In this study, we elucidated a novel concept of reverse translational science by utilizing model-based approach to transfer the knowledge in reverse direction from development to discovery (Fig.1). FcRn affinity profiles and endothelial endocytosis have been shown to play an important role in the disposition of therapeutic monoclonal IgG antibody (TMAb). The minimal physiologically-based pharmacokinetic (mPBPK) model was developed in this study to construct detail quantitative relationships between the endothelial endocytosis rate/FcRn binding affinity and the PK parameters of the TMAb. Such relationships are useful to identify the discovery “sweet spot” in designing future generation of TMAb with desirable PK preclinical and clinical PK properties (Reverse Translational Approach). Furthermore, the mPBPK model developed in the preclinical model was useful to predict the PK of the TMAb in adult human subjects (Forward Translational Approach).
To our knowledge, this is the first mPBPK model developed to quantify the complex relationships between FcRn binding affinity, endothelial endocytosis and disposition of IgG. Such quantiative relationships are useful for the discovery of the “sweet spot” in designing the next generation of anti-VEGF IgG1 antibodies with optimal PK properties. Furthermore, the mPBPK model developed in the preclincial CM model was successfully used to predict the PK of the bevacizumab in adult human subjects.