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一个工程鼠标模型,产生内源性,高亲和度常见光链抗体的多样化谱

Yinghui Rong¹, I-Ling Chen¹, Lance Larrabee¹

¹23andMe, Inc. Therapeutics, 349 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Antibodies (Basel, Switzerland)

|February 23, 2024

概括

一个新的常见光链小鼠模型支持双特异抗体的发现. 这些小鼠产生具有限制光链的多种抗体,适合开发新疗法.

科学领域:

免疫学免疫学免疫学
生物技术是生物技术.
治疗性抗体的发展.

背景情况:

双特异性抗体比单特异性抗体提供治疗优势.
一种常见的轻链策略通过配对具有不同抗原特异性的抗体来促进双特异性抗体的产生.
识别合适的抗体对需要有效的方法来产生与共享光链的抗体.

研究的目的:

创建和描述一种新的常见光链 (CLC) 鼠标模型.
评估基因修饰对B细胞发育和抗体谱系多样性的影响.
评估CLC小鼠模型对双特异抗体发现的有用性.

主要方法:

通过用修改后的IGKV10-96/IGKJ1片段取代内源IGKJ集群来生成CLC小鼠模型.
通过流细胞计和测序来评估B细胞发育和抗体谱的多样性.
用卵蛋白对CLC小鼠进行免疫接种,并对抗卵蛋白抗体进行表征,包括亲和度测量.

主要成果:

基因改造没有对CLC小鼠的B细胞发育产生不利影响.
这些CLC小鼠产生了具有多样化的VH基因段使用的抗体谱,与野生型小鼠相比.
轻链多样性仅限于工程IGKV10-96/IGKJ1生殖系,克隆型多样性与野生型水平相匹配.
在CLC小鼠中生成的抗体的亲属性略低于野生型小鼠的亲属性,但适用于两种特异性抗体的产生.

结论:

开发的CLC小鼠模型是可行的,不会损害B细胞发育或整体抗体库的多样性.
这种模型有效地限制了轻链的使用,促进了用于双特异性抗体开发的抗体对的发现.
CLC小鼠模型代表了推进双特异性抗体治疗的宝贵工具.

关键词:

发现抗体的发现.两种特异性的抗体.常见的光链链常见的光链基因改造的小鼠模型

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