Hmiel Laura K, Brorson Kurt A, Boyne Michael T
Center for Drug Evaluation and Research, Office of Testing and Research, Division of Pharmaceutical Analysis, United States Food and Drug Administration, Saint Louis, MO, 63110, USA.
Anal Bioanal Chem. 2015 Jan;407(1):79-94. doi: 10.1007/s00216-014-8108-x. Epub 2014 Sep 10.
The size, heterogeneity, and biological production process of protein therapeutics like monoclonal antibodies create unique challenges for their analysis and regulation compared with small molecules. Complete structural characterization of a molecule 1000-fold heavier than aspirin is no small feat. Biological post-translational modifications such as glycosylation further complicate their characterization and regulation. Even approved protein therapeutics are known to contain multiple structural variants in differing amounts. Structural modification occurs during production and storage as well as within patients after administration. Thus, the goals of manufacturers and regulators are to control and characterize this heterogeneity, not take on the impossible task of eliminating it. The aim of this review is to describe the structural heterogeneities known to occur with immunoglobulin G (IgG), note current detection and analytical strategies, establish their causes, and define their potential effects on the ultimate safety, purity, and potency of antibody therapeutics when known.
与小分子药物相比，单克隆抗体等蛋白质治疗药物的大小、异质性和生物生产过程给其分析和监管带来了独特的挑战。对一个比阿司匹林重1000倍的分子进行完整的结构表征绝非易事。糖基化等生物翻译后修饰进一步使其表征和监管复杂化。即使是已获批的蛋白质治疗药物也已知含有不同数量的多种结构变体。结构修饰在生产和储存过程中以及给药后在患者体内都会发生。因此，制造商和监管机构的目标是控制和表征这种异质性，而不是承担消除它这一不可能完成的任务。本综述的目的是描述已知与免疫球蛋白G（IgG）相关的结构异质性，介绍当前的检测和分析策略，确定其产生原因，并在已知的情况下定义其对抗体治疗药物最终安全性、纯度和效力的潜在影响。
