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.