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

Schoch Angela; Kettenberger Hubert; Mundigl OlafWinter GerhardEngert JuliaHeinrich JuliaEmrich Thomas

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

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

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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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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第19期|5997-6002|共6页
作者
Schoch Angela; Kettenberger Hubert; Mundigl OlafWinter GerhardEngert JuliaHeinrich JuliaEmrich Thomas;
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作者单位

Roche Innovat Ctr Penzberg, Large Mol Bioanalyt Res & Dev Pharmaceut Sci, D-82377 Penzberg, Germany;

Roche Innovat Ctr Penzberg, Large Mol Res Biochem & Analyt Res, Large Mol Res, D-82377 Penzberg, Germany;

Roche Innovat Ctr Penzberg, Large Mol Res Discovery, D-82377 Penzberg, GermanyUniv Munich, Inst Pharmaceut Technol & Biopharmaceut, D-81377 Munich, Germany;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
FcRn; pharmacokinetics; antibody; charge; engineering;

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

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