivery of Fc-fused immunodominant factor VIII domains or peptides.Haematologica · 2025Article
- Impact of DO, agitation, aeration and copper concentration on lactate metabolism and charge heterogeneity for monoclonal antibody production by CHO cells in fed-batch culture.Cytotechnology · 2025Article
- Binding of therapeutic Fc-fused factor VIII to the neonatal Fc receptor at neutral pH associates with poor half-life extension.Haematologica · 2025Article
- Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation.Communications biology · 2025Article
- Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end.Communications biology · 2025Article
65 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here, we investigated the influence of the variable fragment (Fv) of IgG antibodies on the binding to the neonatal Fc receptor (FcRn) as well as on FcRn-dependent pharmacokinetics (PK). FcRn plays a key role in IgG homeostasis, and specific manipulation in the crystallizable fragment (Fc) is known to affect FcRn-dependent PK. Although the influence of the antigen-binding fragment (Fab) on FcRn interactions has been reported, the underlying mechanism is hitherto only poorly understood. Therefore, we analyzed the two IgG1 antibodies, briakinumab and ustekinumab, that have similar Fc parts but different terminal half-lives in human and systematically engineered variants of them with cross-over exchanges and varied charge distribution. Using FcRn affinity chromatography, molecular dynamics simulation, and in vivo PK studies in human FcRn transgenic mice, we provide evidence that the charge distribution on the Fv domain is involved in excessive FcRn binding. This excessive binding prevents efficient FcRn-IgG dissociation at physiological pH, thereby reducing FcRn-dependent terminal half-lives. Furthermore, we observed a linear correlation between FcRn column retention times of the antibody variants and the terminal half-lives in vivo. Taken together, our study contributes to a better understanding of the FcRn-IgG interaction, and it could also provide profound potential in FcRn-dependent antibody engineering of the variable Fab region.
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