用于抗体药物药代动力学评估的FcRn人源化大鼠

Introduction: Biocytogen's B-hFcRn rat model serves as a practical tool for assessing the pharmacokinetics/pharmacokinetics and safety of human IgG therapeutics. The model capitalizes on the rat's larger size, which allows for serial blood sampling and thus more efficient and continuous data collection compared to mice, where animal welfare considerations necessitate staggered sampling across subgroups. This is combined with the presence of human FcRn, a pH-dependent receptor that binds and recycles IgG, protecting it from lysosomal degradation to extend its plasma half-life. Methods: l B-hFcRn rats were generated by inserting a chimeric cDNA encoding full-length human FCGRT, followed by its 3'UTR and stop codon right after the rat Fcgrt start codon, thereby replacing exons 2-4 and placing human FcRn expression under the control of the endogenous rat promoter while disrupting the native rat gene.l For protein expression analysis, liver, kidney, and spleen tissue lysates were collected from wild-type SD rats (+/+), homozygous B-hFcRn rats (H/H), and then analyzed by western blot with species-specific anti-FcRn antibody. l SD rats and B-hFcRn rats were intravenously injected with Bevacizumab (commercial), and serum was collected for pharmacokinetic (PK) analysis. Results: l Western blot analysis results indicated that Rat FcRn was only detectable in wild-type SD rats. Human FcRn was exclusively detectable in the liver, kidney, and spleen of homozygous B-hFcRn rats.l Linear pharmacokinetics were observed in B-hFcRn rats after a single intravenous bolus administration of the monoclonal antibody and serial blood collection. PK data suggest that the B-hFcRn rat model enables reliable prediction of the FcRn-mediated pharmacokinetics and efficacy of IgG antibodies in humans. Conclusions: The B-hFcRn rat model is used for pharmacokinetics, pharmacodynamics, and safety evaluation of human immunoglobulin G (IgG) and is based on the Fc domain therapeutics.