Novel Oral Yeast Immunotherapies for Ulcerative Colitis (Fast-track)

Abstract Ulcerative colitis and Crohn’s disease are major forms of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and gut microbiota dysbiosis. IBD has been associated with poor quality of life and often results in complications requiring hospitalizations and surgical procedures that causes significant morbidity and financial losses in the US. In past decade, anti-tumor necrosis factor alpha (TNF-a) have become the cornerstone of treatment for IBD, but the long-term use of these systemically delivered biologics is often associated with the loss of effects and the risks of generalized immunosuppression. To overcome the hurdles, we developed an oral immunotherapeutic lead, designated as FZ006, by utilizing a probiotic Saccharomyces boulardii to deliver a potent bi-specific neutralizing antibody against human TNF-a to the intestines in order to treat ulcerative colitis. In our preliminary studies, we generated a prototype of S. boulardii strain secreting an anti-mouse TNF-a antibody (Sb-amTNF) and proof-of-concept data demonstrating that oral Sb-amTNF significantly ameliorated dextran sodium sulfate and bacterial colitis in mice. In this Fast- track SBIR, we will pursue the Specific Aim 1 in Phase I study to perform biochemical and genetic characterization of FZ006. In Phase II studies, Aim 2 will investigate pharmacokinetic and safety profiles of FZ006, and Aim 3 will perform IND-enabling preclinical efficacy evaluation of FZ006 in human TNF-a transgenic mice. All proposed activities will be guided by an exceptional advisory/consultant team with specialized expertise in business development, biologics regulation, product development and planning, and clinical development. Upon the completion of the proposed studies, we will pursue Phase IIb for generating GMP product of FZ006, GLP toxicology and IND submission. Our long-term goal is to develop a novel oral yeast immunotherapy against UC, a chronic intestinal disorder that causes tremendous morbidity and financial losses in the US and worldwide.