驼单域抗体和哺乳动物抗体之间的物理化学差异
Nazlı Eda Eskier1,2, Doğa Eskier1,2, Esin Firuzan3
1İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkiye.
Turkish journal of biology = Turk biyoloji dergisi
|April 29, 2024
概括
纳米体 (VHH) 工程可以通过理解与人类抗体 (VHs) 的结构差异来改进. 关键VHH残留物和框架区域为增强的纳米体设计提供了场所,缓解免疫性,同时保持功能.
科学领域:
- 结构生物学是结构生物学.
- 免疫学 免疫学 免疫学
- 生物技术是生物技术.
背景情况:
- 单域抗体 (纳米体) 与免疫球蛋白G (IgG) 相比,具有优势,包括更好的溶解性,更快的清除和更低的生产成本.
- 纳米体是从驼类重链仅免疫球蛋白Gs (hcIgGs) 衍生出来的,特别是可变域 (VHH).
- 驼类VHHs和人类可变重域 (VHs) 之间的高序列同质性使它们适合纳米体开发,但结构差异需要进行工程研究.
研究的目的:
- 分析VHs和VHHs.之间的结构和物理化学差异.
- 确定VHHs中的关键残留物和区域,用于改进纳米体的工程.
- 在保持稳定性,功能性和抗原特异性的同时,为减轻纳米体免疫性提供信息的策略.
主要方法:
- 从公共数据库中获取VH和VHH序列.
- 使用Chothia编号方案执行多个序列对齐.
- 通过逻辑回归和Boruta-Random Forest算法对帕拉托普长度,结合预测,图案,二硫化物桥梁,盐桥梁和物理化学性质进行了分析.
主要成果:
- 与VHs相比,VHs表现出更长,更少变化的帕拉托普序列,具有更高的结合潜力.
- VHHs具有比VHs更多的非正规二硫化物桥梁,而VHs显示出更异质的非正规二硫化物键模式.
- 在VHs中,很少在VHs中发现VHs中特有的盐桥 (位置94-101),并且在保存的框架区域 (FW2,FW3) 的物理化学模式中存在显著差异.
结论:
- 确定了区分VHs和VHHs的独特结构和物理化学特征.
- 突出了特定的VHH残留物和框架区域作为纳米体工程的关键目标.
- 这些发现为设计下一代纳米体提供了基础,这些纳米体具有降低的免疫性和增强的治疗潜力.
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