Vlasak J, Ionescu R
Biologics and Vaccines PR&D, MRL, Merck & Co. Inc., West Point, PA 19486, USA.
Curr Pharm Biotechnol. 2008 Dec;9(6):468-81. doi: 10.2174/138920108786786402.
The expanding field of monoclonal antibody-based pharmaceuticals has triggered increased interest in analytical characterization of these large proteins and in understanding of their heterogeneity and degradation pathways. As a result, a large number of enzymatic modifications as well as chemical and physical degradations have been reported in monoclonal antibodies in recent years. Most heterogeneity is related to changes in the surface charge of the antibody, either directly, as a change in the number of charged residues, or indirectly as a chemical or physical alteration that changes surface-charge distribution. This review presents an overview of the sources of charge-related heterogeneity in monoclonal antibodies and the methods used for their detection. A detailed section is dedicated to deamidation of asparagine and isomerization of aspartic acid residues, two ubiquitous degradation pathways detected in antibodies and other proteins as well. Finally, kinetic modeling of the accumulation of antibody variants is presented as a tool to determine the expected fraction of molecules that have undergone one or more degradation reactions.
基于单克隆抗体的药物领域不断拓展，引发了人们对这些大蛋白的分析表征以及对其异质性和降解途径理解的更大兴趣。因此，近年来在单克隆抗体中报道了大量的酶促修饰以及化学和物理降解。大多数异质性与抗体表面电荷的变化有关，要么直接表现为带电残基数量的变化，要么间接表现为改变表面电荷分布的化学或物理改变。本综述概述了单克隆抗体中与电荷相关的异质性来源及其检测方法。其中一个详细部分专门介绍了天冬酰胺的脱酰胺作用和天冬氨酸残基的异构化，这是在抗体及其他蛋白质中均检测到的两种普遍存在的降解途径。最后，介绍了抗体变体积累的动力学模型，作为一种确定经历了一次或多次降解反应的分子预期比例的工具。
