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Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity.
mAbs ( IF 5.6 ) Pub Date : 2020-09-17 , DOI: 10.1080/19420862.2020.1816312
Theresa K Cloutier 1 , Chaitanya Sudrik 1 , Neil Mody 2 , Sathish A Hasige 2 , Bernhardt L Trout 1
Affiliation  

Preferential interactions of excipients with the antibody surface govern their effect on the stability of antibodies in solution. We probed the preferential interactions of proline, arginine.HCl (Arg.HCl), and NaCl with three therapeutically relevant IgG1 antibodies via experiment and simulation. With simulations, we examined how excipients interacted with different types of surface patches in the variable region (Fv). For example, proline interacted most strongly with aromatic surfaces, Arg.HCl was included near negative residues, and NaCl was excluded from negative residues and certain hydrophobic regions. The differences in interaction of different excipients with the same surface patch on an antibody may be responsible for variations in the antibody's aggregation, viscosity, and self-association behaviors in each excipient. Proline reduced self-association for all three antibodies and reduced aggregation for the antibody with an association-limited aggregation mechanism. The effects of Arg.HCl and NaCl on aggregation and viscosity were highly dependent on the surface charge distribution and the extent of exclusion from highly hydrophobic patches. At pH 5.5, both tended to increase the aggregation of an antibody with a strongly positive charge on the Fv, while only NaCl reduced the aggregation of the antibody with a large negative charge patch on the Fv. Arg.HCl reduced the viscosities of antibodies with either a hydrophobicity-driven mechanism or a charge-driven mechanism. Analysis of this data presents a framework for understanding how amino acid and ionic excipients interact with different protein surfaces, and how these interactions translate to the observed stability behavior.



中文翻译:

脯氨酸、精氨酸 HCl 和 NaCl 与 IgG1 抗体的优先相互作用的分子计算及其对聚集和粘度的影响。

赋形剂与抗体表面的优先相互作用决定了它们对溶液中抗体稳定性的影响。我们通过实验和模拟探讨了脯氨酸、精氨酸.HCl (Arg.HCl) 和 NaCl 与三种治疗相关的 IgG1 抗体的优先相互作用。通过模拟,我们研究了赋形剂如何与可变区 (Fv) 中不同类型的表面贴剂相互作用。例如,脯氨酸与芳香族表面的相互作用最强,Arg.HCl 包含在负残基附近,而 NaCl 被排除在负残基和某些疏水区域之外。不同赋形剂与抗体上相同表面贴剂之间相互作用的差异可能是导致每种赋形剂中抗体聚集、粘度和自缔合行为发生变化的原因。脯氨酸减少了所有三种抗体的自结合,并减少了抗体的聚集,具有结合限制的聚集机制。Arg.HCl 和 NaCl 对聚集和粘度的影响高度依赖于表面电荷分布和高度疏水性斑块的排斥程度。在 pH 5.5 时,两者都倾向于增加 Fv 上带有强正电荷的抗体的聚集,而只有 NaCl 减少了 Fv 上带有大负电荷贴片的抗体的聚集。Arg.HCl 通过疏水性驱动机制或电荷驱动机制降低抗体的粘度。对这些数据的分析提供了一个框架,用于了解氨基酸和离子赋形剂如何与不同的蛋白质表面相互作用,

更新日期:2020-09-18
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