Enhanced antibody half-life improves in vivo activity

Abstract

A correlation between drug exposure and efficacy has never been demonstrated for therapeutic antibodies. Zalevsky et al. use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity. Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1−/− mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.