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A Novel TNF Alpha Inhibitor: New Generation of Superior Nature-Inspired Therapeutics for Treating Inflammation
Yeda R&D Co. Ltd Israel flag Israel
Abstract ID: 1628
Inflammation is characterized by elevated levels of TNF-alpha. Neutralizing TNF-alpha activity was shown to be beneficial for patients with chronic autoimmune inflammatory diseases such as rheumatoid arthritis (RA)...
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Introduction/Background

Inflammation is characterized by elevated levels of TNF-alpha. Neutralizing TNF-alpha activity was shown to be beneficial for patients with chronic autoimmune inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, current treatments of such conditions include general anti-inflammatory and immunosuppressive drugs that are of limited effectiveness and may cause serious side effects. Another class of drugs includes targeted therapies directed against TNF-alpha, that are associated with serious infections including tuberculosis (TB) and sepsis as well as increased risk of cancer in some cases.

Aims/Hypothesis

Thus, there is an urgent need for highly selective, safer and more effective drugs for inflammatory conditions that involve TNF-alpha as a key mediator.

Results

The A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-alpha converting enzyme (TACE), has been defined as the major shedding protease for a broad range of substrates predominantly the key immuno-regulatory cytokines TNF-alpha. Cleavage by TACE renders TNF-alpha pro-inflammatory, highlighting ADAM17 as a rationale target for treatment of autoimmune diseases such as IBD and arthritis. A team of researchers at the Weizmann institute headed by Prof. Irit Sagi, has employed a sophisticated approach towards TACE targeting by exploiting its autoinhibitory pro-domain as a platform for the alphasmart designalpha of TACE selective natural inhibitors. The therapeutic potential of TACE pro-domain was demonstrated in IBD mouse models, where TACE pro-domain administration showed significant improvement in multiple parameters such as reduced mortality and weight lost, in a dose dependent manner. Additional in vivo studies demonstrated that the TACE pro-domain is highly stable in vivo and harbours specificity towards the activated immune cells located in colon lesions. Thus, the novel TACE inhibitor presented in this technology leads to significant therapeutic effects and is beneficial in controlling inflammation in IBD disease manifestations in mice.

Conclusion

The present technology introduces a novel generation of candidate drugs that selectively inhibit the processing of TNF-alpha, thereby preventing it from exerting its pro-inflammatory properties. This technology provides a framework for the development of safer and more effective therapeutics for IBD and related autoimmune disorders.

Relevance/Opportunity

Treatment of autoimmune inflammatory conditions such as IBD and RA. Treatment of neuroinflammatory conditions such as multiple sclerosis (MS). Treatment of other inflammatory mediated diseases such as psoriasis, systemic sclerosis and ankylosing spondylitis. Please enquire quoting reference no. 1628 regarding licensing or codevelopment partnerships.
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FEATURED
Last Updated May 2015
Technology Type THERAPEUTIC
Phase of Development PRECLINICAL
CORPORATION