Predicting the Pharmacokinetics of T-Cell Engagers as a Function of Target-Mediated Drug Disposition

Abstract

T-Cell Engagers (TCEs) are biological multi-specific molecules designed to co-engage targets on T cells and on a target cell for destruction. Molecular formats are typically derived from IgG monoclonal antibodies or similar fusion proteins with FcRn-mediated recycling, such as albumin binders. Despite this similarity, TCEs are often observed to have much attenuated half-lives of a few days, compared to the weeks expected of IgG monoclonal antibodies; furthermore, the usual ranking of half-lives in humans being greater than those in the non-human primate (NHP) is not preserved and we demonstrate that the usual methods of PK scaling by allometry are poor predictors of human PK. The half-life of biological molecules may be reduced due to clearance from target-mediated drug disposition (TMDD). In this paper we identify how the TMDD of the TCE from interactions with both the T-cell (via CD3) and its tumor-associated antigen on the target cell determines the PK across species and present a method for the prediction of TCE PK in both the NHP and human patients. This method was tested against a selection of published TCEs and 16 of 18 TCEs' half-lives were predicted within 2-fold, compared to only 10 from 17 by allometry alone, and with a mean absolute error of 1.48 versus 2.22, respectively.