药代动力学性质是影响成药性的最为关键因素之一，是早期成药性评价的重点。由于蛋白质类药物具有分子量大、结构复杂、稳定性差等特点，目前对蛋白质类大分子代谢性质的基础研究和分析手段都不能满足早期成药性评价的需求，导致缺少基于代谢特征的蛋白质类药物早期成药性评价体系，在很大程度上增加了其新药研制的风险。本项目拟对蛋白质分子体内清除机制的关键因素进行系统研究，解析酶水解代谢和受体介导清除这两类复杂的体内代谢过程，阐明关键控制因素；建立代谢特征体外评价方法，确立特征参数，构建蛋白质类药物代谢特征体外分析体系；研究蛋白质药物体内外代谢参数的相关性，建立体内药代动力学参数预测模型；最终建立基于体外代谢特征的蛋白质药物早期成药性评价体系并指导分子设计与改构。本课题的顺利完成将阐明控制蛋白质分子体内代谢的关键因素，建立完善的蛋白质类药物早期成药性评价体系，为蛋白质类药物研制提供理论基础和方法指导。

Pharmacokinetic property is one of the critical factors of druggability and the key point of early evaluation for druggability. Due to the high molecular weight, complicated structure and poor stability of the protein molecules, current research and analysis methods targeting the metabolism characters of protein drugs cannot meet the needs of early evaluation of druggability, which leads to a lack of early evaluation system for protein druggability based on metabolic characteristics and greatly increases the risk of new drugs discovery and development. This project aims to systematically study the key factors of protein elimination mechanism, analyze in vivo metabolism of protein through enzyme hydrolysis and receptor-mediated elimination and clarify the key controlling factors; it also aims at the establishment of in vitro evaluation methods for metabolism characteristics and in vitro analysis system for metabolic characteristics of protein drugs. In addition, this project also covers the study of the correlation of in vivo and in vitro metabolic parameters of protein drugs and the establishment of a mathematical prediction model of in vivo pharmacokinetics. Finally, the goal is to establish an early evaluation system of druggability of protein drugs based on their metabolic characteristics and guide drug design and optimization. This project would clarify the key factors controlling the in vivo metabolism of protein molecules, establish a completed early evaluation system for protein duggability, and provide both theoretical basis and methodological guidance for the research and development of protein drugs.