Orally-active peptide agonists of the IL-27 receptor for treatment of inflammatory bowel disease and other autoimmune disorders

Medikine, Inc., Menlo Park CA

Investigators

Abstract

Project Summary/Abstract Medikine will use SBIR funding to develop a novel therapeutic approach for inflammatory bowel disease (IBD). The two most prevalent forms of IBD are ulcerative colitis (UC) and Crohn?s disease (CD), characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss, inflammation and ulceration. IBD is believed to result from an abnormal response of intestinal immune cells when exposed to bacterial antigens via a compromised luminal barrier. Treatments are typically immunosuppressive, ranging from glucocorticoid therapy to more recently available anti-cytokine agents, such as anti-TNF antibodies. Many patients, however, remain refractory to current therapeutic options. A 2015 report estimates 1.3% (~3M) of the adult US population has received a diagnosis of IBD. The burden of IBD is quite high, both on patient quality of life, and on the health care system, with estimates of hospitalization rates of 8.2-17 per 100,000 annually, and annual treatment costs of $6.8B. Therefore, a high medical need exists for more efficacious, durable, and safe treatments for IBD. Medikine will address this need by using SBIR funding to develop novel peptide mimics of IL-27 ? a key cytokine that has recently been shown to have anti-inflammatory effects in the GI tract. IL-27 receptor (IL-27R) is composed of two different subunits (IL-27R? and gp130), which initiate signaling when they form a ternary complex with IL-27. There is convincing evidence of a role for IL-27 in the course of IBD. For example, it was shown that utilizing bacterial delivery of IL-27 directly to the intestinal lumen, strongly beneficial effects in experimental IBD models were observed. Also, in an acute murine colitis model (rectal infusion of 2,4,6-trinitrobenzene sulfonic acid, TNBS), mucosal delivery of IL-27 attenuated TNBS-induced colitis, weight loss, colon weight-to-length ratio, and disease activity index. Limitations for the use of IL-27 for the treatment of IBD are that systemic administration via injection has limited therapeutic effect, and that the IL- 27 protein in not stable in the harsh environment of the GI tract if given orally. Further, IL-27 delivery via drug- producing bacteria lacks precise dosage control. These limitations will be addressed by Medikine?s SBIR program to develop novel, orally-administered peptides for the treatment of IBD. In Phase I of this SBIR proposal, we will identify novel heterodimeric peptide compounds, with sequences unrelated to that of IL-27, which are agonists of the IL-27 receptor. This will be done by building on our preliminary data to identify sets of peptide ligands for each of the two IL-27R subunits, assembling these ligands into a diverse collection of heterodimeric ligands, and then testing the heterodimers for in vitro IL-27R agonist activity in both IL-27- responsive cell lines and human T-cells. In the Medikine Phase II program, we will further optimize selected heterodimers for affinity, engineer these compounds for gastric stability, test them in animal models of IBD, and select a candidate for clinical development.