Development of sIgA from human milk as a therapeutic for Inflammatory bowel disease

PROJECT SUMMARY Inflammatory Bowel disease (IBD) is a collective term encompassing Crohn's disease, which can affect any part of the gastrointestinal (GI) tract, and ulcerative colitis, which specifically targets the distal colon and rectum. Globally, the prevalence of IBD is estimated at 4.9 million cases, with nearly 1% of the U.S. population affected, leading to healthcare costs approaching $31.6 billion annually in the U.S. Current pharmacotherapy for IBD primarily involves the use of aminosalicylates, corticosteroids, immunomodulators, and biologics to manage symptoms. However, these treatments can be associated with significant side effects. The challenges of primary non-response, secondary loss of response, and therapeutic intolerance in biologic treatments further underscore the need for alternative therapies. Given these challenges, there is an urgent medical need to develop new therapeutics for IBD that are safe, cost-effective, and efficient. Secretory IgA is the predominant humoral antibody response in the GI tract, serving critical protective functions by preserving mucosal barrier integrity and maintaining a balanced gut microbiota. In individuals with IBD, elevated secretory IgA (sIgA) levels are observed in the intestinal mucosa, reflecting an immune response to the ongoing inflammation and dysregulation characteristic of the disease. Lactiga is committed to developing proprietary human milk-derived sIgA for oral delivery, aimed at protecting against IBD. This initiative is grounded in the well-established premise that human milk-derived products confer potent protection against intestinal inflammation. The efficacy of this therapeutic approach will be rigorously tested using innovative in vitro and in vivo humanized models. In Aim 1, the protective role of human milk-derived sIgA on mucosal barrier and immune function will be assessed using human HT29 colonocytes and primary enteroid cultures derived from healthy subjects and IBD patients. Anti-inflammatory and barrier protection by sIgA will be demonstrated by the reduction in transepithelial electrical resistance (TEER), fluorescein-sulfonic acid flux and IL-8 cytokine levels when compared with controls. In Aim 2, the efficacy of milk- derived sIgA in treating IBD will be demonstrated in vivo in humanized microbiota IBD mouse models, namely an acute dextran sulphate sodium (DSS)-induced colitis model and a IL-10 deficient chronic colitis model. Therapeutic efficacy will be demonstrated in both IBD models by improvements in clinical symptoms and histological and molecular colitis scores. The successful completion of this STTR Phase I project will lay the foundation of a Phase II STTR proposal to further test the efficacy and safety of Lactiga’s human milk-derived sIgA and to establish optimal delivery and pharmacokinetics/pharmacodynamics for treatment. The STTR Phase II R&D plan will generate the necessary data to support an IND application with the FDA that will pave the way to a first-in-human clinical study to collect evidence of safety and efficacy in the treatment for IBD.