人源化 FcRn 小鼠模型:预测治疗性抗体人类 PK 的卓越平台

Monoclonal antibodies (mAbs) are a rapidly expanding class of biotherapeutics with broad applications spanning oncology, autoimmune disorders, and infectious diseases. A key factor driving their clinical efficacy and dosing strategy is their pharmacokinetic (PK) profile, particularly serum half-life. While mice remain the preferred in vivo model for preclinical PK studies assessing absorption, distribution, metabolism, and excretion, conventional inbred and outbred strains fall short when it comes to accurately modeling the PK behavior of human mAbs and other human-derived biologics. The neonatal Fc receptor (FcRn) plays a pivotal role in regulating the extended half-life and homeostasis of immunoglobulin G (IgG) in vivo. By binding to IgG in a pH-dependent manner within acidic endosomes, FcRn rescues it from lysosomal degradation and recycles it back to the systemic circulation. This salvage pathway is a critical determinant of the PK profile of therapeutic mAbs. However, significant differences in the FcRn-IgG interaction exist between species, often leading to poor translatability of PK data from conventional mouse models, such as C57BL/6, to humans. To bridge this translational gap, we have developed a novel humanized FcRn mouse model, which expresses the human FcRn transgene while being deficient in the murine counterpart, providing a more reliable platform for evaluating the PK properties of human mAbs. In vivo PK studies comparing IgG1 and Keytruda in the humanized FcRn model versus wild-type C57BL/6 mice demonstrated a significantly improved correlation with known human PK profiles. The humanized FcRn model accurately recapitulated the expected serum half-life observed in patients, whereas wild-type mice exhibited artificially prolonged clearance due to murine FcRn-mediated recycling. To date, this FcRn humanized mouse model is the only validated rodent system capable of predicting the serum half-life of human IgG-based therapeutics. It serves as an essential tool for the non-clinical screening of mAb candidates to optimize half-life, reliably forecast human pharmacokinetics, and strategically guide clinical development plans.