The transmembrane metalloprotease ADAM10 cleaves ligands and receptors of the Notch, Eph and erbB families, among other targets, thereby activating key signalling pathways of critical importance in tumour proliferation and maintenance, neo-angiogenesis and metastasis. ADAM10 is also over-expressed in a variety of cancers in which these pathways are deregulated, suggesting it as a promising target for therapy. Following our identification of a substrate-binding pocket within the non-catalytic Cys-rich (C) domain of ADAM101, which specifies substrate cleavage, we raised antibodies against this region as potential inhibitors.
We generated a monoclonal antibody (mAb 8C7) against the ADAM10 substrate-binding domain, which inhibits substrate cleavage and ADAM10-mediated cell signalling and function. Structural and functional studies now show 8C7 displays novel selectivity for an active conformation of ADAM10 preferentially found in tumours compared to normal tissues. 8C7 particularly targets cancer stem-like cells (CSCs) with high Notch signalling, which it inhibits. It also inhibits tumour growth in mouse models of colorectal cancer, most effectively following chemotherapy, in keeping with CSC involvement in chemoresistance. Our results thus indicate 8C7 is a potential therapeutic to target ADAM10-dependent tumour growth and drug resistance.