DRUG DESIGN FOR TREATMENT OF INFLAMMATORY BOWEL DISEASE

治疗炎症性肠病的药物设计

• 批准号: 2545709
• 负责人: MICHAEL J BRISKIN
• 金额: $ 50.79万
• 依托单位: LEUKOSITE, INC.
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-15 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2545709
• 关键词: antibody specificity; antiinflammatory agents; cell adhesion; cell adhesion molecules; complement; drug design /synthesis /production; gastrointestinal disorder chemotherapy; human tissue; immunoglobulin genes; immunotherapy; inflammatory bowel diseases; inhibitor /antagonist; integrins; laboratory mouse; lymphocyte; molecular cloning; monoclonal antibody; peptide chemical synthesis; tissue /cell culture; transfection

Excessive infiltration of lymphocytes has been implicated in the pathogenesis of several inflammatory conditions, including inflammatory bowel disease (IBD). The mucosal vascular addressin, MAdCAM-1 is a tissue specific endothelial adhesion receptor selectively expressed in mucosal lymphoid tissues including Peyer's patches and in the lamina propria. Cell adhesion assays and in vivo homing experiments have shown that the alpha 4 beta 7 integrin, expressed on both B and T cell subsets, defines a mucosal homing receptor which preferentially interacts with MAdCAM-1. We have now demonstrated effective inhibition of recruitment of alpha 4 beta 7 positive lymphocytes to inflammatory sites in murine models of IBD and attenuation of symptoms by treatment with an anti-alpha 4 beta 7 monoclonal antibody in a primate model of colitis. As a major step in developing a first generation drug for IBD, we will humanize and test this antibody for affinity and specificity. In addition, a high throughput drug screen was developed and employed to identify small molecule inhibitors of alpha 4 beta 7 binding to MAdCAM-1. We will continue to develop the best leads into specific, orally active, high affinity inhibitors that will be tested in our murine IBD models. This proposal will therefore lay the foundation for a new class of anti-inflammatory drugs. PROPOSED COMMERCIAL APPLICATION: Humanization of an efficacious monoclonal antibody and development of small molecule inhibitors of alpha 4 beta 7 binding to MAdCAM-1 will be a major step in the evolution of a new class of drugs to treat inflammatory bowel disease.

淋巴细胞的过度浸润与 几种炎性疾病的发病机制，包括炎性 肠道疾病（IBD）。粘膜血管地址素MAdCAM-1是一种组织 选择性表达的特异性内皮细胞粘附受体 淋巴组织，包括派尔集合淋巴结和固有层。细胞 粘附测定和体内归巢实验表明，α 4 在B和T细胞亚群上表达的β 7整联蛋白定义了一种粘膜 优先与MAdCAM-1相互作用的归巢受体。 我们现在已经 证明了对α 4 β 7募集的有效抑制 IBD小鼠模型中炎症部位的阳性淋巴细胞， 通过抗α 4 β 7治疗减轻症状 单克隆抗体在灵长类动物结肠炎模型中的作用。作为一个重要步骤， 开发第一代IBD药物，我们将人性化并测试它， 抗体的亲和力和特异性。此外，高通量药物 筛选被开发并用于鉴定小分子抑制剂， α 4 β 7与MAdCAM-1的结合。我们将继续开发最好的 导致特定的，口服活性，高亲和力抑制剂， 在我们的小鼠IBD模型中进行了测试。因此，这项建议将奠定 一种新型抗炎药的基础。 拟定商业应用：有效单克隆抗体的人源化 抗体和α 4 β 7小分子抑制剂的开发 与MAdCAM-1的结合将是一个新类别进化的重要一步 治疗炎症性肠病的药物。