Advanced human FcRn knock-in mice for pharmacokinetic profiling of therapeutic antibodies

Abstract

Abstract IgG-based therapeutic antibodies are increasingly adopted for diverse human diseases, such as cancer and autoimmune disorders displaying remarkable therapeutic performance. A key factor in their success lies in the extended half-life of IgG molecules, which is regulated by the pH-dependent interaction between IgG and neonatal Fc receptor (FcRn). This interaction prevents lysosomal degradation of IgG. Despite the frequent use of humanized rodent models expressing human FcRn (hFcRn) in preclinical studies, these models often fail to accurately replicate human antibody pharmacokinetics (PK) due to the use of non-native promoters that influence FcRn expression. To overcome this limitation, we developed an innovative humanized FcRn knock-in (hiFcRn) mouse model using CRISPR/Cas9 technology. This model integrates hFcRn cDNA into the endogenous locus of the mouse Fcgrt gene, completely replacing native mouse FcRn (mFcRn) expression. The hiFcRn mouse model offers a more human-relevant platform for the preclinical evaluation of therapeutic antibodies and Fc-fusion proteins.

Keywords

• FcRn
• Pharmacokinetics
• Therapeutic IgG
• Antibody recycling