Preferential Antibody and Drug Conjugate Targeting of the ADAM10 Metalloprotease in Tumours

Simple Summary ADAM10 is a cell surface protein that releases other proteins from cells, thereby controlling a range of functions during normal development. Its activity is normally tightly regulated, but it can become deregulated in cancer calls. We previously showed that an active form of ADAM10 is elevated in tumours in both mice and humans, and that we could detect this active form using an antibody which we developed that binds to a specific region of ADAM10, which is apparently hidden in the inactive form. We now provide insight explaining the specificity of our antibody (8C7) for active ADAM10, and show that it preferentially targets tumours when injected into mice. We thus conjugated cytotoxic drugs to 8C7 in order to preferentially bind and kill tumour cells that contain activated ADAM10. Our experiments show that our '8C7 antibody-drug conjugates' specifically kill cells expressing 8C7-reactive ADAM10, and can inhibit the growth of tumours in mice, without significant side effects, suggesting their potential as a novel approach for targeted cancer therapy. ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody-drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody-drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition.