PT  - JOURNAL ARTICLE
AU  - Xiazi Qiu
AU  - Michael Zhuo Wang
TI  - Quantification of Neonatal Fc Receptor and Beta-2 Microglobulin in Human Liver Tissues by Ultraperformance Liquid Chromatography–Multiple Reaction Monitoring–based Targeted Quantitative Proteomics for Applications in Biotherapeutic Physiologically-based Pharmacokinetic Models
AID  - 10.1124/dmd.120.000075
DP  - 2020 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 925--933
VI  - 48
IP  - 10
4099  - http://dmd.aspetjournals.org/content/48/10/925.short
4100  - http://dmd.aspetjournals.org/content/48/10/925.full
SO  - Drug Metab Dispos2020 Oct 01; 48
AB  - Neonatal Fc receptor (FcRn) and beta-2 microglobulin (β2M) play an important role in transporting maternal IgG to fetuses, maintaining the homeostasis of IgG and albumin in human body, and prolonging the half-life of IgG- or albumin-based biotherapeutics. Little is known about the influence of age, gender and race, and interindividual variability of human FcRn and β2M on the protein level. In this study, an ultraperformance liquid chromatography–multiple reaction monitoring mass spectrometry–based targeted quantitative proteomic method was developed and optimized for the quantification of human FcRn and β2M. Among the 39 human livers studied (age 13–80 years), the mean (±S.D.) concentrations of FcRn and β2M were 147 (±39) and 1250 (±460) pmol/g of liver tissue, respectively. A four-fold interindividual variability (63–243 pmol/g of liver tissue) was observed for the hepatic FcRn concentration. A moderate correlation was found between the hepatic β2M and FcRn expression levels. Influences of age, gender, and race on the hepatic expression of FcRn and β2M were evaluated. The findings from this study may aid the development of physiologically-based pharmacokinetic models that incorporate empirical FcRn tissue concentrations and interindividual variabilities, and the development of personalized dosing of biopharmaceuticals.SIGNIFICANCE STATEMENT This is the first study to evaluate the influence of age, gender, and race on the expression of neonatal Fc receptor (FcRn) and beta-2 microglobulin (β2M) and their interindividual variability in human livers. This study describes a validated ultraperformance liquid chromatography–multiple reaction monitoring–based targeted quantitative proteomic method for quantifying human FcRn and β2M in biological tissues. Results from this study may aid current development of physiologically-based pharmacokinetic models for biotherapeutics, where FcRn plays a significant role in clearance mechanism, and its expression level and interindividual variability are largely unknown.