I型TNF受容体選択的アンタゴニストの創出とその自己免疫疾患治療薬としての可能性

Abstract

Onset and exacerbation of autoimmune disease, such as rheumatoid arthritis and Crohn's disease would be regulated with hundreds of disease-related proteins changing in quality and quantity. Recently, tumor necrosis factor-alpha (TNF-alpha) comes to be known that is the key molecule for development of the autoimmune diseases and recognized as the drug target which should be inhibited to overcome the diseases using neutilizing antibodies. Because the functions of TNF-alpha are regulated with the manner binding to two receptors, TNFR1 and TNFR2, unexpected side-effects would happen with complete inhibition or activation of the TNF receptor signaling. Thus, it is essential to develop a novel drug developing technology, which regulates the binding pattern of TNF-alpha definitely for therapeutic purposes. In this regard, we have aimed to create the TNF-alpha mutant, which has selectivity for binding TNFR1 or TNFR2 and regulates the onset and exacerbation of inflammatory diseases. Recently, we have succeeded in creating several TNF-alpha mutants by phage display techniques which can substitute aimed amino acids to the other, randomly. In this review, we introduce our unique TNFR1-selective antagonist, which can only inhibit the function via TNFR1 correlating with the onset and exacerbation of autoimmune disease. This TNFR1-selective antagonist does not inhibit the host defense function via TNFR2. This mutant TNF-alpha did not show the increase of virus infection suggested that it may overcome the risk of infectious disease, which is a major side-effect of anti-TNF-alpha therapy. These results would provide widely the strategy of regulating protein function in molecular level and would show the attractive approach to create safe and effective medical drug reducing side-effects.