通过破坏连续的正面表面潜力和使用替代人类框架减少电荷,改善了抗体的药理动力学
Romain Ollier1, Aline Fuchs1, Florence Gauye1
1Research, AC Immune SA, Lausanne, Switzerland.
mAbs
|July 6, 2023
概括
在临床前模型中,工程单克隆抗体 (mAb) 表面电荷减少了清除和改善了半衰期. 这种充电工程方法优化了用于治疗抗体开发的药物动力学特性.
科学领域:
- 生物制药开发 生物制药开发
- 蛋白质工程是指蛋白质工程.
- 药理动力学 药理动力学
背景情况:
- 最佳的药理动力学 (PK) 特性对于治疗性单克隆抗体 (mAbs) 是至关重要的.
- 基于结构的充电工程与临床前模型相结合,有助于选择具有适合PK的人性化mAbs.
- 针对小鼠的TDP-43 mAb ACI-5891被人性化以提高其治疗潜力.
研究的目的:
- 为了设计一个人性化的mAb (ACI-5891) 的电荷特性,以优化其药理动力学特征.
- 评估表面电荷修改对临床前物种mAb清除和半衰期的影响.
- 评估人类FcRn转基因小鼠模型对预测人类PK的有用性.
主要方法:
- 使用具有高序列同质性的框架,对一种小鼠mAb (ACI-5891) 的人性化.
- 代人性化修改表面电荷特性并减少同电点 (pI).
- 在非人类灵长类动物 (NHPs) 和Tg32小鼠 (人类FcRn转基因模型) 中的药理动力学评估.
主要成果:
- 最初的人性化mAb (ACI-5891.1) 在NHPs中显示出快速清除.
- 第二种人性化变体 (ACI-5891.9) 具有降低的PI和更平坦的表面潜力,在NHP中显示清除率下降六倍,半衰期增加.
- ACI-5891.9在Tg32小鼠中表现出一致的低清除,与预测的人类PK相关.
结论:
- mAb表面电荷是体内配置和PK特性的一个关键决定因素.
- 基于结构的充电工程是开发过程中优化mAb PK的有效策略.
- Tg32小鼠作为一个有价值的模型来预测人类PK的工程 mAbs.
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