Characterisation of protein aggregation with the Smoluchowski coagulation approach for use in biopharmaceuticals,Soft Matter

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Characterisation of protein aggregation with the Smoluchowski coagulation approach for use in biopharmaceuticals
Soft Matter ( IF 2.9 ) Pub Date : 2018-07-04 00:00:00 , DOI: 10.1039/c8sm00919h
Mitja Zidar _{1,

2,

3,

4,

5} , Drago Kuzman _{5,

6,

7,

8,

9} , Miha Ravnik _{1,

2,

3,

4,

10}

Affiliation

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.

中文翻译：

用Smoluchowski混凝方法对生物制药中的蛋白质聚集进行表征

蛋白质聚集是生物制药行业中越来越重要的领域。聚集的颗粒降低了药物的效力，并与其他风险相关，例如免疫原性增加。本文探讨了使用Smoluchowski凝固方程和类似模型预测聚集体颗粒形成的可能性。分析了表现出不同聚集途径的三种不同的单克隆抗体。实验数据通过凝结模型计算得到的聚集动力学得到了补充。凝血方程方法采用了不同的过程，以覆盖生物药物聚集过程中观察到的实际现象，例如天然单体的初始构象变化和较小寡聚物的可逆性。当描述较大颗粒的形成时，研究了不同聚集核参数对相应粒径分布的影响。还分析了总分形性质对总体粒度分布的显着影响。更广泛地说，这项工作旨在建立一种介观的现象学方法来表征生物药物中的蛋白质聚集现象，该方法能够涵盖从纳米到微米的各种聚集体尺寸范围，并根据需要达到长达数年的大时间范围。药物开发。

更新日期：2018-07-04

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