Immunoregulatory Therapeutics for Ulcerative Colitis

溃疡性结肠炎的免疫调节治疗

基本信息

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
项目类别：
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&apos 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

项目摘要

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疗法 Biotherapeutics，Inc（BTI）是一家新兴的生物技术公司，协同结合了其力量通过翻译实验的高级计算建模，以加速新型精确医学和健康的产品。炎症性肠病（IBD）是胃肠道的慢性炎症性疾病这遭受了200万美国人和全球超过500万人的困扰。当前的治疗剂不成功保持缓解，并与严重的副作用有关。 BTI最近发现了一种新型化学物质抑制IL-18的家族，IL-18，这是胃肠道上皮细胞产生的炎性细胞因子至激活产生IFNγ的Th1细胞的分化和炎症巨噬细胞的极化。我们的原型在DSS挑战之后，NCE显着降低了结肠椎板的结肠评分和Th1，在与拟议的IL-18阻滞机制一致的结肠炎的赞助MDR1A - / - 模型。这个项目将进一步表征IBD中IL-18信号的机制，并验证IL-18抑制的治疗效率体内和人类原代细胞。 SBIR I期应用程序的具体目的是： AIM 1。评估体外IL-18抑制剂的相对治疗效率。我们将评估 IL-18通过结合和功能分析抑制。 AIM 2。确定IBD小鼠模型中IL-18抑制的治疗潜力。我们将使用 CD45RBHI自适应转移和结肠炎的DSS模型，以表征对IL-18的体内剂量反应通过组织学，转录和免疫学分析。目标3。验证人类UC患者细胞对IL-18信号传导和抑制的反应。我们将检查健康和UC PBMC和LPMC对IL-18暴露和药物抑制的反应。预期的成功结果将包括：i）响应于IL-18的IFNγ产生≥50％之后体外治疗； ii）≥70％的结肠炎自适应转移和DSS模型中的组织学评分降低；和 III）IL-18抑制作用的人UC PBMC中IFNγ产生≥50％。 SBIR II期应用将确定IL-18的治疗效率中的暴露响应关系在慢性结肠炎模型中抑制，进行药代动力学（PK）和大鼠的安全研究，评估药物代谢和脱靶影响，并进一步验证IL-18作为人类UC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颖的免疫调节理论，更安全，更多有效治疗IBD，并为目标患者提供资产商业化的途径超过500万的人口未满足临床需求，而治疗市场不断增长160亿美元。