Novel Anti-inflammmatory Antibody Therapy for Inflammatory Bowel Disease

治疗炎症性肠病的新型抗炎抗体疗法

基本信息

批准号：
9202065
负责人：
SUSAN C WRIGHT
金额：
$ 22.47万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9202065
关键词：
Abdominal Pain Adverse event Affect American Amino Acids Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antibodies Antibody Therapy Appetite Regulation Attenuated Binding Biological Biological Response Modifier Therapy Biopsy Cells Characteristics Chronic Clinical Colectomy Colitis Colon Containment Crohn&apos s disease Data Development Disease Disease remission Drug Kinetics Enterocolitis Epithelial Cells Equilibrium Evaluation Event Exposure to Failure Feedback Fever Fibrosis Generations Goals Healed Health Care Costs Hemorrhagic colitis Hospitalization Human Immune Immune response Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Integrin alpha4 Interleukin-10 Interleukin-12 Intestines Knockout Mice Libraries Life Link Malaise Metabolism Minority Modeling Monoclonal Antibodies Mucous Membrane Non-Hodgkin&apos s Lymphoma Operative Surgical Procedures Oryctolagus cuniculus Pain Pathway interactions Patients Phage Display Pharmaceutical Preparations Pharmacologic Substance Phase Production Quality of life Receptor Gene Relapse Research Risk Rodent Model Role Signal Transduction Stimulus Sulfonic Acids Susceptibility Gene Symptoms T-Lymphocyte TNF gene Testing Therapeutic Time Tissues Toxic effect Trinitrobenzenes Ulcerative Colitis Up-Regulation Work abstracting base cytokine economic impact effective therapy efficacy testing genome wide association study healing human monoclonal antibodies immune activation in vitro testing in vivo loss of function mutation melanin-concentrating hormone melanin-concentrating hormone receptor melanoma monocyte novel novel therapeutics peptide hormone permanent cell line phase 2 study pre-clinical receptor

项目摘要

Abstract Inflammatory Bowel Disease (IBD), including primarily Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, debilitating condition with no effective treatment. The economic impact is disproportionally high because it affects primarily young individuals (10-40 years old), and the characteristic periods of remission and relapse necessitate frequent hospitalizations. Furthermore, some 20-30% of patients with total bowel involvement will have colectomy, and 70%-80% of patients with CD require some type of surgical intervention during their lifetime. Symptoms like bloody diarrhea, abdominal pain, general malaise, and fever significantly compromise quality of life. IBD affects 1.4 million Americans with annual healthcare costs approaching $2 billion. Current therapies (anti-inflammatory drugs, immunosuppressants, antibiotics, and drugs for symptomatic relief) are only modestly effective, and often cause unacceptable adverse events, particularly with long-term use. A new generation of biologics targets pathways of immune activation to block proinflammatory signaling. All seven biologics showing clinical benefits in IBD are monoclonal antibodies, including TNF-α, α4 integrin, and IL-12/23 blockers. Mucosal healing and long-term remission occur in only a minority of patients. Significantly, rare but life-threatening conditions, including increased risk for serious infections, non-Hodgkin's lymphoma, and melanoma, have been associated with chronic exposure to anti-TNFα. therapies The pharmaceutical management of IBD, despite the revolutionizing use of biological therapies, remains problematic. Recent data support the hypothesis that melanin-concentrating hormone (MCH) is a crucial link in inflammatory events affecting the mucosa. Results from four animal models support a pivotal role for MCH signaling in IBD. Both MCH and MCH receptor (MCHR1) expression levels are elevated in biopsies of inflamed mucosa from IBD patients relative to non-involved mucosa from the same patients. A polyclonal rabbit anti-MCH antibody attenuates chronic colitis and fibrosis in two animal models of colitis. Further supporting a role for MCH in IBD, MCH-knock-out mice are protected from experimental colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). During this Phase I project, we will identify and characterize a neutralizing anti-MCH human monoclonal antibody (humAb). Evaluation in both in vitro cellular and in vivo rodent models will be carried out. We are optimistic that this work will result in a new therapeutic for CD and UC. This biological therapy will reduce inflammation, fibrosis and prolong periods of remission among patients suffering from IBD.

抽象的炎症性肠病（IBD），主要包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种慢性、令人衰弱的疾病，没有有效的治疗方法，其经济影响非常高。因为它主要影响年轻人（10-40岁），并且缓解和缓解的特征期此外，约 20-30% 的患者患有全肠疾病。受累者将进行结肠切除术，70%-80% 的 CD 患者需要某种类型的手术干预在他们的一生中出现明显的症状，如血性腹泻、腹痛、全身不适和发烧。 IBD 影响着 140 万美国人的生活质量，每年的医疗费用接近 2 美元。目前的治疗方法（抗炎药、免疫抑制剂、抗生素和治疗药物）症状缓解）的效果有限，并且经常导致不可接受的不良事件，特别是新一代生物制剂针对免疫激活途径来阻断促炎症。对 IBD 具有临床益处的所有七种生物制剂均为单克隆抗体，包括 TNF-α、α4。整合素和 IL-12/23 阻滞剂仅少数患者出现粘膜愈合和长期缓解。值得注意的是，罕见但危及生命的疾病，包括严重感染、非霍奇金病的风险增加淋巴瘤和黑色素瘤与长期接触抗 TNFα 药物有关。尽管生物疗法的革命性使用，IBD 的药物管理仍然存在最近的数据支持黑色素浓缩激素 (MCH) 是一种至关重要的假设。四种动物模型的结果支持了影响粘膜的炎症事件的关键作用。 IBD 中的 MCH 信号传导在 IBD 活检中 MCH 和 MCH 受体 (MCHR1) 表达水平均升高。 IBD 相关患者的发炎粘膜与同一患者的未受累粘膜。抗 MCH 抗体可减轻两种结肠炎动物模型中的慢性结肠炎和纤维化。 MCH 在 IBD 中的作用，MCH 敲除小鼠可免受 2,4,6- 诱导的实验性结肠炎的影响在第一阶段项目中，我们将鉴定并表征三硝基苯磺酸（TNBS）。中和抗 MCH 人单克隆抗体 (humAb) 的体外细胞和体内评估。我们乐观地认为这项工作将产生一种新的 CD 治疗方法。这种生物疗法将减少炎症、纤维化并延长患者的缓解期。患有炎症性肠病。