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

一种治疗溃疡性结肠炎的新型免疫定向活体生物治疗产品

• 批准号: 10729110
• 负责人: Gary Fanger
• 金额: $ 100.2万
• 依托单位: RISE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729110
• 关键词: Novel; Immunological; Directed; Live; Biotherapy

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.

项目概要 该项目的目标是开发一种新型免疫导向活生物治疗产品（LBP）， 利用天然微生物组途径抑制肠道炎症过程来治疗炎症 肠道疾病 (IBD) 在美国有超过 300 万成年人患有 IBD，这是一个涵盖两种疾病的总称。 胃肠道慢性炎症性疾病：克罗恩病（CD）和溃疡性结肠炎（UC）1。 IBD 通常在生命的第二个或第三个十年被诊断出来，并且是终生的，并且目前 IBD 无法治愈。 治疗可能会产生严重的副作用，并且患者会变得难以接受安全且新的疗法。 有效的方法，特别是恢复肠膜屏障，是必要的，并且将改变生活。 肠道免疫调节信号严格控制着健康的肠道稳态，它们的崩溃可能会导致 IBD39. 人类微生物组含有数万亿细菌，是这些机制的关键调节者。 共生细菌的功能是维持肠上皮屏障的完整性并调节先天性和适应性 免疫细胞功能40. 表面层蛋白 (Slps)，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 最近，我们的研究小组证明，SlpA 是在稳态和患病条件下41-44。 SlpA 与 C 型凝集素特异性细胞内粘附结合，发挥主要的抗炎作用。 分子 3 抓取树突状细胞内层表达的非整联蛋白同源相关 3 (SIGNR3) 受体 肠道可在多种模型中预防实验诱导的结肠炎15。 称为 R-3750 或 R110）减少炎症细胞因子，增强粘膜屏障，并且 支持肠道炎症动物模型中更健康的微生物群组成64。 在 Signr3-/- 小鼠中未观察到 SlpA 介导的保护作用，表明 SlpA 与 SIGNR3 相互作用 在调节疾病状况中发挥关键的保护作用15。 我们的目标是开发 R-3750，一种表达 SlpA 的乳酸乳球菌 (L.) 菌株，作为一种新型口服给药 免疫治疗药物，减少肠道炎症，改善胃肠粘膜屏障 功能，并恢复 IBD 患者的天然微生物组构成，乳酸乳球菌具有两个关键优势： 用于将 SlpA 输送至肠道的输送载体：1) 它已在以下国家安全地用于人体临床试验： 野生型和基因操纵形式16、45 19和2)它不表达任何天然Slps，但可以 旨在选择性过度表达 SlpA。该快速通道 SBIR 应用的重点是获得人类。 通过完成首次人体 1 期概念验证临床试验来验证 R-3750。 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 1 期临床试验，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) 为第二阶段药品生产准备 GMP 放大生产工艺。