基于规则的减轻电荷不对称触发的单克隆抗体自我组装
Inna Brakti1, Anette Henriksen2, Maria Łucja Tomczak3
1Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark 2100; Biophysical Analysis, CMC Analytical Support, Novo Nordisk A/S, Måløv, Denmark 2760.
Journal of pharmaceutical sciences
|February 21, 2026
概括
单克隆抗体 (mAb) 自组合与整个分子的电荷分布有关,而不仅仅是变量区域. 了解电荷不对称有助于防止在配方中不必要的抗体聚合.
科学领域:
- 生物制药开发 生物制药开发
- 蛋白质化学 蛋白质化学
- 配方科学科学 配方科学
背景情况:
- 单克隆抗体 (mAbs) 的非特异性自我组装是生物制药开发中的一个关键挑战.
- 目前的分析通常集中在变量区域,可能会忽视常量区域对聚合的贡献.
- 了解全长mAb电荷分布对于预测和控制自组装至关重要.
研究的目的:
- 调查整个mAb表面电荷不对称性及其自我组装倾向之间的关系.
- 确定电荷分布如何影响蛋白质-蛋白质相互作用和次可见粒子形成.
- 为合理的配方设计提供基础,以防止不必要的mAb聚合.
主要方法:
- 选择3个mAbs,具有不同的电荷不对称性.
- 使用小角度X射线散射 (SAXS),动态光散射 (DLS) 和微流成像来评估自我相互作用.
- 分析自组装作为mAb度和离子强度的函数.
主要成果:
- 带有相反电荷的Fab和Fc域的mAbs表现出有吸引力的蛋白质-蛋白质相互作用,并形成了多样化的可见形态.
- 自组装倾向与这些mAbs的mAb度和离子强度有非线性变化.
- 一个带有类似充电的Fab和Fc域的mAb表现出排斥的行为,没有显著的自我组装.
结论:
- 电荷分布在整个mAb表面上,包括常数区域,显著影响自组装倾向.
- 识别电荷不对称是预测和减轻不必要的mAb聚合的关键.
- 这种方法可以合理开发稳定的mAb配方.
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