Mechanistic understanding of metal-catalyzed oxidation of polysorbate 80 and monoclonal antibody in biotherapeutic formulations

化学 聚山梨酯 组氨酸 氧化还原 动力学 单克隆抗体 水解 肺表面活性物质 生物化学 有机化学 氨基酸 抗体 量子力学 生物 物理 免疫学
作者
Fethi Bensaid,Camille Dagallier,Jean‐René Authelin,Héloïse Audat,Vasco Filipe,Christine Narradon,Pierre Guibal,Séverine Clavier,Pierre Wils
出处
期刊:International Journal of Pharmaceutics [Elsevier BV]
卷期号:615: 121496-121496 被引量:27
标识
DOI:10.1016/j.ijpharm.2022.121496
摘要

Surfactants are commonly used in biotherapeutic formulations to prevent the formation of aggregates and protect proteins from denaturation. Among them polysorbates are the most widely used. However, they are known to be prone to degradation, mainly via enzymatic hydrolysis and oxidation. In this study, the impact of different conditions and factors on the oxidation of polysorbate 80 (PS80) and of a monoclonal antibody (mAb) was evaluated. In particular, the role of different formulation components (e.g., mAb concentration, pH, buffer, surfactant grade, chelators) was investigated in the presence of iron as transition metal contaminant. The results of our studies demonstrated that PS80 oxidation was accelerated even in the presence of iron levels as low as 20 ppb. In addition, the results showed that the oxidation of a specific solvent-exposed mAb methionine increased with PS80 oxidation, in particular under accelerated stress conditions and that the oxidation phenomenon was hindered in absence of iron or after addition of EDTA. Our results showed that PS80 "all oleate" (PS80-AO) was more sensitive to oxidative degradation than PS80 "multi-compendial" (PS80-MC). Contrary to acetate and citrate buffers, the results showed that the kinetics of PS80 oxidation was pH-dependent in presence of histidine buffer. It was also demonstrated that, when increasing its concentration, the mAb exhibited a protective effect against metal catalyzed PS80 and methionine oxidation. Our systematic studies on the role of the formulation components and potential contaminants (i.e., iron) demonstrated the complexity of the oxidative mechanism and the importance of different competitive systems, including pro-oxidant factors (e.g., iron, pH, PS80 quality) and antioxidant factors (e.g., protein concentration, EDTA, citrate) that may occur in biologic formulations containing PS80.
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