Immunoregulatory Therapeutics for Ulcerative Colitis

溃疡性结肠炎的免疫调节治疗

• 批准号: 10697464
• 负责人: Andrew Leber
• 金额: $ 35.61万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697464
• 关键词: ABCB1 gene; Acceleration; Address; Adoptive Transfer; Adverse effects; Affect; Aftercare; American; Binding; Biological Assay; Biological Response Modifier Therapy; Biotechnology; CD4 Positive T Lymphocytes; Cells; Chemicals; Chronic; Clinical; Clinical Trials; Colitis; Colon; Computer Models; Crohn' s disease; Development; Digestive System Disorders; Disease; Disease remission; Dose; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Family; Flow Cytometry; Foundations; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Genetic Transcription; Goals; Histologic; Histopathology; Human; IL18 gene; Immunology procedure; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injections; Interferon Type II; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-15; Interleukin-2; Intestinal Mucosa; Lamina Propria; Large Intestinal Mucosa; Lead; Link; Macrophage; Marketing; Measures; Medical; Medical Care Costs; Membrane; Mendelian randomization; Modeling; Mus; Oral; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Precision Health; Prevention; Production; Proliferating; Rattus; Role; Sampling; Signal Transduction; Small Business Innovation Research Grant; Specificity; Target Populations; Technology; Th1 Cells; Therapeutic; Treatment Efficacy; Ulcerative Colitis; United States; Up-Regulation; commercial application; commercialization; cytokine; design; dextran sulfate sodium induced colitis; drug metabolism; effective therapy; efficacy validation; immune modulating agents; immunoregulation; in vivo; indexing; inhibitor; interleukin-23; intestinal epithelium; meter; monocyte; mouse model; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient population; pharmacologic; precision medicine; prototype; public health relevance; receptor; response; safety study; scaffold; side effect; standard of care; success; therapeutic target; therapeutically effective; translational applications

Immunoregulatory Therapeutics for Ulcerative Colitis BioTherapeutics, Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. Inflammatory bowel disease (IBD) is a chronic and disabling inflammatory disease of the gastrointestinal tract that afflicts 2 million Americans and over 5 million people worldwide. Current therapeutics are unsuccessful in maintaining remission and have been linked to serious side effects. BTI recently uncovered a novel chemical family that inhibits IL-18, an inflammatory cytokine produced by epithelial cells of the gastrointestinal tract to activate differentiation of IFNγ-producing Th1 cells and polarization of inflammatory macrophages. Our prototype NCE significantly reduced colonic scores and Th1 in the colonic lamina propria after DSS challenge and in the spontaneous Mdr1a-/- model of colitis, consistent with the proposed IL-18-blocking mechanism. This project will further characterize mechanisms of IL-18 signaling in IBD and validate the therapeutic efficacy of IL-18 inhibition in vivo and in human primary cells. The Specific Aims for this SBIR Phase I application are to: AIM 1. Evaluate the relative therapeutic efficacy of IL-18 inhibitors in vitro. We will assess the potency of IL-18 inhibition through binding and functional assays. AIM 2. Determine the therapeutic potential of IL-18 inhibition in mouse models of IBD. We will use the CD45RBhi adoptive transfer and DSS models of colitis to characterize the in vivo dose response to IL-18 inhibition through histological, transcriptional and immunological assays. AIM 3. Validate the responsiveness of in human UC patient cells to IL-18 signaling and inhibition. We will examine responses of healthy and UC PBMCs and LPMCs to IL-18 exposure and pharmacological inhibition. Expected successful outcomes will include: i) ≥ 50% reduction of IFNγ production in response to IL-18 after treatment in vitro; ii) ≥ 70% reduction of histological scores in adoptive transfer and DSS models of colitis; and iii) ≥ 50% reduction in IFNγ production in human UC PBMCs with IL-18 inhibition. The SBIR Phase II application will determine exposure-response relationships in therapeutic efficacy of IL-18 inhibition in chronic colitis models, conduct pharmacokinetic (PK) and safety studies in rats, evaluate the drug metabolism and off-target effects, and further validate the role of IL-18 as a therapeutic target in human UC and Crohn’s disease (CD). The long-term goal of this project is to develop a novel immunomodulatory therapeutic that is safer and more effective for treating IBD and provide a path towards commercialization of an asset with a target patient population of over 5 million with unmet clinical needs and a growing therapeutic market of $16 billion.

溃疡性结肠炎的免疫调节治疗 BioTherapeutics，Inc（BTI）是一家新兴的生物技术公司，它协同结合了 先进的计算建模与平移实验，以加速开发新的 精准医疗和健康产品。 炎症性肠病（IBD）是一种慢性和致残性胃肠道炎性疾病 影响了200万美国人和全世界500多万人。目前的治疗方法不成功， 维持缓解并与严重的副作用有关。BTI最近发现了一种新的化学物质 IL-18是一个抑制IL-18的家族，IL-18是一种由胃肠道上皮细胞产生的炎性细胞因子， 激活产生IFNγ的Th 1细胞的分化和炎性巨噬细胞的极化。我们的原型 NCE显著降低了DSS激发后结肠固有层中的结肠评分和Th 1， 自发性Mdr 1a-/-结肠炎模型，与提出的IL-18阻断机制一致。该项目将 进一步表征IBD中IL-18信号传导的机制并验证IL-18抑制的治疗功效 在体内和在人原代细胞中。 SBIR第一阶段应用的具体目标是： AIM 1.体外评价IL-18抑制剂的相对疗效。我们将评估 通过结合和功能测定的IL-18抑制。 AIM 2.确定IL-18抑制在IBD小鼠模型中的治疗潜力。我们将使用 结肠炎的CD 45 RBhi过继转移和DSS模型，以表征对IL-18抑制的体内剂量反应 通过组织学、转录和免疫学分析。 AIM 3.检测人UC患者细胞对IL-18信号传导和抑制的反应性。我们 将检查健康和UC PBMC和LPMC对IL-18暴露和药理学抑制的反应。 预期的成功结果将包括：i）在治疗后，响应于IL-18的IFNγ产生减少≥ 50%， ii）在结肠炎的过继转移和DSS模型中组织学评分降低≥ 70%;和 iii）在IL-18抑制的情况下，人UC PBMC中IFNγ产生减少≥ 50%。 SBIR II期申请将确定IL-18治疗效果的确定-应答关系 在慢性结肠炎模型中进行抑制，在大鼠中进行药代动力学（PK）和安全性研究，评估药物 本发明的目的在于进一步验证IL-18作为人UC和UC-2中的治疗靶标的作用。 克罗恩病（CD）。 该项目的长期目标是开发一种新的免疫调节治疗药物， 并为目标患者提供资产商业化途径 人口超过500万，临床需求未得到满足，治疗市场不断增长，达到160亿美元。