Altered specificity proteases that cleave and inactivate IL-23
IL-23 (interleukin 23) is a cytokine that is known to play a major role in the immune system and the development of auto-immune disorders and cancer. IL-23 acts by enhancing the expansion of Th17 cells which in turn produce IL-17, IL-6 and TNFα to mount an immune response. Hyperactivity in the IL-23 pathway has previously been implicated in many autoimmune disorders. Not surprisingly, regulating IL-23 activity has been the focus of many efforts through the use of small molecule inhibitors, antagonists or neutralizing antibodies.
Dr. David Liu’s lab has exploited the well-known, but currently limited potential of proteases to alter IL-23 activity. Using phage-assisted continuous evolution (PACE), the laboratory has been able to reprogram a chymotrypsin-like protease to target a specific sequence within IL-23 and modulate its activity. This discovery has been reported in Packer et al.,.
The finding that a protease can be redirected to modulate the effects of interleukins provides a new modality to treat numerous immune-based disorders such as psoriasis, rheumatoid arthritis and ulcerative colitis. Moreover, as IL-23 has been implicated on other disease areas, the applications extend beyond autoimmunity and can include diabetic wound healing, immunooncology and post menopausal bone loss. Lastly, the availability of such a protease could also be used a research tool to study IL-23.
This technology opens the door to further protease re-programing efforts to target other proteins that are implicated in human diseases involving hyperactivity of the IL-23 inflammatory pathway.