Utility of in silico prediction of target suppression for antibodies against soluble targets: static versus dynamic models

Abstract

Purpose Antibodies that bind soluble targets such as cytokines belong to an important class of immunotherapies. Target levels can significantly accumulate after antibody administration due to formation of antibody-target complex, accompanied with suppression in free target which is often difficult to measure. Being a surrogate for pharmacodynamic activity, free target suppression is often predicted using in silico tools. The objective of this work is to illustrate the utility of modelling and to compare static versus dynamic models in the prediction of free target suppression. Methods Using binding principles, we have derived a static equation to predict free target suppression at steady state (FTSS). This equation operates with five input parameters and accounts for target accumulation over time. Its predictivity was compared to a dynamic model and to other existing metrics in literature via simulations and assumptions were illustrated. Results We demonstrated the utility of in silico tools in prediction of free target suppression using static and dynamic models and clarified the assumptions in key input parameters and their limitations. Predicted values using the FTSS equation correlate very well with those from the dynamic model at level > 20% target suppression, relevant for antagonistic antibodies. Conclusion In silico tools are needed to predict target suppression by antibody drugs. Static or dynamic models can be used dependant on the scope, available data and undertaken assumptions. These tools can be used to guide discovery and development of antibodies and has the potential to reduce clinical failure.