General Quasi-Equilibrium Multivalent Binding Model to Study Diverse and Complex Drug-Receptor Interactions of Biologics

Abstract

Abstract Pharmacokinetics and pharmacodynamics of many biologics are influenced by their complex binding to biologic receptor. Biologics consist of diverse groups of molecules with different binding kinetics to its biological receptors including IgG with simple one-to-one drug receptor bindings, bispecific antibody (BsAb) that binds to two different receptors, and biologics that can bind to six or more receptors. As binding process is much faster than elimination and distribution processes of biologics and receptors, quasi-equilibrium (QE) binding models are commonly used to describe drug-receptor binding kinetics of biologics. However, no general QE modeling framework is available to describe complex binding kinetics for diverse classes of biologics. In this paper, we described a novel approach of using differential algebraic equations (DAE) to develop first DAE-based QE multivalent drug-receptor binding (QEMB) model platform and successfully used this novel model platform to develop three different QEMB models in describing binding kinetics of three-body equilibria of BsAb, engineered IgG variant (Multabody) that can bind to 24 target receptors, and IgG with modified neonatal Fc receptor (FcRn) binding affinity that compete for the same FcRn receptor with the endogenous IgG. The model parameter estimates were obtained by fitting developed model to all observed data simultaneously. The developed models allowed us to study potential roles of cooperative binding on bell-shaped drug exposure-response relationships of BsAb, and concentration-depended distribution of different drug-receptor complexes for Multabody. This developed DAE-based QEMB model platform can serve as an important first step to better understand complex binding kinetics of diverse classes of biologics.