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治疗性抗体候选物的功能通过在变量区域中从氨酸转变为氨酸的一次突变而恢复

Marie Hautiere¹, Irene Maffucci^2,3, Narciso Costa¹

¹Département Médicaments et Technologies pour la Santé (DMTS), SPI, Université Paris-Saclay, CEA, Gif-sur-Yvette, France.

Human vaccines & immunotherapeutics

|November 27, 2023

概括

针对内甲蛋白B受体 (ETB) 的Rendomab-B49抗体 (RB49) 的化学化导致功能丧失. 突变一种特定的プロ林残留物恢复了抗体.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
结构生物学结构生物学

背景情况:

单克隆抗体 (mAbs) 是重要的治疗方法.
伦多马布-B49 mAb针对内分泌蛋白B受体 (ETB),这是许多癌症的关键驱动因素.
mAbs的奇米化可能会影响其功能.

研究的目的:

为了在抗体药物联合疗法中进行临床前评估,合成RB49 mAb (创建xiRB49).
为了研究RB49化学化的结构和功能后果.
了解xiRB49.9的结构功能关系.

主要方法:

在RB49 mAb.Ab的奇米化过程中.
蛋白A净化和可溶性/聚合性的评估.
变量区域的IMGT分析.
在模 mAb 建模.
在体外功能测试.

主要成果:

净化后的xiRB49是可溶和非聚合的,但失去了ETB结合.
在重链中第125位发现了一种不寻常的proline.
在和体外研究表明,在125位的プロ林会改变光链CDR3形状.
在125位的普罗林转变为氨酸,完全恢复了抗体功能.

结论:

在xiRB49重链中的125位的proline负责ETB结合的丧失.
将这种残留物恢复为氨酸,可以挽救抗体的功能.
这一发现对于开发针对ETB的抗体疗法至关重要.

关键词:

单克隆抗体是一种单克隆抗体.仿真化 (chimerization) 是一种过程.在模拟模型中.普罗林是什么意思普罗林是什么意思

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