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: 10546328
• 负责人: Gary Fanger
• 金额: $ 36.06万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546328
• 关键词: Adult; Animal Model; Anti-Inflammatory Agents; Bacteria; Binding; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biopsy Specimen; Blood specimen; Bulla; C-Type Lectins; C-reactive protein; Cell Adhesion Molecules; Cells; Chemistry; Climacteric; Clinical; Clinical Data; Clinical Research; Clinical Trials; Colitis; Consent; Containment; Crohn' s disease; Dendritic Cell Pathway; Dendritic Cells; Development; Diagnosis; Digestive System Disorders; Disease; Documentation; Dose; Drug Delivery Systems; Engineering; Enteral; Excipients; Feces; Florida; Formulation; Future; Genetic Engineering; Goals; Growth; Gut Mucosa; Homeostasis; Homologous Gene; Human; Human Microbiome; Immune; Immunity; Immunologics; Immunotherapy; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Infrastructure; Intestinal permeability; Intestines; Investments; Label; Lactococcus; Leukocyte L1 Antigen Complex; Life; Ligands; Maintenance; Measurement; Measures; Mediating; Medical; Membrane; Mucous Membrane; Mus; Oral; Pathway interactions; Patients; Pattern recognition receptor; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Play; Probiotics; Process; Production; Property; Proteins; Recombinants; Recommendation; Refractory; Research; Role; Running; Safety; Sampling; Ships; Sigmoidoscopy; Signal Transduction; Signaling Protein; Small Business Innovation Research Grant; Solubility; Surface; Symptoms; Testing; Therapeutic; Time; Ulcerative Colitis; Universities; Validation; base; capsule; chronic inflammatory disease; clinical biomarkers; clinical development; clinical research site; commensal bacteria; commercialization; cost; cytokine; data management; delivery vehicle; design; drug development; first-in-human; gastrointestinal; genetic manipulation; gut homeostasis; gut inflammation; gut microbiome; improved; innovation; intestinal barrier; intestinal epithelium; lactic acid bacteria; lipoteichoic acid; manufacturing process; microbiome; microbiota; novel; novel therapeutics; operation; overexpression; prevent; receptor; research clinical testing; response biomarker; scale up; side effect; stool sample; sugar; transcriptome sequencing; vaccine delivery

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.

项目摘要 该项目的目标是开发一种新型的免疫导向的活生物素产品（LBP）， 利用天然微生物组途径来抑制肠道炎症过程，用于治疗炎症 肠道疾病（IBD）。在美国，超过300万成年人患有IBD，这是一个涵盖两个 胃肠道的慢性炎性疾病：克罗恩病（CD）和溃疡性结肠炎（UC）1. IBD通常在生命的第二或第三个十年被诊断出来，是终身的，并且没有治愈方法。当前IBD 治疗可能具有严重的副作用，并且患者变得难治。新的治疗方法是安全的， 有效的，特别是恢复肠膜屏障，是需要的，将改变生活。 肠道免疫调节信号严格控制健康的肠道稳态，它们的破坏可能导致 IBD 39。人类的微生物组中含有数万亿的细菌，是这些机制的关键调节器。 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） 与天然免疫肠细胞上表达的模式识别受体（PRR）相互作用以精细免疫 在稳定状态和患病条件下41 -44。最近，我们的研究小组证明，SlpA是 主要的抗炎Slp信号。SlpA与C型凝集素特异性细胞内粘附的结合 树突状细胞衬里上表达的非整合素同源物相关3（SIGNR 3）受体 肠道在多种模型中预防实验诱导的结肠炎15。通过L.乳酸菌（也 称为R-3750或R110）减少炎性细胞因子，加强粘膜屏障， 支持肠道炎症动物模型中更健康的微生物群构成64。值得注意的是， 在Signr 3-/-小鼠中未观察到SlpA介导的保护作用，表明SlpA与SIGNR 3的相互作用 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R-3750，一种表达SlpA的乳球菌（L.）乳酸菌菌株，作为一种新的，口服给药 作为免疫疗法的药物，以减轻肠道炎症，改善胃肠道粘膜屏障 功能，并恢复IBD患者的天然微生物组组成。L. lactis提供了两个关键优势， 用于将SlpA输送到肠道的递送载体：1）它已经安全地用于人类临床试验， 野生型和遗传操作的形式16，45 19和2）它不表达任何天然Slps，但可以是 被工程化以选择性地过表达SlpA。这个快速通道SBIR应用程序的重点是获得人类 通过完成首次人体I期概念验证临床试验，对R-3750进行验证。具体目标 是：1）准备并向FDA提交IND，2）完成胶囊生产以支持临床研究， 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）准备用于2期药物制造的GMP规模化生产工艺。