tumour necrosis factor shed form   Click here for help

GtoPdb Ligand ID: 5074

Abbreviated name: TNF shed form
Synonyms: cachectin | necrosin | TNF alpha soluble form | tumor necrosis factor soluble form
Immunopharmacology Ligand
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 [2]. 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 [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
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
tumor necrosis factor receptor 1 Ligand is endogenous in the given species Hs None - - - -
Selectivity at ligand targets
Key to terms and symbols Click column headers to sort
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
Key to terms and symbols Click column headers to sort
Ligand Sp. Type Action Value Parameter Concentration range (M) Reference
infliximab Peptide Approved drug Primary target of this compound 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 Peptide Approved drug Primary target of this compound Hs Antibody Binding 8.0 pKd - 9
pKd 8.0 (Kd 1x10-8 M) [9]
compound 1 [PMID: 28611375] Small molecule or natural product 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 Peptide Primary target of this compound Hs Antibody Binding 9.0 pEC50 - 1
pEC50 9.0 (EC50 9.85x10-10 M) [1]
golimumab Peptide Approved drug Primary target of this compound 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 Peptide Approved drug Primary target of this compound Hs Antibody Binding - - - 8
[8]
Description: Note IC90 value of 3ng/ml is provided
etanercept Peptide Approved drug Primary target of this compound Hs Antagonist Inhibition - - - 3,5
[3,5]
remtolumab Peptide Primary target of this compound Hs Antibody Binding - - -