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

2018; Nature Portfolio; Volume: 8; Issue: 3 Linguagem: Inglês

10.1002/psp4.12369

2163-8306

Johannes Schropp, Antari Khot, Dhaval K. Shah, Gilbert Koch,

Toxin Mechanisms and Immunotoxins

Bispecific antibodies (BsAbs) 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 (TMDD) model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi‐equilibrium (QE) 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 BsAbs, which will immediately create and maintain maximal possible TC concentration, is presented.