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

尽管单抗(MAb)药物的可用性越来越高，并且它们已被证明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，但早期识别具有理想的可制造性、稳定性和递送属性的蛋白质候选分子仍然是一个巨大的挑战。自缔合和不良的溶液行为，表现为相应浓度下的高粘度/乳浊度，或相分离和稳定性问题，是mAb疗法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支配的，然而，使用目前的方法在实验上测量这些结合并预测溶液行为是具有挑战性的。这一应用的目的是开发一种通用的方法，在相关条件下直接测量蛋白质的自结合，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聚集敏感性的候选对象的可能性，这反过来可以提高开发急需的单抗治疗药物的效率。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早期、不必要地从开发管道中移除具有治疗前景的mAb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.