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Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations

机译：基于IgG的疗法的N-联糖基化变异原理：药代动力学和功能性考虑

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The development of recombinant therapeutic proteins has been a major revolution in modern medicine. Therapeutic-based monoclonal antibodies (mAbs) are growing rapidly, providing a potential class of human pharmaceuticals that can improve the management of cancer, autoimmune diseases, and other conditions. Most mAbs are typically of the immunoglobulin G (IgG) subclass, and they are glycosylated at the conserved asparagine position 297 (Asn-297) in the CH2 domain of the Fc region. Post-translational modifications here account for the observed high heterogeneity of glycoforms that may or not impact the stability, pharmacokinetics (PK), efficacy, and immunogenicity of mAbs. These modifications are also critical for the Fc receptor binding, and consequently, key antibody effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, mAbs produced in non-human cells express oligosaccharides that are not normally found in serum IgGs might lead to immunogenicity issues when administered to patients. This review summarizes our understanding of the terminal sugar residues, such as mannose, sialic acids, fucose, or galactose, which influence therapeutic mAbs either positively or negatively in this regard. This review also discusses mannosylation, which has significant undesirable effects on the PK of glycoproteins, causing a decreased mAbs’ half-life. Moreover, terminal galactose residues can enhance CDC activities and Fc–C1q interactions, and core fucose can decrease ADCC and Fc–FcγRs binding. To optimize the therapeutic use of mAbs, glycoengineering strategies are used to reduce glyco-heterogeneity of mAbs, increase their safety profile, and improve the therapeutic efficacy of these important reagents.
机译：重组治疗性蛋白质的开发是现代医学的重大革命。基于治疗的单克隆抗体（mAb）迅速增长，提供了一类潜在的人类药物，可以改善癌症，自身免疫性疾病和其他疾病的管理。大多数mAb通常是免疫球蛋白G（IgG）的亚类，它们在Fc区CH2域的保守的天冬酰胺位置297（Asn-297）处被糖基化。这里的翻译后修饰解释了所观察到的糖型的高度异质性，该异质性可能会或不会影响mAb的稳定性，药代动力学（PK），功效和免疫原性。这些修饰对于Fc受体结合也至关重要，因此，关键的抗体效应子功能包括抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。此外，在非人细胞中产生的单克隆抗体表达通常在血清IgG中不存在的寡糖，当施用于患者时可能会导致免疫原性问题。这篇综述总结了我们对末端糖残基（如甘露糖，唾液酸，岩藻糖或半乳糖）的理解，这些残基在这方面对治疗性单克隆抗体有正面或负面影响。这篇综述还讨论了甘露糖基化作用，它对糖蛋白的PK具有明显的不良影响，导致单抗的半衰期缩短。此外，末端半乳糖残基可以增强CDC活性和Fc-C1q相互作用，核心岩藻糖可以降低ADCC和Fc-FcγRs的结合。为了优化mAb的治疗用途，糖工程技术用于降低mAb的糖异质性，增加其安全性并改善这些重要试剂的治疗功效。

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