Anti-carcinoembryonic antigen single-chain variable fragment antibody variants bind mouse and human neonatal Fc receptor with different affinities that reveal distinct cross-species differences in serum half-life.

The Journal of Biological Chemistry
Jan Terje AndersenInger Sandlie

Abstract

Serum half-life of IgG is controlled by the neonatal Fc receptor (FcRn) that interacts with the IgG Fc region and may be increased or decreased as a function of altered FcRn binding. Preclinical evaluations of modified IgGs are frequently carried out in mice, but such IgGs may bind differently to mouse and human FcRn (mFcRn and hFcRn). Here, we report a detailed characterization of a matched set of mouse-human chimeric T84.66 scFv-Fc variants with specificity for the tumor carcinoembryonic antigen and mutations in the FcRn-binding site. Binding to soluble mFcRn and hFcRn was measured using in vitro assays, and the results were compared with blood clearance in vivo in normal (mFcRn bearing) and hFcRn transgenic mice. All variants bound better to mFcRn than to hFcRn. The loss of affinity varied among the mutants, however, and also the hierarchy of binding differed depending on the receptor. The mutations had no major impact on binding to the classical Fcγ receptors. Importantly, the trend of blood clearance in both strains of mice correlated with the hierarchy of binding obtained using soluble FcRn. Consequently, in vitro interaction analysis of engineered IgGs regarding their cross-species FcRn binding ability provides informati...Continue Reading

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Citations

Mar 1, 2011·Therapeutic Delivery·Chao Han, Honghui Zhou
Jan 1, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Stian FossJan Terje Andersen
Jan 25, 2013·Scientific Reports·Jan Terje AndersenInger Sandlie
Jun 10, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Malin BernJan Terje Andersen
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Feb 13, 2015·Frontiers in Immunology·Kine Marita Knudsen SandJan Terje Andersen
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Dec 19, 2020·Antibodies·Geert van TeteringJeanette Leusen

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Methods Mentioned

BETA
x-ray crystallography
enzyme-linked
surface plasmon resonance
transgenic
transfection
chips
MDS
ELISA
biosensor
chip

Software Mentioned

BIAevaluation
GraphPad
GraphPad Prism
PyMOL

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