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.
Public Health Relevance Statement: Narrative Ulcerative colitis is chronic intestinal inflammatory disease associated with poor quality of life and often results in complications requiring hospitalizations and surgical procedures. This project aims to develop a first-in-class oral medicine by utilizing a probiotic yeast to therapeutic proteins to patient intestines and directly block inflammatory process in order to treat ulcerative colitis.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Animals; Antibodies; Attention; Bacteria; Biological Assay; Assay; Bioassay; Biologic Assays; Blood Circulation; Bloodstream; Circulation; Centers for Disease Control and Prevention (U.S.); CDC; Centers for Disease Control; Centers for Disease Control and Prevention; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Colitis; Ulcerative Colitis; Ulcerated Colitis; Crohn's disease; Crohn disease; Crohn's; Crohn's disorder; Granulomatous Enteritis; eleocolitis; regional enteritis; Disease; Disorder; Animal Disease Models; intravenous administration; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Future; Genetic Identity; Biochemical Genetics; Goals; Health; Hospitalization; Hospital Admission; Human; Modern Man; Immunoglobulin A; IgA; Immunoglobulin G; 7S Gamma Globulin; IgG; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Inflammation; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Intestinal Diseases; Intestinal Disorder; intestine disease; intestine disorder; Intestinal Secretions; Intestines; Intestinal; bowel; Lead; Pb element; heavy metal Pb; heavy metal lead; Transgenic Mice; Microcapsules drug delivery system; microcapsule; Morbidity - disease rate; Morbidity; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; Oral Medicine; Stomatology; Patients; Drug Kinetics; Pharmacokinetics; Phenotype; Quality of life; QOL; Risk; Saccharomyces; Safety; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Tissues; Body Tissues; Toxicology; Yeasts; Sodium Dextran Sulfate; Businesses; Treatment Cost; analytical method; base; improved; Acute; Chronic; Phase; Biological; Biochemical; Bispecific Antibodies; Bi-specific antibodies; Bifunctional Antibodies; bsAb; Ensure; Excretory function; excretion; Development Plans; Therapeutic; Genetic; Inflammatory; Adoptive Transfer; Oral; Clinic; System; neutralizing antibody; gastrointestinal; Probiotics; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; novel; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; TNF gene; Regulation; Modeling; Property; response; native protein drug; pharmaceutical protein; protein drug agent; therapeutic protein; immune drugs; immune-based therapeutics; immunologic preparation; immunologic therapeutics; immunotherapeutics; immunotherapy agent; Immunotherapeutic agent; Data; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; Process; Development; developmental; immunosuppressed; fight against; immunogenicity; design; designing; inflammatory disease of the intestine; gut inflammation; inflammatory disorder of the intestine; intestinal autoinflammation; intestinal inflammation; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Outcome; prototype; product development; preclinical efficacy; pre-clinical efficacy; gut microbiota; GI microbiota; Gastrointestinal microbiota; enteric microbial community; enteric microbiota; gastrointestinal microbial flora; gut commensal; gut community; gut flora; gut microbe community; gut microbial community; gut microbial composition; gut microbial consortia; gut microbiotic; gut microflora; intestinal flora; intestinal microbes; intestinal microbiota; intestinal microflora; intestinal tract microflora; phase 1 study; Phase I Study; phase 2 study; phase II study; efficacy study; clinical development; dysbiosis; dysbacteriosis; dysbiotic; microbial imbalance; genomic locus; gene locus; genetic locus
