使用临床验证的Fc突变调节高度IgG1抗体的粘度
Joel Heisler1, Daniel Kovner2, Saeed Izadi2
1Department of Antibody Engineering, Genentech, Inc, South San Francisco, CA, USA.
mAbs
|July 19, 2024
概括
Fc突变可以显著降低像奥马利祖马布这样的治疗抗体的高粘度,有助于配方和皮下输送. 这项研究探讨了Fc变体.
科学领域:
- 生物化学 生物化学
- 蛋白质工程是指蛋白质工程.
- 药理学 药理学是指药理学的学科.
背景情况:
- 治疗性抗体自我关联增加粘度,使制造,配方和皮下注射复杂化.
- 降低抗体粘度的策略包括可变域突变和辅助剂添加.
- Fc突变对抗体粘度的影响在很大程度上仍未被探索.
研究的目的:
- 调查常见和临床验证的Fc突变对IgG1抗体粘度的影响.
- 阐明Fc突变影响抗体自我关联和粘度的机制.
主要方法:
- 评估的粘度的 omalizumab 和 trastuzumab 与各种Fc突变.
- 采用分子动力学模拟来分析Fc突变对表面特性和稳定性的影响.
主要成果:
- Fc突变 (M252Y:S254T:T256E和N297G) 降低了分别10.7倍和2.2倍的奥马利祖马布粘度.
- 单个突变S254T和T256E使奥马利祖马布粘度降低了约6倍.
- 另一种Fc突变 (M428L:N434S) 增加了奥马利祖马布粘度的1.5倍;特拉斯图祖马布粘度的变化很小.
- 分子动力学模拟揭示了Fc突变对静电/疏水性质和Fc稳定性的影响.
结论:
- Fc突变可以有效地减轻某些IgG1抗体的高粘度.
- 抗体工程提供了一种新的策略,用于开发抗体治疗药物,以改善皮下输送的特性.
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