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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

Andersen, Jan Terje; Foss, Stian; Kenanova, Vania E; Olafsen, Tove; Leikfoss, Ingvild Sørum; Roopenian, Derry C; Wu, Anna M; Sandlie, Inger
Journal article; PublishedVersion; Peer reviewed
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25.+zbc22927.pdf (3.566Mb)
Year
2012
Permanent link
http://urn.nb.no/URN:NBN:no-57612

CRIStin
948430

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Appears in the following Collection
  • Institutt for molekylær biovitenskap [120]
  • Farmasøytisk institutt [1364]
  • Det medisinske fakultet [269]
  • Institutt for medisinske basalfag [1415]
  • CRIStin høstingsarkiv [15984]
Original version
Journal of Biological Chemistry. 2012, 287 (27), 22927-22937, DOI: http://dx.doi.org/10.1074/jbc.M112.355131
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 information for prediction of in vivo pharmacokinetics.

This research was originally published in: Journal of Biological Chemistry. © the American Society for Biochemistry and Molecular Biology.
 
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