从自然变量域库中发现依赖pH的抗α-cobratoxin抗体的菌体显示辅助发现
Tulika Tulika1, Rasmus W Pedersen1, Charlotte Rimbault1
1Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
Protein science : a publication of the Protein Society
|October 28, 2023
概括
这项研究发现了一种新的回收抗体,使用无丁的方法. 这种方法可以在不引入序列负债的情况下实现治疗应用的pH依赖结合,为抗体开发提供了一种新的策略.
科学领域:
- 免疫学 免疫学 免疫学
- 生物化学 生物化学
- 蛋白质工程是指蛋白质工程.
背景情况:
- 循环IgG抗体在生理pH时结合抗原,并在酸性内分体中释放它们,以进行FcRn介导的循环.
- 这种回收机制允许较低的治疗剂量与非回收抗体相比.
- 目前开发回收抗体的方法通常涉及histidine兴奋剂,这可能会引入序列负债.
研究的目的:
- 开发一种方法来发现pH依赖的回收抗体,从一个天真的抗体菌体显示库,而无需histidine兴奋剂.
- 为了识别以pH依赖的方式结合α-cobratoxin的抗体.
主要方法:
- 利用了具有自然变量域的天真抗体菌体显示库.
- 对表现出与α-cobratoxin依赖pH结合的抗体进行选.
- 采用生物层干涉度测量以测量不同pH值的结合动力学.
- 进行了分子动力学模拟,以调查pH依赖结合的结构基础.
主要成果:
- 在pH 5.5时发现抗体,其脱离率在pH 7.4时比pH 5.5高7倍.
- 鉴定到的抗体的可变域缺乏胺残留物.
- 证明了pH依赖的结合,即使是对无西丁抗原突变的结合.
- 分子动力学模拟表明,除丁外的可定位残留物有助于pH依赖的结合.
结论:
- 取决于pH值的抗原-抗体结合并非完全由胺残留物驱动.
- 使用天真图书馆的无histidine方法可以成功发现回收抗体.
- 这种方法提供了一种多功能策略,用于从一开始开发新型治疗抗体.
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