ADAM multidomain topology was exploited by first isolating an inhibitory human antibody (D1) that bound TACE-specific noncatalytic regions exclusively through its variable heavy (VH) domain. A D1-VH biased scFv phage-display library was then used to selectively isolate a new variable light (VL) chain that could simultaneously bind to the TACE catalytic domain. The resulting “cross-domain” human IgG1 antibody [D1(A12)] ab215268 is a previously undescribed biochemically holistic ADAM ectodomain inhibitor and demonstrates a unique alternative to small-molecule metalloprotease inhibition.

Note from inventor: ab215268 is conformation sensitive and sees only a specific form of the native enzyme (reflecting its redox state). It does not work by IHC or WB. It was designed as a potential drug, active in native situations.