人体组织中TCR类抗体治疗药物的生理相互作用
Estelle Marrer-Berger1, Annalisa Nicastri2,3, Angelique Augustin1
1Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070, Basel, Switzerland.
Nature communications
|April 16, 2024
概括
开发新的TCR类抗体需要严格的安全测试. 这项研究提出了一个新的质谱平台,用于识别人体组织中的抗体相互作用体,确保临床试验前的治疗安全性和有效性.
科学领域:
- 免疫学和癌症治疗学
- 蛋白质组学和质谱学
背景情况:
- 治疗性T细胞受体 (TCR) 类抗体必须选择性地结合由人类白细胞抗原 (HLA) 呈现的瘤特异性抗原,以获得安全性和有效性.
- 目前用于评估抗体选择性的方法,如体库查和预测建模,有局限性.
- 准确评估目标外相互作用对于患者在TCR类抗体开发中的安全至关重要.
研究的目的:
- 开发和验证一个实验平台,用于直接在人体组织中识别TCR类抗体互动体.
- 使用质谱测量来评估TCR类抗体的选择性和潜在的非向活动.
- 为评估TCR类抗体治疗药物的非临床安全性概况提供可靠的方法.
主要方法:
- 开发一种新的实验平台,利用质谱法进行新的互动原子识别.
- 应用该平台来确认MAGE-A4特异性TCR样抗体的标表位.
- 确定人肝组织中ESK1 TCR类抗体的交叉反应性序列.
主要成果:
- 该平台成功证实了MAGE-A4特异性TCR样抗体的标表位.
- 在人类肝脏组织中发现了ESK1抗体的交叉反应性序列,证实了已知的目标外活性.
- 脱的相互作用与T细胞激活和组织损伤有关,通过特定的氨基酸基因介导.
- 识别的基因模仿了HLA结构内目标的相互作用.
结论:
- 开发的基于质谱的平台提供了一个准确和可扩展的方法来评估类似TCR的抗体安全性.
- 这一策略能够全面评估相关人体组织中的抗体选择性和非标相互作用.
- 这些发现支持在临床应用之前对TCR类抗体治疗药物的临床前安全性评估.
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