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 没有有效治疗的慢性衰弱状态。对经济的影响高得不成比例 因为它主要影响年轻人(10-40岁)，以及典型的缓解期和 复发需要频繁住院治疗。此外，约20%-30%的全肠道患者 累及大肠需要切除结肠，70%-80%的CD患者需要某种类型的手术干预 在他们有生之年。症状如血性腹泻、腹痛、全身不适和明显发烧 折衷生活质量。IBD影响着140万美国人，每年的医疗费用接近2美元 十亿美元。目前的治疗方法(抗炎药物、免疫抑制剂、抗生素和治疗 症状缓解)仅适度有效，并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作用 发信号。所有七种显示临床疗效的生物制剂都是单抗，包括肿瘤坏死因子-α，α4。 整合素和IL-12/23阻滞剂。粘膜愈合和长期缓解只发生在少数患者中。 值得注意的是，罕见但危及生命的情况，包括严重感染的风险增加，非霍奇金氏 淋巴瘤和黑色素瘤与长期接触抗肿瘤坏死因子α有关。治疗方法 IBD的药物管理，尽管使用了革命性的生物疗法，但仍然 这是个问题。最近的数据支持这一假设，即黑色素浓缩激素(MCH)是至关重要的 在影响粘膜的炎症事件中有联系。来自四个动物模型的结果支持了 IBD中的MCH信号转导。乳腺癌组织中MCH及其受体(MCHR1)的表达水平均升高 炎症性肠病患者的炎性黏膜相对于同一患者的非受累黏膜。一只多克隆兔 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。进一步支持 MCH在IBD中的作用MCH基因敲除小鼠对2，4，6-氨基丁酸诱导的实验性结肠炎的保护作用 三硝基苯磺酸(TNBS)。在此第一阶段项目中，我们将确定和描述 中和抗MCH人源性单抗(HumAb)。体外细胞和体内评价 开展啮齿动物模型研究。我们乐观地认为，这项工作将产生一种新的CD和 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.