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

• 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
• 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' 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' 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

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），包括原发性克罗恩病（CD）和溃疡性结肠炎（UC）是 慢性，令人衰弱的状况，没有有效的治疗。经济影响过高 因为它影响了年轻人（10-40岁），以及可缓解的特征时期 复发经常住院。此外，大约20-30％的肠患者 参与将进行集体术，并且有70％-80％的CD患者需要某种类型的手术干预 在他们的一生中。诸如血腥腹泻，腹痛，全身不适和发烧等症状 妥协的生活质量。 IBD影响140万美国人，年度医疗保健费用接近2美元 十亿。当前疗法（抗炎药，免疫抑制剂，抗生素和药物 症状缓解）仅是适度的有效，并且通常会引起不可接受的广告事件，尤其是在 长期使用。新一代的生物制剂靶向免疫激活的途径来阻止促炎 信号。所有七种在IBD中均显示出临床益处的生物制剂都是单克隆抗体，包括TNF-α，α4 整合素和IL-12/23阻滞剂。粘膜愈合和长期缓解仅发生在少数患者中。 值得注意的是，罕见但威胁生命的疾病，包括严重感染的风险增加，非霍奇金 淋巴瘤和黑色素瘤与慢性暴露于抗TNFα有关。治疗 IBD的药物管理，使命，革命性地使用生物疗法，仍然存在 有问题的。最近的数据支持了黑色素浓缩马酮（MCH）是至关重要的假设 影响粘膜的炎症事件的联系。四种动物模型的结果支持关键作用 MCH信号在IBD中。在活检中，MCH和MCH受体（MCHR1）表达水平均升高 相对于同一患者的非涉及粘膜，IBD患者的粘膜发炎。多克隆兔子 抗MCH抗体在两种动物结肠炎模型中减弱了慢性结肠炎和纤维化。进一步支持a MCH在IBD中的作用，MCH敲出小鼠受到2,4,6-诱导的实验性结肠炎的保护 三硝基苯磺酸（TNB）。在这个阶段我的项目中，我们将确定并表征 中和抗MCH人单克隆抗体（Humab）。在体外和体内评估 啮齿动物模型将进行。我们很乐观，这项工作将为CD和 UC。这种生物疗法将减少患者之间的炎症，纤维化和缓解延长 患有IBD。