Repolarization of Activated Th1 Cells: a Novel Means to Treat IBD

DESCRIPTION (provided by applicant): Current treatment regimens for Crohn's Disease (CD) are unsatisfactory, as evidenced by the high percentage of complications in the disease, frequently necessitating debilitating intestinal resection. CD is thought to result from both an excess of pathogenic Th1/Th17 cells and a deficiency of tolerance-inducing antigen (Ag) specific T regulatory CD4+ cells, in particular Tr1 cells (FOXp3-CD25-IL-10high, FOXp3-CD25-IL-4high). In the absence of suitable levels of regulatory T-cells, the impact of pathogenic Th1/Th17 cells is unopposed, resulting in mucosal inflammation and injury. Beyond a threshold loss of mucosal integrity, bacterial translocation from the gut lumen takes place, which then elicits a positive feedback loopof submucosal infection, inflammation, tissue injury, and greater barrier dysfunction. To meet this need, Radikal Therapeutics is developing a novel fusion protein (hR-411) that induces targeted immune tolerance in antigen (Ag)-specific activated T-cells.hR-411 is constructed from Ig-Fc and CXCL11, a CXCR3-binding ligand that has been recently identified as a counter- regulatory chemokine. Therapy with mR-411, the murine homologue of hR-411, profoundly suppresses experimental allergic encephalomyelitis (EAE), a classic autoimmune model system in rodents, even when treatment is initiated after disease onset. Moreover, Ag-specific effector Th1 cells isolated from EAE donors treated in vivo with mR-411 redirect their polarization into Tr1 cells and suppress EAE in adoptive transfer experiments. In contrast to pan-suppressive immunomodulators, mR-411 induces tolerance that is Ag-specific for the active disease yet preserves generalized immunity to previously encountered antigens. Phase 1 Specific Aim: Establishthat mR-411 dose-dependently attenuates established colitis in an adoptive T-cell transfer model of intestinal inflammation We will carry out a dose-escalation placebo-controlled investigation of mR-411 in recombinase-activating gene-1 deficient (RAG-/-)mice rendered colitic via the adoptive transfer of CD4+CD45RBhigh T-cells. Treatment with mR-411 or dexamethasone will begin 4 weeks after adoptive T-cell transfer. mR-411 is expected to dose-dependently improve gut histology score and prevent neutrophil infiltration. Phase 2 Specific Aim: Establish the pre-clinical safety of hR-411, as demonstrated by GLP studies of toxicology and safety pharmacology in rats and primates. We will develop: 1) a high-producing CHO cell line for production of hR-411 in serum-free media, 2) validated analytical methods to support manufacturing in- process and release testing, and 3) GMP-grade batches of hR-411 drug substance and product to support GLP toxicology and safety pharmacology studies and GCP clinical trials. We will then undertake acute safety pharmacology and subacute and chronic toxicology investigations in Marmoset non-human primates. PUBLIC HEALTH RELEVANCE: Crohn's Disease remains recalcitrant to existing therapies, with a high percentage of patients enduring recurrent bouts of inflammation and intestinal damage. We are developing a novel drug that specifically blocks the inflammatory process in this condition yet does not interfere with general immunity. We will test this agent in a clinically-relevant animal model of autoimmune colitis.