An L-Selectin Ligand Antibody for Therapy of Asthma

描述(申请人提供)：本提案的目的是开发一种新的黏附阻断抗体，用于治疗哮喘和类风湿性关节炎等慢性炎症性疾病。目前的治疗方法包括类固醇或抑制炎性细胞因子。另一种方法是调节细胞黏附，预计这将限制炎性细胞的招募，而不会受到抗肿瘤坏死因子α或类固醇治疗固有的免疫抑制。白细胞黏附是由选择素介导的。L-选择素与单抗IgM MECA-79所定义的内皮细胞配体结合。在哮喘患者的支气管周围活检和类风湿滑膜中发现了MecA-79反应性血管。MECA-79表位包括功能上关键的N-乙酰氨基葡萄糖的6-O-硫化反应，所述N-乙酰氨基葡萄糖包含在内皮粘蛋白上的O-葡聚糖的唾液-刘易斯X型封端基团中。我们已经证明，MECA-79治疗对哮喘羊是有治疗作用的。因此，MECA-79表位是基于抗体的抗黏附治疗的一个有吸引力的靶点。在特定目的1中，将从噬菌体展示文库中产生针对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是获得另一组抗体，在体外和体内阻断淋巴细胞的黏附和迁移。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。如果有疗效，将开发一种临床铅。

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.