（Crown Bio）ヒトFcRnトランスジェニックマウスを用いた抗体薬物複合体のヒト薬物動態予測精度の向上

要旨

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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