Harnessing the natural inhibitory domain to control TNFα Converting Enzyme (TACE) activity in vivo

Abstract

Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto-inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell-surface TACE, but not the related ADAM10, and effectively modulated TNFα secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFα in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors.

ADAM 17 selectively activates the IL ‐6 trans‐signaling/ ERK MAPK axis in KRAS ‐addicted lung cancer

“…Specifically, the highly selective blockade of ADAM17 using either genetic or inhibitor‐based approaches in preclinical genetically engineered and xenograft model systems suppresses the oncogenic actions of mutant KRAS in LAC. In this regard, a key finding of our study was the robust anti‐cancer activity of a novel class of highly selective ADAM17 inhibitor, A17pro, modeled on its auto‐inhibitory prodomain (Wong et al , ). Importantly, A17pro is cross‐species reactive (i.e., mouse and human) and thus provides an advantage over human‐specific ADAM17 antibodies which cannot be evaluated for efficacy in genetically engineered mouse models of cancer (Richards et al , ).…”

“…Although ADAM17 SMIs show anti‐cancer efficacy in numerous preclinical models, these inhibitors are highly toxic due to the non‐specific targeting of other metalloproteinases (e.g., ADAM10), thus highlighting the need for highly selective ADAM17 inhibitors with an alternate mode of action (Moss & Minond, ). Recently, a recombinant protein of the auto‐inhibitory prodomain of ADAM17, A17pro, has been developed which specifically abrogates the sheddase activity of ADAM17, but not ADAM10, and shows marked therapeutic efficacy without toxicity in numerous in vivo inflammatory disease models (Kefaloyianni et al , ; Wong et al , ). Notably, A17pro treatment of KRAS mutant human A549 and NIH‐H23 LAC cells significantly reduced cell viability and proliferation, along with sIL‐6R levels in culture supernatants, compared to control vehicle‐treated cells (Fig EV5D–F), thus mimicking ADAM17‐deficient cells (Fig I–K).…”

“…Here, we reveal that threonine phosphorylation (i.e., activation) of ADAM17 by p38 MAPK is a key feature of KRAS mutant LAC. In proof‐of‐concept preclinical studies involving genetically engineered and xenograft (human cell line and patient‐derived) KRAS mutant LAC models, the genetic and therapeutic targeting of ADAM17, the latter with a new class of specific ADAM17 prodomain inhibitor (Wong et al , ), markedly suppressed tumor growth. Strikingly, the reliance by oncogenic KRAS for ADAM17 associated with the preferential processing of the ADAM17 substrate, IL‐6R, to produce soluble (s) IL‐6R that activated ERK1/2 MAPK via IL‐6 trans‐signaling (Garbers et al , ).…”

Meprin β induces activities of A disintegrin and metalloproteinases 9, 10, and 17 by specific prodomain cleavage

“…1 I ). Isolated ADAM17 prodomain can act as a specific inhibitor for catalytically active ADAM17 (30). Hence, we speculated whether meprin β cleavage inside ADAM17 prodomain can prevent its inhibitory capacity.…”

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

“…The therapeutic potential of 4mut was evaluated in inflammatory disease models. At 4 mg/kg 4mut decreases levels of TNFα ∼10‐fold (from 3 mg/mL to 0.35 mg/mL) in the LPS‐induced C57/BL mouse sepsis shock model . In the DBA/lLacJ mouse model of collagen‐induced arthritis, mice treated with 4mut displayed a significantly lower arthritis severity index score and histological score, as well as lowered serum antibodies specific to type II collagen, in a concentration‐dependent manner .…”