Biology of TACE inhibition

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor alpha (TNF alpha) in inflammatory diseases. As a re sult of this work, a number of biological agents that neutralise the activi ty of this cytokine have entered the clinic. The recent clinical data obtai ned with etanercept and infliximab highlight the relevance of this strategy . TNFa converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNF alpha (proTNF alpha) to the 17 kDa soluble component. Although a number of proteases have been shown to proces s proTNF alpha, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinic al development. These inhibitors effectively block TACE mediated processing of proTNFa and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNF alpha is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitr o, TACE inhibition has also been implicated in shedding of p55 and p75 surf ace TNF alpha receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibito rs are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNF alpha. In many studies greater efficacy is observed with the TALE inhibitors, presumably owing to greater penetration to the site of TNF alpha production.