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

Project Summary Abstract Medikine will use SBIR funding to develop a novel therapeutic approach for inflammatory bowel diseaseIBDThe two most prevalent forms of IBD are ulcerative colitisUCand Crohn s diseaseCDcharacterized by episodes of abdominal paindiarrheabloody stoolsweight lossinflammation and ulcerationIBD is believed to result from an abnormal response of intestinal immune cells when exposed to bacterial antigens via a compromised luminal barrierTreatments are typically immunosuppressiveranging from glucocorticoid therapy to more recently available anti cytokine agentssuch as anti TNF antibodiesMany patientshoweverremain refractory to current therapeutic optionsAreport estimatesMof the adult US population has received a diagnosis of IBDThe burden of IBD is quite highboth on patient quality of lifeand on the health care systemwith estimates of hospitalization rates ofperannuallyand annual treatment costs of $BThereforea high medical need exists for more efficaciousdurableand safe treatments for IBDMedikine will address this need by using SBIR funding to develop novel peptide mimics of ILa key cytokine that has recently been shown to have anti inflammatory effects in the GI tractILreceptorILRis composed of two different subunitsILRand gpwhich initiate signaling when they form a ternary complex with ILThere is convincing evidence of a role for ILin the course of IBDFor exampleit was shown that utilizing bacterial delivery of ILdirectly to the intestinal lumenstrongly beneficial effects in experimental IBD models were observedAlsoin an acute murine colitis modelrectal infusion oftrinitrobenzene sulfonic acidTNBSmucosal delivery of ILattenuated TNBS induced colitisweight losscolon weight to length ratioand disease activity indexLimitations for the use of ILfor the treatment of IBD are that systemic administration via injection has limited therapeutic effectand that the ILprotein in not stable in the harsh environment of the GI tract if given orallyFurtherILdelivery via drugproducing bacteria lacks precise dosage controlThese limitations will be addressed by Medikine s SBIR program to develop novelorally administered peptides for the treatment of IBDIn Phase I of this SBIR proposalwe will identify novel heterodimeric peptide compoundswith sequences unrelated to that of ILwhich are agonists of the ILreceptorThis will be done by building on our preliminary data to identify sets of peptide ligands for each of the two ILR subunitsassembling these ligands into a diverse collection of heterodimeric ligandsand then testing the heterodimers for in vitro ILR agonist activity in both ILresponsive cell lines and human T cellsIn the Medikine Phase II programwe will further optimize selected heterodimers for affinityengineer these compounds for gastric stabilitytest them in animal models of IBDand select a candidate for clinical development Project Narrative Inflammatory bowel diseaseIBDwhich effects approxof the adult U Spopulationis characterized by episodes of abdominal paindiarrheabloody stoolsweight lossinflammation and ulcerationand is believed to result from an abnormal response of intestinal immune cells when exposed to bacterial antigensThe cytokine protein ILhas shown efficacy in mouse models of IBD when administered via secretion from bacteria applied to the gutbut oral administration of the ILitself is not possible due to its instability in the harsh gastric environmentand bacterial secretion suffers from poor dosage controlMedikine will develop a novel peptide mimetic of ILthat retains the therapeutic potential of the proteinbutas a chemicallymodifiable peptidewill be engineered for stability in the GI tractand therefore will represent a novel orallyadministered therapeutic approach for treating IBD