Development of Novel Immunoregulatory Therapeutics for Asthma Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision immunology. We have filed patent applications related to novel methods of suppressing inflammation during autoimmune disease, asthma, and allergy. The goal of this project is to develop and innovative treatment for asthma that targets a new immunoregulatory pathway in immune and epithelial cells. Asthma is a chronic, widespread allergic disease with total expenses exceeding $80 billion annually in the U.S. Current therapies for asthma are modestly successful but leave significant subpopulations of patients without adequate response. Specifically, type 2 asthma patients can develop steroid dependency, while non-type 2 asthma has a lower responsiveness to current treatments. Recent attempts to target this population have been unsuccessful, with anti-TNF, anti-IL-17 receptor and chemokine inhibitors failing in clinical trials [2, 3], while macrolides and methotrexate have shown mild improvement but at high side effect risk [4, 5]. Thus, there is an unmet medical need for safer and more efficacious asthma therapeutics. In the last years, regulatory T cells (Treg) have gained increased recognition in the treatment of inflammatory and allergic diseases. Manipulation of Treg cells to restore their suppressive capacity has been postulated as a promising novel therapeutic approach. This SBIR Phase I application will develop a novel, oral, once-daily, immunoregulatory therapeutic for the treatment of asthma. The Specific Aims are to: AIM 1. Characterize the therapeutic efficacy and route of administration of the novel immunoregulatory compound in mouse models of asthma. We will use the ovalbumin and house dust mite models to determine the therapeutic efficacy by airway resistance, lung histopathology, flow cytometry and cytokine expression. AIM 2. Determine the translational ability of the novel therapeutic in human primary cells from asthma patients, by assessing cytokine and metabolic profile, plus suppressive Treg capacity in coculture studies in bronchial epithelial (HDBE) cells and PBMCs from asthma donors, respectively. Expected successful outcomes are: i) ≥ 50% suppression of airway resistance and ≥ 50% decreased infiltration of neutrophils in the lungs of treated mice; and ii) ≥ 70% reduction in IL-8 and IL-6 expression in treated HDBE. Commercial Application: The impact of this new, oral, immunoregulatory asthma drug has the potential to disrupt an annual market estimated to reach $20 billion by 2026.