重组糖蛋白激素类药物的质量控制和评价关注点:糖基化修饰的“宏观”和“微观”异质性  

Quality control and evaluation concerns of recombinant glycoprotein hormones:"macro"and"micro"heterogeneity of glycosylation modifications

作　　者：李怡君 胡莹莹 韦薇 LI Yi-jun;HU Ying-ying;WEI Wei(Center for Drug Evaluation,National Medical Products Administration,Beijing 100076,China)

机构地区：[1]国家药品监督管理局药品审评中心,北京100076

出　　处：《中国新药杂志》2023年第24期2467-2476,共10页Chinese Journal of New Drugs

摘　　要：糖蛋白激素包括促卵泡激素、促黄体生成素、绒毛膜促性腺激素和促甲状腺激素,是由非共价结合的α亚基和β亚基组成的异源二聚体。糖基化复杂性和结构不均一性是糖蛋白激素类药物结构表征和质量控制的关注点。糖基化修饰位点、修饰类型、唾液酸含量与糖蛋白激素在机体的受体结合、信号转导、生物功能和清除速率密切相关。本文将梳理重组糖蛋白激素类药物的上市产品概况,解析该类药物糖基化修饰的“宏观”和“微观”复杂性,阐明结构异质性与生物功能的关系,梳理用于结构确证和糖链鉴定的分析技术,结合其质量控制难点提出研发路径和药学研究的相关考虑。Glycoprotein hormones,including follicle-stimulating hormone,luteinizing hormone,chorionic gonadotropin,and thyroid stimulating hormone,are heterodimers consisting of non-convalently boundαandβsubunits.Glycosylation complexity and structural heterogeneity are the focus of structural characterization and quality control of glycoprotein hormones.The modification sites,modification types,and sialic acid content of glycosylation are closely related to the receptor binding,signaling,biological function,and clearance rate of glycoprotein hormones in the body.In this paper,we summarize the marketed products of recombinant glycoprotein hormones,analyze the“macro”and"micro"complexity of glycosylation modification of these drugs,clarify the relationship between structural heterogeneity and biological function,sort out the analytical techniques used for structural confirmation and glycan chain identification,and put forward the relevant considerations of R&D pathway and CMC research based on their quality control difficulties.

关 键 词：糖蛋白激素 促卵泡激素 糖基化修饰 生物效力 质量控制 

分 类 号：R95[医药卫生—药学]