Cytokine Tumour Necrosis Factor (TNF)

14:58 EST 17th December 2018 | BioPortfolio

TNF is a compound that is classified as a cytokine which plays a central role in the cellular mechanisms of apoptosis or cell death. However, there are a number of different kinds of TNF, just under twenty, but the family of molecules have very similar actions and characteristics. In different cells, under different circumstances it can induce tumour regression (shrinkage of cancerous cells), septic shock and cachexia.

Different TNF molecules can activate different biological pathways, which cause a cascade of molecular changes. In the care of cellular apoptosis, the pathway that follows involves bid inhibiting the anti-apoptotic factor, blc-2, which allows the apoptotic process to proceed. One of the main features of this is the disruption of the mitochondrial membrane, and activation of Caspase 3 which leads to cell death.

That is just one example of the pathways influenced by TNF. But TNF itself is influenced by a number of factors, including growth factors and external stimuli such as cellular stress. The molecules that have capacity to activate or inhibit are of particular interest to those researching therapeutic options for a number of diseases. Anti-TNF drugs are already in clinical use for arthritis, which is a form of inflammation – a cellular process TNF has been implicated in. Anti-TNF drugs have possible applications in a number of immunological diseases, because inflammation is a response of the  immune-system.

Significant interest lies in TNF activation because of the resulting cell death. If TNF can be activated in tumour cells, there is the possibility of the tumour regressing and thus anti-TNF drugs are a possible cancer treatment, and therefore the subject of much research. TNF blockers are the commercially most successful single-target group of biologic therapies. 2008 sales of the four approved brands were US$ 16.35 bln with double digit growth rates due to indication expansion and new market entrants. Abbott’s fully human antibody Humira recorded 2008 sales growth of 48 % over the previous year which may explain why competitors with the established brands Enbrel and Remicade also have fully human anti-TNF antibodies in their pipeline. Forthcoming patent expiries also may have encouraged to develop next generation anti-TNF antibodies. Clinical indications approved for therapy with TNF blockers include rheumatoid arthritis(RA) and juvenile RA, ankylosing spondylitis, psoriatic arthritis, psoriasis in adults and in children, Crohn’s disease and pediatric Crohn’s disease, and ulcerative colitis.

As in other cases, a clinically validated target with commercial success attracts companies to exploit and leverage their new technologies. Next generations of TNF blockers may bring orally bioavailable versions, locally applied TNF blockers, antagonists with higher binding affinities or better tissue penetration due to smaller size. At least 15 clinical stage and 19 preclinical stage are under evaluation in various indications including ophthalmic use, osteoarthritis, Behcet’s disease, organ transplantation, cutaneous sarcoidosis, oral mucositis, atopical dermatitis and sepsis.

With such ubiquitous molecules, targeting them often leads to side effects, because of the wide range of roles they play in different tissues through the body. More specific pathway knowledge and targeting of activators/inhibitors will help reduce the global impact of possible anti-TNF treatments.

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