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Proc Natl Acad Sci U S A. 2015 May 12;112(19):5997-6002. doi: 10.1073/pnas.1408766112. Epub 2015 Apr 27.

Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics.

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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.
Institute of Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilians University, 81377 Munich, Germany.
Large Molecule Bioanalytical Research and Development, Pharmaceutical Sciences,


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.


FcRn; antibody; charge; engineering; pharmacokinetics

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