Development of conditionally active IL-10 INDUKINE TM molecules for the treatment of inflammatory bowel disease

Abstract

Abstract Inflammatory bowel disease (IBD) encompasses two chronic inflammatory diseases of the gastrointestinal tract, Ulcerative Colitis (UC) and Crohn’s disease. Although great strides have been made in the treatment of IBD, subsets of patients do not respond or lose responsiveness to therapy, underlining a need for new treatments. Interleukin 10 (IL-10) is a immunoregulatory cytokine, known to suppress and inhibit inflammatory responses of a variety of immune cells including monocytes, macrophages, and T cells. Polymorphisms associated with reduced expression of IL-10 and IL-10R have been linked with IBD. Clinical trials using recombinant IL-10 in IBD have been unsuccessful, highlighting a need for further engineering to utilize IL-10 as a therapeutic agent. We have developed IL-10 INDUKINE molecules that are designed as prodrugs containing human IL-10, an inactivation domain and a half-life extension domain tethered together by protease-sensitive linkers. IL-10 INDUKINE molecules are peripherally inactive but due to dysregulation of the protease milieu in the inflamed colon, the linkers are cleaved, and IL-10 is released locally. We have identified proprietary linkers which are cleaved by UC and Crohn’s human colon samples. In a mouse model of colitis, IL-10 INDUKINE molecules prevent weight loss, intestinal damage and inhibit inflammatory cytokine production within the colon. Together these data support the potential of an IL-10 INDUKINE molecule for the treatment of IBD.