Model-informed dose selection for Xentuzumab, a dual insulin-like growth factor-I/II -neutralizing antibody.

Over the past decade, the insulin-like growth factor (IGF)-signalling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanised IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signalling essential for survival and tumour growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterising the dynamics and interactions of IGFs, IGFBPs and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000 mg/week - predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively- was suggested for Phase II.