(Crown Bio) Enhancing the Predictability of Human Pharmacokinetics for Antibody-Drug Conjugates Using Human FcRn Transgenic Mice

Abstract

Accurate prediction of human pharmacokinetics (PK) remains a pivotal challenge in the preclinical development of Antibody-Drug Conjugates (ADCs). A primary determinant of ADC clearance is the interaction between the IgG Fc domain and the neonatal Fc receptor (FcRn), which governs antibody recycling and half-life. However, the species specificity of this interaction means that wild-type (WT) mouse models often fail to recapitulate human FcRn binding and recycling and thus provide poor predictions of human PK, complicating first-in-human (FIH) dose estimation. As demonstrated in foundational studies, transgenic mouse models expressing human FcRn (hFcRn) provide a more physiologically relevant system, showing better correlation with human PK for monoclonal antibodies. However, the predictive value of this model for the more complex ADC PK/PD, which is influenced by additional factors such as linker stability and payload properties, remains less defined. This study investigates the utility of the hFcRn and hAlb/hFcRn transgenic mouse model for predicting the human PK of a diverse panel of approved ADCs, establishing its value as a core component of Crown Bioscience translational ADC DMPK platform.

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