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）药物的可获得性不断增加，并且它们在治疗类风湿性关节炎、多发性硬化、哮喘、特应性皮炎和许多其他疾病中已被证明是成功的，但早期鉴定具有期望的可制造性、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。在相关浓度下表现为高粘度/乳光或相分离和稳定性问题的自缔合和不良溶液行为是mAb治疗剂开发的主要限制因素。溶液行为被认为是由蛋白质的自缔合，然而，这些协会的实验测量和预测的溶液行为是具有挑战性的使用目前的方法。本申请的目的是开发一种通用方法，该方法可直接测量相关条件下的蛋白质自缔合，并可预测药物开发和制剂中的重要属性。该提议是重要的，因为它增加了鉴定具有弱溶液行为和对聚集敏感性的候选物的潜力，这反过来可以导致开发急需的mAb治疗剂的效率提高。此外，在药物发现和开发的早期阶段具有可靠的预测方法将消除早期的、不必要的将有治疗前景的mAb候选药物从开发管道中移除的情况。

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.