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Machine Learning Models of Antibody-Excipient Preferential Interactions for Use in Computational Formulation Design.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-08-14 , DOI: 10.1021/acs.molpharmaceut.0c00629
Theresa K Cloutier 1 , Chaitanya Sudrik 1 , Neil Mody 2 , Hasige A Sathish 2 , Bernhardt L Trout 1
Affiliation  

Preferential interactions of formulation excipients govern their impact on the stability properties of proteins in solution. The ability to predict these interactions without the need to perform experiments would enable formulation design to begin early in the development of a new antibody therapeutic. With that in mind, we developed a feature set to numerically describe local regions of an antibody’s surface for use in machine learning applications. Then, we used these features to train machine learning models for local antibody–excipient preferential interactions for the excipients sorbitol, sucrose, trehalose, proline, arginine·HCl, and NaCl. Our models had accuracies of up to about 85%. We also used linear (elastic net) models to quantify the contribution of antibody surface features to the preferential interaction coefficients, finding that the carbohydrates and proline tend to have similar important features, while the interactions of arginine·HCl and NaCl are governed by charge features. We present several case studies demonstrating how these machine learning models could be used to predict experimental aggregation and viscosity behavior in solution. Finally, we propose an approach to computational formulation design wherein a panel of excipients may be considered while designing an antibody sequence.

中文翻译:

用于计算配方设计的抗体-辅料优先相互作用的机器学习模型。

制剂赋形剂的优先相互作用决定了它们对溶液中蛋白质稳定性特性的影响。无需进行实验即可预测这些相互作用的能力将使制剂设计能够在新的抗体治疗剂开发的早期开始。考虑到这一点,我们开发了一种功能集,以数字方式描述了用于机器学习应用程序的抗体表面的局部区域。然后,我们使用这些功能来训练机器学习模型,以了解赋形剂山梨糖醇,蔗糖,海藻糖,脯氨酸,精氨酸·HCl和NaCl的局部抗体-赋形剂优先相互作用。我们的模型的准确度高达约85%。我们还使用了线性(弹性网)模型来量化抗体表面特征对优先相互作用系数的贡献,发现碳水化合物和脯氨酸具有相似的重要特征,而精氨酸·HCl和NaCl的相互作用受电荷特征支配。我们目前进行了一些案例研究,展示了如何将这些机器学习模型用于预测溶液中的实验聚集和粘度行为。最后,我们提出了一种计算制剂设计的方法,其中在设计抗体序列时可以考虑一组赋形剂。
更新日期:2020-09-09
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