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

项目摘要 炎症性肠病（IBD）影响超过300万美国人，并且通常可以被分类为 克罗恩病（200万）或溃疡性结肠炎（100万）。FDA批准的各种治疗方法 UC，但高达25%的IBD患者是医学难治性的。回肠贮袋-肛门吻合术（IPAA）是 推荐用于这些医学难治性UC患者，但由于侵入性和长期质量 IPAA手术对生活的影响，高达50%的难治性UC患者拒绝接受该手术。有效 因此，管理和治疗医学上难治的UC患者是一个未满足的医疗需求。生物药物有 在许多UC患者中静脉输注时显示有效。这些抗- FDA出于毒性考虑限制了炎性生物药物。例如，强系统性 免疫系统的抑制将显著增加感染性疾病和 癌因此，研究小组假设，在局部输送高浓度的生物药物， 维持较低的全身生物制剂浓度，将增加生物制剂治疗UC的有效性。 Pana Bio正在开发患者胃肠道内的“活药物工厂”来治疗IBD：药物设备 其中工程化L.产生生物药物的罗伊氏细菌通过内窥镜植入。 工程细菌被封装在水凝胶生物材料中，并封闭在多孔笼中， 通过内窥镜夹固定到胃肠道。水凝胶可选择性地渗透小于 100 kD，允许生物药物产品，营养物质和代谢废物的有效扩散，但不允许细菌扩散 和病毒。因此，水凝胶保护工程化细菌免受天然微生物的竞争，并且 通过限制病人体内细菌的数量来控制生物药物的剂量。此外，委员会认为， 由于细菌被植入局部或附近的疾病部位，帕纳生物将能够提供更高的 生物药物剂量增加患者总体缓解率，同时维持相似的毒性特征， 降低全身药物浓度。 在第一阶段的SBIR应用中，Pana Bio团队建议证明精确的局部剂量 控制IL-2。IL-2是一种强大的，FDA批准的细胞因子药物，具有不寻常的多效性： 浓度高于1 nM时促炎，浓度在10 pM之间时抗炎 1 nM。在Pana Bio的解决方案中，生物药物如IL-2在细胞内持续产生和分泌， 以剂量控制的方式治疗患者的胃肠道。具体地说，一株L.罗伊氏菌将在基因上 被工程化以组成性地产生和分泌IL-2，并且这些细菌的数量可以通过以下方式控制： 加载并夹在UC疾病部位的水凝胶颗粒的体积。该团队将证明 IL-2的浓度可以被精确地控制并且可再现地维持稳定状态，证明了 使用IL-2作为UC的抗炎药物的概念验证。

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.