Abstract

Selection of Bispecific Abs Based on Fc Silencing/ The Role of Avidity to Select Therapeutic Bispecific Abs: EGFR x cMet

Mark Chiu, Principal Research Scientist, Janssen R&D Llc

Multispecific proteins, such as bispecific antibodies (BsAbs), that bind to two different ligands are becoming increasingly important therapeutic agents. Such BsAbs can exhibit markedly increased target binding and target residence time when both pharmacophores bind simultaneously to their targets. The cross-arm binding efficiency (?) describes an increase in apparent affinity when a BsAb binds to the second target or receptor (R2) following its binding to the first target or receptor (R1) on the same cell. ? is an intrinsic characteristic of a BsAb mostly related to the binding epitopes on R1 and R2. ? can have significant impacts on the binding to R2 for BsAbs targeting two receptors on the same cell. JNJ-61186372, a BsAb that targets epidermal growth factor receptor (EGFR) and c-Met, was used as the model compound for establishing a method to characterize ?. The ? for JNJ-61186372 was successfully determined via fitting of in vitro cell binding data to a ligand binding model that incorporated ?. The model-derived ? value was used to predict the binding of JNJ-61186372 to individual EGFR and c-Met receptors on tumor cell lines, and the results agreed well with the observed IC50 for EGFR and c-Met phosphorylation inhibition by JNJ-61186372.