Abstract
System-wide quantitative characterization of human neonatal Fc receptor (FcRn) properties is critical for understanding and predicting human PK (pharmacokinetics) as well as the distribution of mAbs and Fc-fusion proteins using PBPK (physiologically-based pharmacokinetic) modeling. To this end, tissue-specific FcRn expression and half-life are important model inputs. Herein, human FcRn tissue expression was measured by peptide immunoaffinity chromatography coupled with high-resolution mass spectrometry. FcRn concentrations across 14 human tissues ranged from low to 230 pmol per gram of tissue. Furthermore, the FcRn half-life was determined to be 11.1 h from a human stable isotope labelled leucine pulse labeling experiment. The spatial and temporal quantitative human FcRn data now promise to enable a refined PBPK model with improved accuracy of human PK predictions for Fc-containing biotherapeutics.
Highlights
Neonatal Fc receptor (FcRn) plays a key role in extending the serum half-life of therapeutic antibodies [1,2]
For human tissue-specific FcRn quantification, multiple FcRn surrogate peptides were directly adapted from the established methodology previously reported for the quantification of human FcRn in
QGTWGGDWPEALAISQR previously used for the human FcRn measurement in Tg32 mouse tissue
Summary
Neonatal Fc receptor (FcRn) plays a key role in extending the serum half-life of therapeutic antibodies [1,2]. FcRn detection either via its mRNA or at the protein level using immunoblotting has been reported from selected mouse and human tissues [6,7,8]. The online peptide immunoaffinity enrichment approach has recently enabled sensitive mass spectrometry measurements and quantitation of human FcRn in transgenic mouse tissues [11]. The comprehensive quantification of FcRn expression in human tissues using a mass spectrometry approach has not yet been reported. We measured the FcRn expression profile in human tissues as well as FcRn half-life in peripheral blood mononuclear cells (PBMCs) collected from a U-13 C-leucine pulse labeling study in normal human healthy volunteers
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