Abstract
Quantitative real-time PCR and Western blot methods were developed to assess neonatal Fc-receptor (FcRn) mRNA and protein expression in human FcRn transgenic mice, Swiss Webster mice, and in select human tissues. Additionally, FcRn turnover was evaluated via pulse-chase. FcRn mRNA expression was significantly higher in transgenic mice when compared to mouse FcRn mRNA in Swiss Webster mice and it ranged from 184-fold higher in the kidney to 109,000-fold higher in the skin. FcRn protein expression was found to be 13-fold lower in kidney to 5.6-fold higher in lung obtained from transgenic mice compared to FcRn protein expression in lung samples obtained from Swiss Webster mice. FcRn protein expression in human liver and small intestine tissues matched more closely with FcRn expression in Swiss Webster mice but were significantly lower when compared to values found from Swiss Webster and transgenic mice. Although FcRn mRNA expression correlated significantly with protein expression (p < 0.0005), the correlation coefficient was only 0.113. As such, the measurement of FcRn protein may be preferred to FcRn mRNA for quantitative applications. Significant differences were found in FcRn expression in transgenic mice, Swiss Webster mice, and human tissues, which may have implications for the use of mouse models in the assessment of monoclonal antibody disposition, efficacy, and safety.
Highlights
Interest in the development of therapeutic monoclonal antibody drugs has grown rapidly in the past few decades
It is appreciated that the rapid clearance of Muromonab-CD3, which is a murine immunoglobulin G (IgG)2a monoclonal antibody (mAb), is partially explained by the poor binding of mouse antibodies to the human neonatal Fc receptor, which protects IgG antibodies from catabolism [2]
The importance of FcRn as a determinant of mAb pharmacokinetics and pharmacodynamics (PK/PD) has led to several publications focusing on the species selectivity of FcRn-IgG interaction and the development of engineered mAb with improved hFcRn binding [3,4,5,6,7,8]
Summary
Interest in the development of therapeutic monoclonal antibody (mAb) drugs has grown rapidly in the past few decades. The finding of important between species differences in FcRn—IgG binding has led to the development of transgenic mouse models that express human FcRn in tissues with the intent that these models would provide more relevant projections of the clinical PK/PD of human or humanized mAb [9,10]. In light of the important role played by FcRn in IgG pharmacokinetics and the common use of wild-type and transgenic animal models in the preclinical assessment of mAb PK/PD, it is somewhat surprising that there has been little investigation of the between-species and between-model differences in FcRn expression [11,12]. We investigated the turnover kinetics of hFcRn in a human umbilical vein endothelial cell line
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