tumour necrosis factor shed form   

GtoPdb Ligand ID: 5074

Abbreviated name: TNF shed form
Synonyms: cachectin | necrosin | TNF alpha soluble form | tumor necrosis factor soluble form
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 anti-TNF biologic called V565 is in early stage clinical development [2]. V565 is a heavy chain only variable domain anti-TNF construct generated in Ilama and modified to further 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 [2]. 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
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Natural/Endogenous Targets
Target
tumor necrosis factor receptor 1
Selectivity at catalytic receptors
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
tumor necrosis factor receptor 1 Hs None - - - -
Selectivity at ligand targets
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
COVA322 Hs Antibody Binding 9.9 pKd - 11
pKd 9.9 (Kd 1.29x10-10 M) [11]
Description: Binding affinity determined using BIAcore technology
Other ligands which bind to or alter the activity of this ligand
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Ligand Sp. Type Action Value Parameter Concentration range (M) Reference
infliximab Hs Antibody Binding 8.7 pKd - 6
pKd 8.7 (Kd 1.8x10-9 M) [6]
Description: Binding affinity of antibody cA2 to recombinant human TNFα
adalimumab Hs Antibody Binding 8.0 pKd - 9
pKd 8.0 (Kd 1x10-8 M) [9]
compound 1 [PMID: 28611375] Hs Inhibitor Binding 5.3 – 8.6 pKd - 7
pKd 8.6 (Kd 2.31x10-9 M) [7]
Description: High affinity binding site identified using gravimetric measurements made by surface acoustic wave (SAW) sensors.
pKd 5.3 (Kd 4.79x10-6 M) [7]
Description: Low affinity binding site identified using gravimetric measurements made by surface acoustic wave (SAW) sensors.
ozoralizumab Hs Antibody Binding 9.0 pEC50 - 1
pEC50 9.0 (EC50 9.85x10-10 M) [1]
golimumab Hs Antibody Binding 10.7 pIC50 - 10
pIC50 10.7 (IC50 1.8x10-11 M) [10]
Description: Affinity for soluble TNFα measured by surface plasmon resonance
certolizumab pegol Hs Antibody Binding - - - 8
[8]
Description: Note IC90 value of 3ng/ml is provided
etanercept Hs Antagonist Inhibition - - - 3,5
[3,5]
remtolumab Hs Antibody Binding - - -