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 该项目的目的是开发一种新型的免疫学指导的实时生物治疗产品（LBP） 利用自然微生物组途径抑制肠道炎症过程来治疗炎症 肠病（IBD）。在美国，超过300万成年人患有IBD，一个雨伞，包括两个 胃肠道的慢性炎症疾病：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三十年中被诊断出来，是终身的，没有治愈方法。当前的IBD 治疗可能会有严重的副作用，并且患者难治性。安全且安全的疗法 有效，尤其是恢复肠膜屏障，需要改变生活。 肠道免疫调节信号严格控制健康的肠稳态，它们的崩溃可能导致 IBD39。人类微生物组含有数万亿个细菌，是这些机制的关键调节剂。 共生细菌的功能可维持肠上皮屏障完整性并调节先天和适应性 免疫细胞功能40。表面层蛋白（SLP），包括SLPA，SLPB，SLPX和Lipoteichoic Acid（LTA） 与在先天免疫肠细胞上表达的模式识别受体（PRR）相互作用 在稳定状态和患病条件下41-44。最近，我们的研究小组表明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结合 分子-3抓住非整合素同源物相关的3（SIGNR3）受体，在树突状细胞衬里表达 肠道可防止多种型号的实验诱导结肠炎15。通过乳酸乳杆菌口服SLPA（也是 称为R-3750或R110）降低炎症细胞因子，增强粘膜膜屏障，并 在肠道注射动物模型中支持了更健康的微生物构成64。值得注意的是，效果和 在SIGRR3 - / - 小鼠中未观察到由SLPA介导的保护，这表明SLPA与SIGNR3的相互作用 在调查疾病状况中起着关键的保护作用15。 我们的目标是开发R-3750，这是一种表达SLPA的乳酸（L.）乳酸菌株，作为一种新型，口服的口服 用作免疫治疗可减少肠道注射，改善胃肠道粘膜屏障的药物 功能，并恢复IBD患者的天然微生物组化妆。 Lactis提供了两个关键优势 将SLPA运送到肠道的送货工具：1）它已经安全地用于人类的临床试验中 野生型和一般操纵的形式16，45 19和2）它不表达任何本地SLP，但可以是 设计为有选择性过表达SLPA。此快速轨道SBIR应用的重点是获得人类 通过完成第一阶段1期概念验证临床试验，对R-3750的验证。具体目标 是：1）准备和提交IND与FDA，2）完整的胶囊制造以支持临床研究， 3）执行第1期临床试验，4）分析来自患者关键药效反应的样本 和临床生物标志物以及5）为2期药物制造准备GMP缩放生产过程。