Modeling the dynamics of antibody-target binding in living tumors

Abstract

Antibodies have become an attractive class of therapeutic agents for solid tumors, mainly because of their high target selectivity and affinity. The target binding properties of antibodies are critical for their efficacy and toxicity. Our lab has developed a bioluminescence resonance energy transfer (BRET) imaging approach that directly supports measurement of the binding dynamics between antibodies and their targets in the native tumor environment. In the present study, we have developed a spatially resolved computational model to analyze the longitudinal BRET imaging of antibody-target binding and to explore the mechanisms of biphasic binding dynamics between cetuximab and its target, the epidermal growth factor receptor (EGFR). The model suggested that cetuximab bound differently to EGFR in the stroma-rich area than in stroma-poor regions, and this difference was confirmed by immunofluorescence staining. Compared to the binding in vitro, cetuximab bound to EGFR to a "slower-but-tighter" degree in the living tumors. These findings have provided spatially resolved characterizations of antibody-target binding in living tumors and have yielded many mechanistic insights into the factors that affect antibody interactions with its targets.