Affinity Enhancement of a Humanized Anti-ICAM Antibody

描述（由申请人提供）：普通感冒是一种良性疾病， 也会导致儿童耳部感染，是儿童“袭击”的主要原因。 哮喘患者普通感冒感染有很大的经济影响，但 目前正在接受旨在缓解症状的OTC药物治疗。人类 鼻病毒引起70%的感冒，包括超过120种不同的血清型。 这种巨大的遗传多样性使得疫苗的开发几乎不可能。 然而，约90%的鼻病毒血清型与鼻上皮细胞结合， 表面受体ICAM- 1。我们已经开发了原型抗ICAM-1抗体 以高亲和力结合ICAM-1并防止ICAM-1表达的融合构建体 在细胞培养测定中鼻病毒感染。高亲和力（低Koff） 抗体是持久保护免受感染所必需的。这项建议 描述了一种体外增强抗体亲和力的新方法， 通过选择性的氨基酸替换。突变残基的选择是 对效率和成功至关重要。氨基酸残基发生突变 单独和一起产生E.基于coli的文库。图书馆是 使用设计用于选择特异性， 高亲和力（低Koff）结合。一旦核心抗体被亲和 增强后，它将用于生成融合结构，用于临床 评价 拟议商业应用：不可用

DESCRIPTION (provided by applicant): The common cold is a benign disease that also causes ear infections in children and is a leading cause of "attacks" in asthmatic patients. Common cold infections have a great economic impact but are currently treated by OTC remedies intended to alleviate symptoms. Human rhinoviruses cause 70 percent of colds and include >120 different serotypes. This large genetic diversity makes development of a vaccine near impossible. However, about 90 percent of rhinovirus serotypes bind to nasal epithelial cell surface receptor, ICAM- 1. We have developed prototype anti-ICAM-1 antibody fusion constructs that bind to ICAM-1 with high affinity and that prevent rhinovirus infection in cell culture assays. High affinity (low Koff) antibodies are essential for durable protection from infection. This proposal describes a novel method for in vitro affinity enhancement of the antibody through selective amino acid substitutions. The choice of residues to mutate is critical for efficiency and success. Amino acid residues are mutated individually and together to generate E. coli based libraries. Libraries are screened using an "off rate" screening method designed to select for specific, high affinity (low Koff) binding. Once the core antibody has been affinity enhanced, it will be used to generate fusion constructs for clinical evaluation. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE