通过可解释的机器学习优化治疗抗体以减少自我关联和非特异性结合
Emily K Makowski1,2, Tiexin Wang2,3, Jennifer M Zupancic2,3
1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
Nature biomedical engineering
|September 4, 2023
概括
机器学习模型可以通过分析结构特征来预测最佳的抗体变体. 这种方法通过优化相互作用,减少非标结合和自我关联来提高抗体的疗效.
科学领域:
- 生物技术是生物技术.
- 免疫学 免疫学 免疫学
- 计算生物学 计算生物学
背景情况:
- 抗体的有效性,药理动力学和配方稳定性取决于抗体-抗原亲和力,非目标相互作用和自我关联.
- 优化这些复杂的相互作用以识别优异抗体变体是抗体开发中的一个重大挑战.
研究的目的:
- 开发和验证可解释的机器学习分类器,用于识别具有优化非亲和相互作用的抗体变体.
- 评估这些模型预测治疗抗体有益突变的能力.
主要方法:
- 使用可解释的机器学习分类器,对抗体变量区域的结构特征进行训练.
- 使用80个临床阶段单克隆抗体的实验数据来训练和测试模型.
- 评估分类器,以预测低目标外结合和低自我关联的能力.
主要成果:
- 开发的分类器成功地识别了具有低目标外结合和低自我关联的最佳组合的抗体.
- 对于具有亚最佳特征的三个临床阶段抗体,预测的突变改善了非亲和相互作用,同时保持了高抗原亲和力.
- 证明了机器学习在预测生理和配方条件下的抗体行为方面的实用性.
结论:
- 可解释机器学习提供了一种强大的方法来优化治疗开发的抗体候选人.
- 这一策略可以指导具有改善生物可用性,药理动力学和配方特性的抗体的工程.
- 机器学习有助于选择和设计具有增强治疗潜力的抗体.
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