Novel display system for antibody affinity maturation

用于抗体亲和力成熟的新型展示系统

• 批准号: 6882322
• 负责人: DAVID S WILSON
• 金额: $ 10万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882322
• 关键词: DNA binding protein; SDS polyacrylamide gel electrophoresis; antigen antibody reaction; antiviral antibody; biotechnology; enzyme linked immunosorbent assay; hybrid antibody; immunogenetics; immunoglobulin structure; monoclonal antibody; peptide library; point mutation; protein protein interaction; protein quantitation /detection; protein sequence; technology /technique development; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): The use of antibodies as therapeutic agents has gained increasing acceptance over the last several years, and there are currently 18 FDA-approved monoclonal antibody therapies. The main advantages of antibody-based therapy over traditional, small molecule approaches are: more rapid development times; lower toxicity; ability to disrupt protein-protein interactions. The success of this approach has been the development of methods for reducing the immunogenicity of antibodies administered to patients. Such methods generally rely on the ability to screen through large numbers of human or humanized antibody candidates. Display systems offer the most efficient mechanism for identifying rare, high affinity members of such antibody libraries. The effectiveness of currently available display systems (phage display, ribosome display, and yeast display), however, is limited by strong selection biases between library members that do not translate to improved antibody affinity. Such biases include differences in heavy and light chain expression levels and/or secretion efficiency, differences in stability/dimerization of scFv's, and differences from avidity effects. The object of this grant is to develop a novel display system that overcomes all of these biases and provides a robust and efficient method for identifying high affinity and specificity human or humanized antibodies against nearly any therapeutic target.

描述（由申请人提供）：在过去几年中，使用抗体作为治疗剂已获得越来越多的认可，目前 FDA 批准了 18 种单克隆抗体疗法。与传统的小分子方法相比，基于抗体的疗法的主要优点是： 开发时间更快；毒性较低；破坏蛋白质-蛋白质相互作用的能力。这种方法的成功在于开发了降低给予患者的抗体的免疫原性的方法。此类方法通常依赖于筛选大量人类或人源化候选抗体的能力。展示系统提供了识别此类抗体库中稀有、高亲和力成员的最有效机制。然而，目前可用的展示系统（噬菌体展示、核糖体展示和酵母展示）的有效性受到文库成员之间强烈选择偏差的限制，而这些偏差并不能转化为改进的抗体亲和力。此类偏差包括重链和轻链表达水平和/或分泌效率的差异、scFv稳定性/二聚化的差异以及亲合力效应的差异。该资助的目的是开发一种新颖的展示系统，克服所有这些偏差，并提供一种强大而有效的方法来识别针对几乎任何治疗靶点的高亲和力和特异性的人类或人源化抗体。