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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要炎症性肠病 (IBD) 影响着超过 300 万美国人，通常可分为以下几类：克罗恩病（200 万）或溃疡性结肠炎（UC，100 万）有多种 FDA 批准的治疗方法。 UC，但高达 25% 的 IBD 患者难以接受回肠储袋肛管吻合术 (IPAA)。推荐用于这些难治性 UC 患者，但由于其侵入性和长期质量由于 IPAA 手术对生活的影响，高达 50% 的难治性 UC 患者实际上拒绝接受该手术。因此，管理和治疗难治性 UC 患者是生物药物尚未满足的医疗需求。静脉注射这些抗-药物的剂量已被证明对许多 UC 患者有效。炎症生物药出于毒性等考虑受到 FDA 的限制。免疫系统的抑制会显着增加感染性疾病的风险经过测试，该团队主张提供高局部浓度的生物药物，同时维持较低的全身生物制剂浓度，将提高生物制剂治疗 UC 的有效性。 Pana Bio 正在患者胃肠道内进行“活体药物开发”，以治疗 IBD：药物装置通过内窥镜植入产生生物药物的工程罗伊氏乳杆菌的组合。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在胃肠道上，水凝胶可以选择性地渗透小于的分子。 100kD，允许生物药品、营养物质和代谢废物有效扩散，但不允许细菌扩散因此，水凝胶可以保护工程细菌免受天然微生物的竞争，并且通过限制患者体内细菌的数量来控制生物药物的剂量。由于细菌被植入到疾病部位或疾病部位附近，Pana Bio 将能够提供更高的效率生物药物的剂量增加了患者的总体反应率，同时保持了相似的毒性特征，因为降低全身药物浓度。在此 1 期 SBIR 应用中，Pana Bio 团队建议展示精确的局部剂量 IL-2 是 FDA 批准的一种强大的细胞因子药物，具有不寻常的多效性：IL-2 是浓度高于 1nM 时具有促炎作用，浓度在 10pM 之间时具有抗炎作用在Pana Bio的解决方案中，IL-2等生物药物在内部不断产生和分泌。具体来说，将以剂量控制的方式对患者的胃肠道进行基因改造。被设计成组成型产生和分泌IL-2，并且这些细菌的数量可以通过以下方式控制该团队将展示加载并夹在 UC 疾病部位的水凝胶颗粒的体积。 IL-2 的浓度可以精确控制并可重复地维持稳定状态，证明使用 IL-2 作为 UC 抗炎药的概念验证。