Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia.
Soft Matter. 2018 Jul 25;14(29):6001-6012. doi: 10.1039/c8sm00919h.
Protein aggregation is a field of increasing importance in the biopharmaceutical industry. Aggregated particles decrease the effectiveness of the drug and are associated with other risks, such as increased immunogenicity. This article explores the possibility of using the Smoluchowski coagulation equation and similar models in the prediction of aggregate-particle formation. Three different monoclonal antibodies, exhibiting different aggregation pathways, are analysed. Experimental data are complemented with aggregation dynamics calculated by a coagulation model. Different processes are implemented in the coagulation equation approach, needed to cover the actual phenomena observed in the aggregation of biopharmaceuticals, such as the initial conformational change of the native monomer and reversibility of smaller oligomers. When describing the formation of larger particles, the effect of different aggregation kernel parameters on the corresponding particle size distribution is studied. A significant impact of the aggregate fractal nature on overall particle size distribution is also analysed. More generally, this work is aimed to establish a mesoscopic phenomenological approach for characterisation of protein aggregation phenomena in the context of biopharmaceuticals, capable of covering various aggregate size scales from nanometres to micrometres and reach large time-scales, up to years, as needed for drug development.
蛋白质聚集是生物制药行业中日益重要的领域。聚集颗粒会降低药物的疗效，并与其他风险相关，如免疫原性增加。本文探讨了使用斯莫鲁霍夫斯基凝聚方程和类似模型预测聚集体形成的可能性。分析了三种表现出不同聚集途径的单克隆抗体。实验数据补充了凝聚模型计算的聚集动力学。在凝聚方程方法中实施了不同的过程，以涵盖生物制药聚集中观察到的实际现象，如天然单体的初始构象变化和较小寡聚物的可逆性。在描述较大颗粒的形成时，研究了不同聚集核参数对相应颗粒尺寸分布的影响。还分析了聚集分形性质对整体颗粒尺寸分布的显著影响。更一般地说，这项工作旨在建立一种介观唯象方法，用于在生物制药背景下描述蛋白质聚集现象，能够涵盖从纳米到微米的各种聚集尺寸范围，并达到数年的大时间尺度，如药物开发所需。
