An L-Selectin Ligand Antibody for Therapy of Asthma

用于治疗哮喘的 L-选择素配体抗体

• 批准号: 6549530
• 负责人: STEFAN HEMMERICH
• 金额: $ 9.95万
• 依托单位: THIOS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2003-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549530
• 关键词: adhesions; antiinflammatory agents; asthma; biotechnology; biotherapeutic agent; clinical research; human tissue; immunologic substance development /preparation; ligands; monoclonal antibody; peptide library; respiratory pharmacology; rheumatoid arthritis; selectins; sheep

DESCRIPTION (provided by applicant): Objective of this proposal is to develop a novel adhesion-blocking antibody for therapy of chronic inflammatory diseases like asthma and rheumatoid arthritis. Current treatments involve steroids or inhibition of inflammatory cytokines. An alternative approach is modulation of cell adhesion that is expected to limit inflammatory cell recruitment without immunosuppression inherent to anti-TNFalpha or steroid therapy. Leukocyte adhesion is mediated by the selectins. L-selectin binds to endothelial ligands defined by the monoclonal IgM MECA-79. MECA-79 reactive vessels are found in peri-bronchial biopsies from asthmatics and in rheumatoid synovium. The MECA-79 epitope includes a functionally critical 6-O-sulfation of N-acetylglucosamine contained within sialyl-Lewisx type capping groups of O-glycans on endothelial mucins. We have shown that MECA-79 treatment is therapeutic in asthmatic sheep. The MECA-79 epitope is therefore an attractive target for antibody-based anti-adhesive therapy. In specific aim 1 humanized single-chain antibodies specific to the MECA-79 epitope will be generated from phage display libraries. Aim 2 is to obtain a subset that blocks L-selectin binding. Aim 3 is to obtain a further set of antibodies that block lymphocyte adhesion and migration in-vitro and in-vivo. In phase II, resulting antibodies will be tested in disease-relevant animal models. Provided efficacy, a clinical lead will be developed.

描述（由申请人提供）：本提案的目的是开发一种新型粘连阻断抗体，用于治疗哮喘和类风湿关节炎等慢性炎症性疾病。 目前的治疗涉及类固醇或抑制炎症细胞因子。 另一种方法是调节细胞粘附，预计可以限制炎症细胞的募集，而无需抗 TNFα 或类固醇疗法固有的免疫抑制。 白细胞粘附是由选择素介导的。 L-选择素与单克隆 IgM MECA-79 定义的内皮配体结合。 MECA-79 反应性血管存在于哮喘患者的支气管周围活检和类风湿滑膜中。 MECA-79 表位包括内皮粘蛋白上 O-聚糖的唾液酸-Lewisx 型封端基团中所含的 N-乙酰氨基葡萄糖的功能关键的 6-O-硫酸化。 我们已经证明 MECA-79 治疗对患有哮喘的绵羊有治疗作用。 因此，MECA-79 表位是基于抗体的抗粘连疗法的一个有吸引力的靶标。 具体目标 1 将从噬菌体展示文库中产生特异于 MECA-79 表位的人源化单链抗体。 目标 2 是获得阻止 L-选择素结合的子集。目标 3 是获得另一组在体外和体内阻断淋巴细胞粘附和迁移的抗体。在第二阶段，产生的抗体将在疾病相关的动物模型中进行测试。 如果有效，将开发临床先导药物。