结构和机器学习指导工程证明,抗PD-1子抗体中的非正规二硫化物不会阻碍抗体开发能力
Wei-Ching Liang1, Hongkang Xi1, Dawei Sun2
1Department of Antibody Engineering, Genentech Inc, South San Francisco, CA, USA.
mAbs
|February 15, 2024
概括
子抗体为药物发现提供了优势. 一个非正规的二硫化键,最初是一个问题,成功地使用结构和机器学习引导的方法来增强治疗性抗体的开发.
科学领域:
- 免疫学 免疫学 免疫学
- 生物技术是生物技术.
- 蛋白质工程是指蛋白质工程.
背景情况:
- 子对抗体产生有价值,因为它们具有强大的免疫反应和独特的谱系特征.
- 在子抗体 (CDR H1-CDR H2) 中常见的一种非正规的二硫化键通常被认为是治疗性抗体发展的负担.
- 关于这种二硫化键对抗体结合,功能和稳定性的影响的数据有限.
研究的目的:
- 为了研究非正规二硫化键在子抗PD-1抗体中的影响.
- 探索蛋白质工程策略,以克服与该债券相关的潜在负债.
- 在抗体工程中展示结构和机器学习引导方法的实用性.
主要方法:
- 发现并对具有非正规二硫化键的交叉反应性子抗PD-1单克隆抗体 (h1340.CC) 进行人性化.
- 蛋白质工程以去除二硫化键和随后的亲和力/活性评估.
- 基于晶体结构和相关的克隆序列的结构引导变体生成 (h1340.SA.LV).
- 机器学习和结构导向的方法用于快速变异生成与恢复的亲和力.
- 对抗体变异的可开发性评估.
主要成果:
- 抗PD-1抗体h1340.CC具有非正规的二硫化键.
- 最初去除二硫化键导致PD-1亲和力和交叉反应率降低.
- 结构引导工程部分恢复了亲和力,产生了具有类似开发能力的h1340.SA.LV.
- 一种无偏见的ML和结构引导的方法有效地产生了具有恢复亲和力的变体.
- 无论是h1340.CC还是h1340.SA.LV都表现出有利的可开发性质.
结论:
- 子抗体中非正规的CDR间二硫化键不是治疗性抗体开发的固有障碍.
- 结合结构和机器学习引导的蛋白质工程,提供了一种快速有效的策略,以改善抗体特性并减轻负债.
- 本案例研究突出了从子来源制造治疗抗体的成功方法.
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