Biology of TACE inhibition

Abstract

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor α (TNFα) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNFα converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNFα (proTNFα) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNFα, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNFα 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 proTNFα is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNFα receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNFα. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNFα production.



Full Text

The Full Text of this article is available as a PDF (166.9 KB).

Figure 1  .

Effect of the addition of TACE inhibitors on soluble TNFα produced by LPS stimulated human monocytes or TSST-1 activated T lymphocytes. The respective cell type was stimulated in the presence of no addition, 1 µM category 1 TACE inhibitor , 1 µM category 2 TACE inhibitor, or 1 µM category 3 TACE inhibitor (see "Materials and methods" for category description).

Figure 2  .

Time course of the release of soluble TNFRII by human monocytes without stimulation or after LPS stimulation in the absence or presence of 1 µM TACE inhibitor, category 1. 

Figure 3  .

Effect of TACE inhibitors with different degrees of selectivity on residual surface expression of TNFRII after antigen activation of human T lymphocytes. Cells were incubated in the absence or in the presence of TSST-1 antigen stimulation to induce TNFRII shedding.

Figure 4  .

Efficacy of TACE inhibition (category 4), given by continuous infusion, in a mouse model of CIA. Animals were untreated or treated at levels of ~20%, ~50%, and ~90% inhibition of LPS-induced TNFα release. Control animals show no paw swelling.

Figure 5  .

Efficacy of TACE inhibition (category 4) in a mouse model of CIA using bolus dosing in comparison with etanercept. Animals were dosed with vehicle, etanercept, or compound at 5 mg/kg or 10 mg/kg, twice a day.

Figure 6  .

Induction of cytokines and the effect of TACE inhibitor (category 4) or etanercept administration on LPS-induced cytokine production after LPS challenge in mice. IFNλ = interferon λ.