通过折叠介导的纯双特异抗体的分泌
Cholpon Tilegenova1, Tun Liu1, Qian Zhao1
1Biologics Discovery, Johnson & Johnson, Spring House, PA, USA.
Nature biotechnology
|October 7, 2025
概括
具有ProAla突变的工程双特异抗体 (bsAbs) 通过防止错误配对来提高纯度. 这种新的方法改善了用于治疗的双特异性IgG类抗体 (bsIgG) 的产生.
科学领域:
- 生物技术是生物技术.
- 免疫学 免疫学 免疫学
- 蛋白质工程是指蛋白质工程.
背景情况:
- 双特异性抗体 (bsAbs) 提供了超越单克隆抗体的先进治疗能力.
- 类似IgG的格式 (bsIgG) 涉及四个独特的多链,导致在联合表达期间潜在的错误配对.
- 由于具有相似的生物物理性质,将错误配对的bsIgG与所需产品分离是具有挑战性的.
研究的目的:
- 开发一种用于增加分泌双特异性IgG类抗体 (bsIgG) 纯度的新方法.
- 设计 bsAbs,尽量减少不配对物种的形成和分泌.
主要方法:
- 在BSIGG重链中引入ProAla突变.
- 利用细胞展开的蛋白质反应途径.
- 在重链中设计更高的折叠能量障碍,以确保相关的配对.
主要成果:
- ProAla突变确保只有相关的重链和轻链才能诱导适当的折叠,伴侣释放和分泌.
- 错误配对的多呈现出与内分泌网膜伴侣BiP的增强相互作用,抑制它们的分泌.
- ProAla突变保持了Fab和Fc区域的原生结构,保持了抗体半衰期和功能.
- 显著增加了分泌的bsIgG的纯度.
结论:
- 通过防止错误配对物种的分泌,ProAla突变策略有效地提高了bsIgG纯度.
- 这种方法为制造高纯度双特异抗体提供了强大的解决方案.
- 通过ProAla工程设计的bsIgG保留了必不可少的抗体功能和药理动力学特性.
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