Rise Therapeutics, LLC SBIR Phase II Award, May 2021

Project Summary Our goal is to develop a novel, immunologically enhanced L. lactis probiotic-based therapeutic for the treatment of Sjögren’s Syndrome (SjS). SjS is a progressive, chronic autoimmune disease characterized by inflammatory cell infiltration of the salivary and lacrimal glands, resulting in acinar epithelial cell atrophy, cell death, and loss of exocrine function 1-6. At least half of SjS patients develop extraglandular inflammatory disease and have a wide range of systemic clinical manifestations that can affect any organ system, including connective tissue, and 5-10% of patients develop life-threatening lymphoma 7, 8. SjS is a debilitating disease affecting as many as 3.1 million individuals in the U.S. 9, 10, with women being nine times more likely to be afflicted with SjS than men 5, 10, 11. Treatment of SjS remains a significant unmet medical need. Current treatment relies on replacement therapies such as artificial saliva and eye lubricants or immunosuppressive agents12, 13. Because of the multiple antigens involved in this disease process, i.e., α-fodrin 14-17, ribonuclear protein Ro/SSA 14, 48, 49, La/SSB 14, 48, 49, and M3R 18, 49, 50, oral tolerance methods become problematic. Thus, the capacity to stimulate regulatory cells independent of knowing the antigen specificity for the disease poses as an attractive therapeutic approach. Originally conceived as a human diarrheal vaccine, we found that colonization factor antigen I (CFA/I) from human enterotoxigenic E. coli (ETEC) is effective at inducing auto-Ag-specific T regulatory cells when administered orally as either a purified protein or delivered via a Salmonella or L. lactis bacterial delivery system 19-21, 61. To avoid challenges associated with producing large quantities of CFA/I protein and improve the mucosal pharmacokinetic (PK) and pharmacodynamic (PD) properties of CFA/I following oral administration, we developed and characterized a vector-containing L. lactis-CFA/I expressing product (referred to as VTC- CFA) and evaluated its efficacy in multiple autoimmune models. Indeed, VTC-CFA was effective at reducing clinical symptoms in a SjS animal model, along with experimental models of RA, diabetes, and MS 22-24. Prior Phase I and II SBIR funding has enabled us to effectively advance VTC-CFA towards clinical testing by developing our clinical candidate that expresses CFA/I from a genome-integrated operon, validating non- clinical biology, and completing upstream and downstream process development. As part of these efforts, we held an FDA pre-IND meeting to finalize our IND-enabling plans and align our CMC/manufacturing strategy. This application is designed to complete VTC-CFA IND enabling studies and file an IND with the FDA. The key aims of this proposal are: 1) complete VTC-CFA GLP toxicology studies, 2) establish cGMP manufacturing infrastructure, 3) perform cGMP manufacturing for drug substance, 4) Fill capsules under cGMP conditions for drug product, and 5) file an IND with the FDA for VTC-CFA. Successful commercialization of VTC-CFA will provide a profound medical advancement for treating SjS.Project Narrative Sjögren’s syndrome (SjS) is a progressive, chronic autoimmune disease resulting in immune-mediated destruction of the salivary and lacrimal glands, extraglandular autoimmune disease, and, in some cases, lymphoma. This project aims to develop a novel L. lactis probiotic bacteria programmed to express and deliver colonization factor antigen I (CFA/I) to induce T regulatory cells for the treatment of SjS. Successful commercialization would ultimately provide a profound front-line medical advancement in the treatment of SjS.