构建“mAb物理药剂学分类系统”以指导mAb制剂的合理和高效设计

Monoclonal antibody (mAb) is the most rapidly emerging class of drug molecules. However, due to its vastly different molecular structure and dosage form compared with small molecules, as well as the absence of in-depth understanding in protein pharmaceutics field, a theoretical framework to guide the druggability assessment and rational formulation design of mAbs is not yet available. In this study, we will carry out point mutations on the CDR region of adalimumab（Humira）to produce a series of model mAbs with different protein structure and surface properties. The unfolding free energy of these mAbs (deltaG) will be determined, and the boundary of high/low mAb concentration and high/low mAb temperature will be defined based on the change of deltaG over mAb concentration and temperature (d(deltaG)/dC and d(deltaG)/dT)). By investigating the stability behaviors of different mAbs under various C/T conditions, we will identify and define “key structure factors” of mAbs and establish a “mAb physical pharmaceutics classification system”. Based on this classification, we will study the impact of various excipients on the stability of different classes of mAbs and conclude the formulation design guideline for different mAbs. The successful accomplishment of this research is expected to transfer mAb formulation design from “trial-and-error” to “rational design”, and will certainly have profound impact on mAb drug development.

单抗（mAb）是当今发展最迅速的一类药物。由于mAb和小分子在结构和制剂方式方面的巨大差异，以及mAb制剂理论研究的滞后，目前尚无理论体系可指导mAb的成药性评估和制剂设计。我们将对adalimumab（Humira）CDR区域进行定点突变，建立一系列具有不同蛋白结构和表面性质的模型mAb。我们将测定mAb的变性自由能deltaG，并根据deltaG随蛋白浓度、溶液温度的变化趋势，定义和区分不同mAb的高/低浓度和高/低温度界限。根据各mAb在不同条件下的溶液行为，我们将归纳其“关键结构因子”，并依此构建“mAb物理药剂学分类系统”。通过研究deltaG随辅料浓度的变化，及mAb的结构表征，我们将探索不同辅料对不同mAb的作用效果和机制，归纳mAb的制剂设计指导原则。成功实施这一研究将实现mAb的制剂研究从“筛选试错”向“合理设计”的转变，对mAb药物的开发无疑将产生深远影响。