皮下组织和淋巴液中降解对皮下注射后Fc融合蛋白的吸收的影响
Miki Yokoyama1, Eiko Suzuki1, Daisuke Nakai1
1Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Drug metabolism and pharmacokinetics
|September 5, 2025
概括
在吸收过程中蛋白质降解会影响皮下Fc融合蛋白质的生物可用性. 测量完整的蛋白质显示生物可用性较低,表明降解会影响药物的疗效.
科学领域:
- 药物动力学
- 生物制药科学
- 蛋白质工程
背景情况:
- 皮下注射是Fc融合蛋白的常见途径.
- 由于吸收的变化,预测皮下注射后人类的生物可用性是复杂的.
研究的目的:
- 在皮下吸收过程中研究蛋白质降解对Fc融合蛋白的生物可用性的影响.
- 使用新的测量技术区分完整和降解的Fc融合蛋白.
主要方法:
- 开发了两个量化方法:Fc/Fc (Fc区域特定) 和蛋白质/Fc (完整蛋白质特定).
- 使用这两种方法对鼠类进行了杜拉格卢提德和罗米普洛司姆的生物可用性评估.
- 在实验室中使用鼠皮同质物和淋巴液进行了稳定性研究,其中包括使用蛋白酶抑制剂.
主要成果:
- 与Fc/ fc方法相比,dulaglutide和romiplostim在老鼠中的生物可用性显著降低.
- 通过蛋白酶抑制剂抑制的杜拉格卢提德和罗米普洛司姆在体外研究中证实了蛋白质区域的降解.
- 在老鼠中,Abatacept和etanercept的体外表现稳定,两种方法的生物可用性相似.
结论:
- 在皮下吸收过程中蛋白质部分的蛋白酶介导降解显著影响Fc融合蛋白的生物可用性.
- 开发的Fc/Fc和蛋白质/Fc方法可以区分易降解和耐降解的蛋白质.
- 了解降解对于预测和优化皮下Fc融合蛋白疗法至关重要.
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