RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 925
OP 933
DO 10.1124/dmd.120.000075
VO 48
IS 10
A1 Xiazi Qiu
A1 Michael Zhuo Wang
YR 2020
UL http://dmd.aspetjournals.org/content/48/10/925.abstract
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.