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

通过局部剂量控制内窥镜递送使 IL-2 成为抗炎剂

• 批准号: 10546579
• 负责人: Moshe Baruch
• 金额: $ 25.5万
• 依托单位: PANA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546579
• 关键词: Affect; Alginates; American; Anastomosis - action; Animal Model; Anti-Inflammatory Agents; Anus; Bacteria; Biocompatible Materials; Biological; Biological Products; Bioreactors; Clip; Colon; Communicable Diseases; Crohn' s disease; Devices; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Implants; Drug usage; Effectiveness; Encapsulated; Engineering; FDA approved; Family suidae; Gastrointestinal tract structure; Genetic Engineering; Genomic Segment; Goals; Human; Human body; Hydrogels; Ileal Reservoirs; Immune system; Immunosuppression; Implant; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-2; Intravenous; Lactobacillus reuteri; Lasers; Lead; Malignant Neoplasms; Medical; Metabolic; Microbe; Microbial Biofilms; Modeling; Monoclonal Antibodies; Mutagenesis; Mutate; Nutrient; Operative Surgical Procedures; Patients; Permeability; Pharmaceutical Preparations; Phase; Plasmids; Primates; Procedures; Production; Property; Proteins; Quality of life; Refractory; Regulatory T-Lymphocyte; Reproducibility; Research; Risk; Rodent; Site; Small Business Innovation Research Grant; Steroids; Toxic effect; Ulcerative Colitis; Virus; base; clinical efficacy; clinical toxicology; cytokine; dosage; effector T cell; efficacy study; genetic element; immunoregulation; in vivo evaluation; ineffective therapies; nitinol; particle; pre-clinical; prototype; ratiometric; response; standard of care; wasting

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.

项目摘要 炎症性肠病（IBD）影响超过300万美国人，通常可以归类为 克罗恩病（200万）或溃疡性结肠炎（UC，100万）。存在各种FDA批准的治疗方法 UC，但多达25％的IBD患者在医学上是难治性的。回肠袋 - 肛门吻合（IPAA）手术是 建议这些医学难治性的UC患者，但由于侵入性和长期质量 IPAA手术的生活影响，多达50％的医学难治性UC患者拒绝了此手术。有效地 因此，管理和治疗医学难治性UC患者是未满足的医疗需求。生物药具有 当静脉注射时，它们在许多UC患者中被证明是有效的。这些抗剂量的剂量 炎症生物药受到FDA的限制，以考虑毒性。例如，强大的系统性 抑制免疫系统将显着增加感染性疾病和 癌症。因此，团队假设提供局部浓度的生物药物，而 保持低全身生物学浓度，将提高生物制剂在治疗UC中的有效性。 Pana Bio正在患者的胃肠道中开发“活着的药工厂”以治疗IBD：药物设备 在内镜下植入了生物药物的l. reuteri细菌的设计组合。 工程细菌封装在水凝胶生物材料中，并封闭在多孔笼中 通过内窥镜夹固定在胃肠道。水凝胶可选择性地渗透到小于小的分子 100KD，可以有效地扩散生物药物，营养素和代谢废物，但不可能有效地扩散细菌 和病毒。这就是水凝胶保护工程细菌免受本地微生物的竞争，以及 通过限制患者体内的细菌数量来控制生物药物的给药。此外， 由于细菌是在疾病部位或附近植入的，因此Pana Bio将能够提供更高的 生物药的剂量增加了患者的总体反应率，同时保持相似的毒性概况 降低全身药物浓度。 在此第1阶段SBIR应用程序中，Pana Bio团队提出了证明精确局部剂量的建议 IL-2的控制。 IL-2是一种功能强大的FDA批准的细胞因子药物，具有不寻常的多效性特性：IL-2 IS 浓度高于1NM的促炎症，浓度在晚上10点以内的抗炎 和1nm。在Pana Bio的解决方案中，在内部不断生产和分泌IL-2等生物药物 患者以剂量控制的方式的胃肠道。具体而言，将L. reuteri细菌的菌株通常是 设计为组成性生产和秘密IL-2，可以通过 将水凝胶颗粒的体积加载并剪切到UC疾病部位。团队将表明 IL-2的浓度可以精确控制并可重复保持稳态，证明 使用IL-2作为UC的抗炎药的概念证明。