Enabling IL-2 as an Anti-inflammatory Agent through Local Dose-controlled Endoscopic Delivery

点击翻译按钮获取中文摘要

PROJECT SUMMARY Inflammatory bowel diseases (IBD) affects more than 3 million Americans, and can generally be classified as Crohn’s disease (2 million) or ulcerative colitis (UC, 1 million). A variety of FDA approved treatments exist for UC, but up to 25% of IBD patients are medically refractory. Ileal pouch-anal anastomosis (IPAA) surgery is recommended for these medically refractory UC patients, but due to the invasiveness and the long-term quality of life impact of IPAA surgery, up to 50% of medically refractory UC patients decline this procedure. Effectively managing and treating medically refractory UC patients is thus an unmet medical need. Biologic drugs have been shown to be effective in many UC patients when infused intravenously. The dosage of these anti- inflammatory biologic drugs are limited by the FDA for considerations of toxicity. For example, strong systemic suppression of the immune system would significantly increase the risk of both infectious diseases and of cancer. Consequently, the team hypothesizes that delivering high local concentrations of biologic drugs, while maintaining low systemic biologic concentrations, would increase the effectiveness of biologics in treating UC. Pana Bio is developing “living drug factories” inside the patient’s GI tract to treat IBD: drug-device combinations in which engineered L. reuteri bacteria producing biologic drugs are implanted endoscopically. The engineered bacteria are encapsulated in a hydrogel biomaterial, and enclosed in a porous cage that is affixed to the GI tract via an endoscopic clip. The hydrogel is selectively permeable to molecules smaller than 100kD, allowing efficient diffusion of biologic drug products, nutrients, and metabolic waste, but not of bacteria and viruses. Thus, the hydrogel protects the engineered bacteria from competition by native microbes, and controls the dosing of the biologic drug by limiting the number of bacteria within a patient’s body. Furthermore, because the bacteria are implanted locally at or near the disease site, Pana Bio will be able to deliver higher doses of biologic drugs increasing patient overall response rate while maintaining similar toxicity profiles due to lowered systemic drug concentrations. In this Phase 1 SBIR application, the Pana Bio team proposes to demonstrate precise local dose control of IL-2. IL-2 is a powerful, FDA-approved cytokine drug with an unusual pleiotropic property: IL-2 is pro-inflammatory at concentrations higher than 1nM, and anti-inflammatory at concentrations between 10pM and 1nM. In Pana Bio’s solution, biologic drugs such as IL-2 are continuously produced and secreted within the patient’s GI tract in a dose-controlled manner. Specifically, a strain of L. reuteri bacteria will be genetically engineered to constitutively produce and secrete IL-2, and the quantity of these bacteria can be controlled via the volume of hydrogel particles loaded and clipped to the UC disease site. The team will show that the concentration of IL-2 can be precisely controlled and reproducibly maintained steady state, demonstrating proof-of-concept for using IL-2 as an anti-inflammatory drug for UC.