Novel Anti-inflammmatory Antibody Therapy for Inflammatory Bowel Disease

摘要 炎症性肠病（IBD），主要包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种常见的肠道疾病。 慢性的，使人虚弱的疾病，没有有效的治疗方法。对经济的影响非常大 因为它主要影响年轻人（10-40岁），以及缓解和 复发需要经常住院。此外，约20-30%的全肠患者 结肠癌患者需要行结肠切除术，70%-80%的CD患者需要某种类型的手术干预 在他们的一生中。症状如带血腹泻、腹痛、全身不适、发热明显 危及生活质量。IBD影响了140万美国人，每年的医疗费用接近2美元 亿目前的治疗方法（抗炎药、免疫抑制剂、抗生素和 症状缓解）效果有限，并且经常导致不可接受的不良事件，特别是在 长期使用。新一代生物制剂靶向免疫激活途径以阻断促炎性反应 发信号。在IBD中显示临床获益的所有7种生物制剂均为单克隆抗体，包括TNF-α、α4 整合素和IL-12/23阻断剂。只有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，包括严重感染的风险增加，非霍奇金淋巴瘤， 淋巴瘤和黑色素瘤与长期暴露于抗TNF α相关。治疗The IBD的药物管理，尽管生物疗法的革命性使用， 有问题最近的数据支持这一假设，即黑色素浓集激素（MCH）是一个至关重要的 与影响粘膜的炎症事件有关。来自四种动物模型的结果支持以下关键作用： IBD中的MCH信号传导。MCH和MCH受体（MCHR 1）的表达水平在乳腺癌活检组织中均升高。 来自IBD患者的发炎粘膜相对于来自相同患者的未受累粘膜。多克隆兔 抗MCH抗体在两种结肠炎动物模型中减弱慢性结肠炎和纤维化。进一步支持 MCH在IBD中的作用，MCH基因敲除小鼠受到保护，免受2，4，6- 三硝基苯磺酸（TNBS）。在第一阶段项目中，我们将确定和描述 中和抗MCH人单克隆抗体（humAb）。体外细胞和体内评价 将进行啮齿动物模型试验。我们乐观地认为，这项工作将产生一种新的CD治疗方法， 加州大学这种生物疗法将减少炎症，纤维化和延长患者的缓解期 患有IBD。

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.