Target-Mediated Drug Disposition Model for Bispecific Antibodies : Properties, Approximation and Optimal Dosing Strategy

Abstract

Bispecific antibodies (BsAb) bind to two different targets, and create two binary and one ternary complex (TC). These molecules have shown promise as immuno-oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here we have presented a general target-mediated drug disposition model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAb, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build-up of the TC. Consequently, a method to compute the optimal dosing strategy of BsAb, which will immediately create and maintain maximal possible TC concentration, is presented.