A Novel Immunological-Directed Live Biotherapy Product for Treating Ulcerative Colitis

项目摘要 该项目的目标是开发一种新型的免疫导向的活体生物治疗产品(LBP) 利用天然微生物群途径抑制肠道炎症过程以治疗炎症 肠道疾病(IBD)。在美国，超过300万成年人患有IBD，这个总括的术语包括两个 胃肠道慢性炎症性疾病：克罗恩病(CD)和溃疡性结肠炎(UC) IBD通常在生命的第二或三十年被诊断出来，是终生的，没有治愈的方法。目前的IBD 治疗可能会有严重的副作用，患者会变得难以治疗。安全和安全的新疗法 有效的，特别是恢复肠道膜屏障是必要的，并将改变人们的生活。 肠道免疫调节信号严格控制着健康的肠道动态平衡，它们的崩溃可能导致 IBD39.人类的微生物群蕴藏着数万亿个细菌，是这些机制的关键调节器。 共生菌对维持肠上皮屏障完整性和调节先天适应性的作用 免疫细胞功能40。表层蛋白(SLP)，包括SLpA、SLpB、SLpX和脂磷壁酸(LTA) 与先天免疫肠道细胞上表达的模式识别受体(PRR)相互作用以提高免疫力 处于稳定状态和患病状态41-44。最近，我们的研究团队证明了SLpA是 抗炎为主的SLP信号。SLPA与C型凝集素特异性细胞内黏附的结合 分子-3抓取非整合素同源受体3(SIGNR3)在树突状细胞衬里表达 在多种模型中，肠道可以预防实验诱导的结肠炎。乳酸乳杆菌对SLpA的口服(另见 称为R-3750或R110)减少炎性细胞因子，增强粘膜屏障，以及 在肠道炎症动物模型中支持更健康的微生物区系组成64。值得注意的是，这些影响和 在Signr3-/-小鼠中未观察到slpA介导的保护作用，提示slpA与SIGNR3相互作用 在调节疾病状况方面起着关键的保护作用15。 我们的目标是开发一种表达SLpA的乳球菌R-3750。乳酸菌菌株，作为一种新的口服药物 一种作为免疫疗法的药物，可减少肠道炎症，改善胃肠道粘膜屏障 功能，恢复炎症性肠病患者的自然微生物群组成。乳酸乳杆菌具有以下两个主要优势： 一种将SLPA输送到肠道的载体：1)它已经在人体临床试验中安全使用 野生型和基因操纵的形式16、45、19和2)它不表达任何本地SLP，但可以 被设计成选择性地过度表达SLpA。此Fast-Track SBIR应用程序专注于获取人力资源 通过完成首个人类第一阶段概念验证临床试验，对R-3750进行验证。具体目标 是：1)准备并向FDA提交IND，2)完成胶囊制造以支持临床研究， 3)进行第一阶段临床试验，4)分析患者样本的关键药效学反应 和临床生物标志物，以及5)为第二阶段药物制造准备GMP放大生产工艺。

Project Summary The goal of this project is to develop a novel immunological-directed Live Biotherapeutic Product (LBP) that leverages natural microbiome pathways to inhibit gut inflammatory processes for the treatment of inflammatory bowel disease (IBD). Over 3 million adults in the U.S. suffer from IBD, an umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tract: Crohn’s disease (CD) and ulcerative colitis (UC)1. IBD is typically diagnosed in the second or third decades of life, is life-long, and there is no cure. Current IBD treatments can have serious side-effects, and patients become refractory. Novel therapies that are safe and effective, particularly restoring the intestinal membrane barrier, are needed and would be life changing. Intestinal immune regulatory signals tightly govern healthy gut homeostasis, and their breakdown may result in IBD39. The human microbiome, harboring trillions of bacteria, is a critical regulator of these mechanisms. Commensal bacteria function to maintain intestinal epithelial barrier integrity and regulate innate and adaptive immune cell function40. Surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA) interact with pattern recognition receptors (PRR) expressed on innate immune intestinal cells to fine immunity in steady state and diseased conditions41-44. Recently, our research team demonstrated that SlpA is the predominant anti-inflammatory Slp signal. SlpA binds to the C-type lectin Specific Intracellular adhesion molecule-3 Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells lining the gut prevents experimentally induced colitis in multiple models15. Oral delivery of SlpA via L. lactis (also known as R-3750 or R110) reduced inflammatory cytokines, strengthened the mucosal membrane barrier, and supported a healthier microbiota make-up in animal models of gut inflammation64. Notably, the effects and protection mediated by SlpA were not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3 plays a key protective role in regulating the disease condition15. Our goal is to develop R-3750, a SlpA-expressing Lactococcus (L.) lactis strain, as a novel, orally administered drug that functions as immune therapy to reduce gut inflammation, improve gastrointestinal mucosal barrier function, and restore the natural microbiome make-up in IBD patients. L. lactis provides two key advantages as a delivery vehicle for conveying SlpA to the gut: 1) it has already been safely used in human clinical trials in wild type and genetically manipulated forms16, 45 19 and 2) it does not express any native Slps but can be engineered to selectively overexpress SlpA. This Fast-Track SBIR application is focused on obtaining human validation for R-3750 by completing a first-in-human Phase 1 proof-of-concept clinical trial. The Specific Aims are: 1) prepare and file an IND with the FDA, 2) complete capsule manufacturing to support the clinical study, 3) perform the Phase 1 clinical trial, 4) analyze samples from the patients for key pharmacodynamic responses and clinical biomarkers, and 5) prepare GMP scale up production processes for Phase 2 drug manufacturing.