Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
J Immunol Res. 2016;2016:5358272. doi: 10.1155/2016/5358272. Epub 2016 Apr 14.
Whilst the amino acid sequence of a protein is determined by its gene sequence, the final structure and function are determined by posttranslational modifications (PTMs), including quality control (QC) in the endoplasmic reticulum (ER) and during passage through the Golgi apparatus. These processes are species and cell specific and challenge the biopharmaceutical industry when developing a production platform for the generation of recombinant biologic therapeutics. Proteins and glycoproteins are also subject to chemical modifications (CMs) both in vivo and in vitro. The individual is naturally tolerant to molecular forms of self-molecules but nonself variants can provoke an immune response with the generation of anti-drug antibodies (ADA); aggregated forms can exhibit enhanced immunogenicity and QC procedures are developed to avoid or remove them. Monoclonal antibody therapeutics (mAbs) are a special case because their purpose is to bind the target, with the formation of immune complexes (ICs), a particular form of aggregate. Such ICs may be removed by phagocytic cells that have antigen presenting capacity. These considerations may frustrate the possibility of ameliorating the immunogenicity of mAbs by rigorous exclusion of aggregates from drug product. Alternate strategies for inducing immunosuppression or tolerance are discussed.
虽然蛋白质的氨基酸序列由其基因序列决定，但最终的结构和功能取决于翻译后修饰（PTMs），包括内质网（ER）中的质量控制（QC）和通过高尔基体的过程。这些过程具有物种和细胞特异性，在开发用于生成重组生物治疗药物的生产平台时，给生物制药行业带来了挑战。蛋白质和糖蛋白也会在体内和体外发生化学修饰（CMs）。个体对自身分子形式具有天然的耐受性，但非自身变体可能会引发免疫反应，产生抗药物抗体（ADA）；聚集形式可能表现出增强的免疫原性，因此开发了 QC 程序来避免或去除它们。单克隆抗体治疗药物（mAbs）是一个特殊情况，因为它们的目的是与靶标结合，形成免疫复合物（ICs），这是一种特殊的聚集形式。具有抗原呈递能力的吞噬细胞可能会清除这些 ICs。这些考虑因素可能会阻碍通过严格排除药物产品中的聚集物来改善 mAbs 的免疫原性的可能性。还讨论了诱导免疫抑制或耐受的替代策略。
