Molecular Computations of Preferential Interaction Coefficients of IgG1 Monoclonal Antibodies with Sorbitol, Sucrose, and Trehalose and the Impact of These Excipients on Aggregation and Viscosity
Molecular Computations of Preferential Interaction Coefficients of IgG1 Monoclonal Antibodies with Sorbitol, Sucrose, and Trehalose and the Impact of These Excipients on Aggregation and Viscosity
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DOI：
10.1021/acs.molpharmaceut.9b00545
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Trout, Bernhardt L.
中科院分区：
文献类型：
--
作者：
Cloutier, Theresa;Sudrik, Chaitanya;Trout, Bernhardt L.
配方赋形剂的优先相互作用控制着它们与蛋白质分子的整体相互作用，分子动力学模拟可以在分子水平上检查相互作用。我们使用分子动力学模拟来检查山梨醇、蔗糖和海藻糖与三种不同 IgG1 抗体的相互作用，以深入了解这些赋形剂如何影响聚集和粘度。我们发现，与山梨醇相比，蔗糖和海藻糖比山梨醇更能减少聚集，因为与山梨醇相比，蔗糖和海藻糖的尺寸更大，并且与高空间聚集倾向残基的相互作用更强。其中两种抗体在乙酸钠缓冲液中具有高粘度，对于这些抗体，我们发现蔗糖和海藻糖往往对粘度具有相反的影响。这里提供的数据进一步深入了解这三种碳水化合物赋形剂与抗体表面的相互作用机制，以及它们对抗体制剂赋形剂稳定性的影响。
Preferential interactions of formulation excipients govern their overall interactions with protein molecules, and molecular dynamics simulations allow for the examination of the interactions at the molecular level. We used molecular dynamics simulations to examine the interactions of sorbitol, sucrose, and trehalose with three different IgG1 antibodies to gain insight into how these excipients impact aggregation and viscosity. We found that sucrose and trehalose reduce aggregation more than sorbitol because of their larger size and their stronger interactions with high-spatial aggregation propensity residues compared to sorbitol. Two of the antibodies had high viscosity in sodium acetate buffer, and for these, we found that sucrose and trehalose tended to have opposite effects on viscosity. The data presented here provide further insight into the mechanisms of interactions of these three carbohydrate excipients with the antibody surface and thus their impact on excipient stabilization of antibody formulations.