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 [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

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

References
1. Beirnaert EAA. (2014) Nanobodies against tumor necrosis factor-alpha. Patent number: US8703131. Assignee: Ablynx N.V.. Priority date: 21/05/2005. Publication date: 22/04/2014.
2. Crowe JS, Roberts KJ, Carlton TM, Maggiore L, Cubitt MF, Clare S, Harcourt K, Reckless J, MacDonald TT, Ray KP et al.. (2018) Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease. Sci Rep, 8 (1): 4941. [PMID:29563546]
3. Feldman M, Taylor P, Paleolog E, Brennan FM, Maini RN. (1998) Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn's disease: analysis of the mechanism of action predicts utility in other diseases. Transplant Proc, 30 (8): 4126-7. [PMID:9865320]
4. Gahring LC, Carlson NG, Kulmar RA, Rogers SW. (1996) Neuronal expression of tumor necrosis factor alpha in the murine brain. Neuroimmunomodulation, 3 (5): 289-303. [PMID:9218250]
5. Goldenberg MM. (1999) Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. Clin Ther, 21 (1): 75-87; discussion 1-2. [PMID:10090426]
6. Le J, Vilcek J, Dadonna P, Ghrayeb J, Knight D, Siegel SA. (1997) Methods of treating TNF-α-mediated Crohn's disease using chimeric anti-TNF antibodies. Patent number: US5656272. Assignee: New York University Medical Center, Centocor, Inc.. Priority date: 18/03/1991. Publication date: 12/08/1997.
7. Mouhsine H, Guillemain H, Moreau G, Fourati N, Zerrouki C, Baron B, Desallais L, Gizzi P, Ben Nasr N, Perrier J et al.. (2017) Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening. Sci Rep, 7 (1): 3424. [PMID:28611375]
8. Nesbitt A, Fossati G, Bergin M, Stephens P, Stephens S, Foulkes R, Brown D, Robinson M, Bourne T. (2007) Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis, 13 (11): 1323-32. [PMID:17636564]
9. Salfeld JG, Allen DJ, Hoogenboom HRJM, Kaymakcalan Z, Labkovsky B, Mankovich JA, McGuinness BT, Roberts AJ, Sakorafas P, Schoenhaut D. (2001) Human antibodies that bind human TNFα. Patent number: US6258562. Assignee: Basf Aktiengesellschaft. Priority date: 09/02/1996. Publication date: 10/07/2001.
10. Shealy DJ, Cai A, Staquet K, Baker A, Lacy ER, Johns L, Vafa O, Gunn 3rd G, Tam S, Sague S et al.. (2010) Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α. MAbs, 2 (4): 428-39. [PMID:20519961]
11. Silacci M, Lembke W, Woods R, Attinger-Toller I, Baenziger-Tobler N, Batey S, Santimaria R, von der Bey U, Koenig-Friedrich S, Zha W et al.. (2016) Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases. MAbs, 8 (1): 141-9. [PMID:26390837]
12. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther, 117 (2): 244-79. [PMID:18155297]

References

1. Beirnaert EAA. (2014)
Nanobodies against tumor necrosis factor-alpha.
Patent number: US8703131. Assignee: Ablynx N.V.. Priority date: 21/05/2005. Publication date: 22/04/2014.

2. Crowe JS, Roberts KJ, Carlton TM, Maggiore L, Cubitt MF, Clare S, Harcourt K, Reckless J, MacDonald TT, Ray KP et al.. (2018)
Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.
Sci Rep, 8 (1): 4941. [PMID:29563546]

3. Feldman M, Taylor P, Paleolog E, Brennan FM, Maini RN. (1998)
Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn's disease: analysis of the mechanism of action predicts utility in other diseases.
Transplant Proc, 30 (8): 4126-7. [PMID:9865320]

4. Gahring LC, Carlson NG, Kulmar RA, Rogers SW. (1996)
Neuronal expression of tumor necrosis factor alpha in the murine brain.
Neuroimmunomodulation, 3 (5): 289-303. [PMID:9218250]

5. Goldenberg MM. (1999)
Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis.
Clin Ther, 21 (1): 75-87; discussion 1-2. [PMID:10090426]

6. Le J, Vilcek J, Dadonna P, Ghrayeb J, Knight D, Siegel SA. (1997)
Methods of treating TNF-α-mediated Crohn's disease using chimeric anti-TNF antibodies.
Patent number: US5656272. Assignee: New York University Medical Center, Centocor, Inc.. Priority date: 18/03/1991. Publication date: 12/08/1997.

7. Mouhsine H, Guillemain H, Moreau G, Fourati N, Zerrouki C, Baron B, Desallais L, Gizzi P, Ben Nasr N, Perrier J et al.. (2017)
Identification of an in vivo orally active dual-binding protein-protein interaction inhibitor targeting TNFα through combined in silico/in vitro/in vivo screening.
Sci Rep, 7 (1): 3424. [PMID:28611375]

8. Nesbitt A, Fossati G, Bergin M, Stephens P, Stephens S, Foulkes R, Brown D, Robinson M, Bourne T. (2007)
Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents.
Inflamm Bowel Dis, 13 (11): 1323-32. [PMID:17636564]

9. Salfeld JG, Allen DJ, Hoogenboom HRJM, Kaymakcalan Z, Labkovsky B, Mankovich JA, McGuinness BT, Roberts AJ, Sakorafas P, Schoenhaut D. (2001)
Human antibodies that bind human TNFα.
Patent number: US6258562. Assignee: Basf Aktiengesellschaft. Priority date: 09/02/1996. Publication date: 10/07/2001.

10. Shealy DJ, Cai A, Staquet K, Baker A, Lacy ER, Johns L, Vafa O, Gunn 3rd G, Tam S, Sague S et al.. (2010)
Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.
MAbs, 2 (4): 428-39. [PMID:20519961]

11. Silacci M, Lembke W, Woods R, Attinger-Toller I, Baenziger-Tobler N, Batey S, Santimaria R, von der Bey U, Koenig-Friedrich S, Zha W et al.. (2016)
Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases.
MAbs, 8 (1): 141-9. [PMID:26390837]

12. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. (2008)
Tumor necrosis factor antagonist mechanisms of action: a comprehensive review.
Pharmacol Ther, 117 (2): 244-79. [PMID:18155297]