Assessment of self-association of monoclonal antibody molecules by analysis of the protein layer detected at the proximity of a solid surface

尽管单克隆抗体（mAb）药物的可用性越来越高，并且在治疗类风湿性关节炎、多发性硬化症、哮喘、特应性皮炎和许多其他疾病方面取得了成功，但早期鉴定具有理想可制造性、稳定性和递送特性的候选蛋白分子仍然是一个巨大的挑战。在相关浓度下表现为高粘度/乳白色，或在相分离和稳定性问题上表现为自关联和不良溶液行为，是单克隆抗体治疗药物发展的主要限制因素。溶液行为被认为是由蛋白质的自结合所控制的，然而，用现有的方法对这些自结合的实验测量和溶液行为的预测是具有挑战性的。本应用的目的是开发一种在相关条件下直接测量蛋白质自结合的通用方法，并预测药物开发和配方中的重要属性。这一建议意义重大，因为它增加了识别具有弱溶液行为和对聚集易感性的候选药物的潜力，这反过来又可以提高开发急需的单克隆抗体治疗药物的效率。此外，在药物发现和开发的早期阶段拥有可靠的预测方法，将消除开发管道中早期、无根据地移除治疗前景良好的单抗候选药物。

Despite the increasing availability of monoclonal antibody (mAb) drugs and their proven success in treatment of rheumatoid arthritis, multiple sclerosis, asthma, atopic dermatitis, and many other diseases, the early identification of the protein candidate molecules with desirable manufacturability, stability and delivery attributes remains a big challenge. Self-association and poor solution behavior, manifested in high viscosity/opalescence at relevant concentrations or in phase separation and stability issues, are major limiting factors in development of mAb therapeutics. Solution behavior is believed to be governed by protein self-association, however, measurement of these associations experimentally and prediction of the solution behavior are challenging using the current methods. The objective in this application is to develop a versatile method that directly measures the protein self-association under relevant conditions and is predictive of the important attributes in drug development and formulation. This proposal is significant because it increases the potential to identify the candidates with weak solution behavior and susceptibility to aggregation which, in turn, can lead to enhanced efficiency in development of much needed mAb therapeutics. In addition, having reliable predictive methods at the early stages of drug discovery and development would eliminate the early, unwarranted removal of therapeutically promising mAb drug candidates from development pipelines.