Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain

Treatment of diseases of the central nervous system by monoclonal antibodies may be limited by the restricted uptake of antibodies across the blood brain barrier (BBB). An antibody targeting transferrin receptor (TfR) has been shown to take advantage of the receptor-mediated transcytosis properties of TfR in order to cross the BBB in mice, with the uptake in the brain being dependent on the affinity to TfR. In the bispecific format with arms targeting both TfR and beta-secretase 1 (BACE1), altering the affinity to TfR has been shown to impact systemic exposure and safety profiles. In this work, a mathematical model incorporating pharmacokinetic/pharmacodynamic (PKPD) and safety profiles is developed for bispecific TfR/BACE1 antibodies with a range of affinities to TfR in order to guide candidate selection. The model captures the dependence of both systemic and brain exposure on TfR affinity and the subsequent impact on brain AN lowering and circulating reticulocyte levels. Model simulations identify the optimal affinity for the TfR arm of the bispecific to maximize A beta reduction while maintaining reticulocyte levels. The model serves as a useful tool to prioritize and optimize preclinical studies and has been used to support the selection of additional candidates for further development. (C) 2016 Elsevier B.V. All rights reserved.