Novel display system for antibody affinity maturation

描述（由申请人提供）：在过去几年中，抗体作为治疗剂的使用获得了越来越多的认可，目前有18种FDA批准的单克隆抗体疗法。与传统的小分子方法相比，基于抗体的治疗的主要优点是：更快的开发时间;更低的毒性;破坏蛋白质-蛋白质相互作用的能力。这种方法的成功是开发了用于降低施用于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或人源化抗体候选物的能力。展示系统提供了用于鉴定这种抗体文库的稀有、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的强选择偏倚的限制，所述强选择偏倚不转化为改善的抗体亲和力。这样的偏差包括重链和轻链表达水平和/或分泌效率的差异、scFv的稳定性/二聚化的差异以及来自亲合力效应的差异。该授权的目的是开发一种新的展示系统，该系统克服了所有这些偏差，并提供了一种用于鉴定针对几乎任何治疗靶标的高亲和力和特异性人或人源化抗体的稳健且有效的方法。

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.