Oxidation and Deamidation of Monoclonal Antibody Products: Potential Impact on Stability, Biological Activity, and Efficacy
Oxidation and Deamidation of Monoclonal Antibody Products: Potential Impact on Stability, Biological Activity, and Efficacy
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DOI：
10.1016/j.xphs.2021.11.024
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发表时间：
2022-03-26
影响因子：
3.8
通讯作者：
Rathore, Anurag S.
中科院分区：
文献类型：
--
作者：
Gupta, Surbhi;Jiskoot, Wim;Rathore, Anurag S.
一般而言，治疗性蛋白质，特别是单克隆抗体（mAb）在人类健康中的作用是显著的，并且正在不断发展。大量的时间和资源首先投入到mAb产品开发，然后投入到产品的临床检查。在生产、加工、储存、处理和给药过程中可能发生物理和化学降解。治疗性蛋白质可经历各种化学降解过程，包括氧化、脱酰胺、异构化、水解、去糖基化、外消旋化、二硫键断裂和形成、美拉德反应和β-消除。氧化和脱酰胺是mAb最常见的化学降解过程，这可能导致物理性质的变化，如疏水性、电荷、二级或/和三级结构，并可能降低解折叠的热力学或动力学屏障。这可能使产品易于发生聚集和其他化学修饰，从而改变产品的结合亲和力、半衰期和功效。这篇综述总结了过去十年中关于氧化和脱酰胺作用对mAb产品稳定性、生物活性和功效的影响的主要发现。作用机制、影响因素、表征工具、临床影响和风险缓解策略已得到解决（C）2021年美国药学协会。爱思唯尔公司出版All rights reserved.
The role in human health of therapeutic proteins in general, and monoclonal antibodies (mAbs) in particular, has been significant and is continuously evolving. A considerable amount of time and resources are invested first in mAb product development and then in clinical examination of the product. Physical and chemical degradation can occur during manufacturing, processing, storage, handling, and administration. Therapeutic proteins may undergo various chemical degradation processes, including oxidation, deamidation, isomerization, hydrolysis, deglycosylation, racemization, disulfide bond breakage and formation, Maillard reaction, and beta-elimination. Oxidation and deamidation are the most common chemical degradation processes of mAbs, which may result in changes in physical properties, such as hydrophobicity, charge, secondary or/and tertiary structure, and may lower the thermodynamic or kinetic barrier to unfold. This may predispose the product to aggregation and other chemical modifications, which can alter the binding affinity, half-life, and efficacy of the product. This review summarizes major findings from the past decade on the impact of oxidation and deamidation on the stability, biological activity, and efficacy of mAb products. Mechanisms of action, influencing factors, characterization tools, clinical impact, and risk mitigation strategies have been addressed (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.