A Novel Immunological-Directed Live Biotherapy Product for Treating Ulcerative Colitis

Project Summary The goal of this project is to develop a novel immunological-directed Live Biotherapeutic Product (LBP) that leverages natural microbiome pathways to inhibit gut inflammatory processes for the treatment of inflammatory bowel disease (IBD). Over 3 million adults in the U.S. suffer from IBD, an umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tract: Crohn’s disease (CD) and ulcerative colitis (UC)1. IBD is typically diagnosed in the second or third decades of life, is life-long, and there is no cure. Current IBD treatments can have serious side-effects, and patients become refractory. Novel therapies that are safe and effective, particularly restoring the intestinal membrane barrier, are needed and would be life changing. Intestinal immune regulatory signals tightly govern healthy gut homeostasis, and their breakdown may result in IBD39. The human microbiome, harboring trillions of bacteria, is a critical regulator of these mechanisms. Commensal bacteria function to maintain intestinal epithelial barrier integrity and regulate innate and adaptive immune cell function40. Surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA) interact with pattern recognition receptors (PRR) expressed on innate immune intestinal cells to fine immunity in steady state and diseased conditions41-44. Recently, our research team demonstrated that SlpA is the predominant anti-inflammatory Slp signal. SlpA binds to the C-type lectin Specific Intracellular adhesion molecule-3 Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells lining the gut prevents experimentally induced colitis in multiple models15. Oral delivery of SlpA via L. lactis (also known as R-3750 or R110) reduced inflammatory cytokines, strengthened the mucosal membrane barrier, and supported a healthier microbiota make-up in animal models of gut inflammation64. Notably, the effects and protection mediated by SlpA were not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3 plays a key protective role in regulating the disease condition15. Our goal is to develop R-3750, a SlpA-expressing Lactococcus (L.) lactis strain, as a novel, orally administered drug that functions as immune therapy to reduce gut inflammation, improve gastrointestinal mucosal barrier function, and restore the natural microbiome make-up in IBD patients. L. lactis provides two key advantages as a delivery vehicle for conveying SlpA to the gut: 1) it has already been safely used in human clinical trials in wild type and genetically manipulated forms16, 45 19 and 2) it does not express any native Slps but can be engineered to selectively overexpress SlpA. This Fast-Track SBIR application is focused on obtaining human validation for R-3750 by completing a first-in-human Phase 1 proof-of-concept clinical trial. The Specific Aims are: 1) prepare and file an IND with the FDA, 2) complete capsule manufacturing to support the clinical study, 3) perform the Phase 1 clinical trial, 4) analyze samples from the patients for key pharmacodynamic responses and clinical biomarkers, and 5) prepare GMP scale up production processes for Phase 2 drug manufacturing.