tumour necrosis factor shed form

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Ligands
tumour necrosis factor shed form (Human)

GtoPdb Ligand ID: 5074

Abbreviated name: TNF shed form

Synonyms: cachectin | necrosin | TNF alpha soluble form | tumor necrosis factor soluble form

Compound class: Endogenous peptide in human, mouse or rat

Comment: TNFα is a pro-inflammatory, acute phase cytokine involved in systemic inflammation.
The TNF precursor is expressed as a membrane-bound ligand, which is cleaved by TACE/ADAM17 to form this shed (or 'soluble') bioactive cytokine containing just the extracellular domain, and that circulates predominantly as a homotrimer. Recombinant TNF is used as an immunostimulant under the INN tasonermin.

Circulating active TNF-α is the principal molecular target of the anti-TNF therapeutics infliximab and adalimumab. A smaller and longer acting and orally deliverable anti-TNF biologic called V565 is in early stage clinical development [3]. Considering alternative modes of administration, V565 is a heavy chain only variable domain anti-TNF nanobody generated in Ilama that is further modified to enhance resistance to protease-mediated degradation. It binds shed TNF-α with similar affinity to infliximab and adalimumab, and also inhibits biological responses mediated by membrane-bound TNF-α [3]. If this design strategy proves successful, V565 will be the first orally active anti-TNF therapy. V565 is being evaluated for potential to treat Crohn's disease (see Phase 2 study NCT02976129).

Species: Human

View more information in the IUPHAR Pharmacology Education Project: tumour necrosis factor alpha

Immunopharmacology Comments
TNFα is predominantly produced by activated macrophages, and to a lesser extent by CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons [5]. As a result of its role in a variety of human diseases anti-TNFα strategies have been developed by the pharmaceutical industry- see Tracey et al. (2009) for a review of the mechanisms of action of anti-TNFα therapies (antagonists and antibodies) in immune-mediated inflammatory diseases [14].

Immunopharmacology Comments

TNFα is predominantly produced by activated macrophages, and to a lesser extent by CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons [5].

As a result of its role in a variety of human diseases anti-TNFα strategies have been developed by the pharmaceutical industry- see Tracey et al. (2009) for a review of the mechanisms of action of anti-TNFα therapies (antagonists and antibodies) in immune-mediated inflammatory diseases [14].