An L-Selectin Ligand Antibody for Therapy of Asthma

描述（由申请人提供）：本申请的目的是开发一种新型粘连阻断抗体，用于治疗慢性炎症性疾病，如哮喘和类风湿关节炎。目前的治疗方法包括类固醇或抑制炎症细胞因子。另一种方法是调节细胞粘附，这有望限制炎症细胞的募集，而不需要抗tnfalpha或类固醇治疗固有的免疫抑制。白细胞粘附是由选择素介导的。l -选择素结合到由单克隆IgM MECA-79定义的内皮配体上。MECA-79反应性血管见于哮喘患者和类风湿滑膜的支气管周围活检。MECA-79表位包括内皮粘蛋白上o -聚糖的sialyl-Lewisx型盖帽基团中n -乙酰氨基氨基的功能关键6- o -硫酸化。我们已经证明MECA-79治疗哮喘羊是有效的。因此，MECA-79表位是基于抗体的抗粘附治疗的一个有吸引力的靶标。在特异性目标中，将从噬菌体展示库中产生针对MECA-79表位的人源化单链抗体。目的2是获得阻断l -选择素结合的子集。目的3是进一步获得一组体外和体内阻断淋巴细胞粘附和迁移的抗体。在第二阶段，产生的抗体将在与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。

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.