抗体轻链CDR-1中的氨酸硫化增加了对INTERLEUKINE-4的结合亲和力和中和力
Aaron M D'Antona1, Julie M Lee2, Melvin Zhang3
1BioMedicine Design, Pfizer Research & Development, 610 Main Street, Cambridge, MA 02139, USA.
International journal of molecular sciences
|February 10, 2024
概括
氨酸硫化是一种翻译后的修饰,增强了抗体的亲和力和功效. 这项研究确定了针对抗介素-4抗体的特异性氨酸硫化,改善了其治疗潜力.
科学领域:
- 生物化学 生化学
- 免疫学 免疫学 免疫学
- 蛋白质工程是指蛋白质工程.
背景情况:
- 翻译后修改 (PTMs) 显著影响治疗抗体功能.
- 氨酸 (Tyr) 硫化是一种在戈尔吉装置中发生的PTM,为蛋白质添加负电荷.
研究的目的:
- 为了研究PTMs对抗介质素 (IL) - 4抗体的影响.
- 确定负责抗体特性变化的特定PTM及其功能后果.
主要方法:
- 在HEK293细胞中产生抗IL-4IgG1.
- 使用质谱法 (MS) 隔离和描述酸性抗体物种.
- 使用酸和铁蛋白硫转移酶基因调节硫化水平;通过MS和突变性突变通过特定地点识别.
主要成果:
- 一种抗IL-4抗体表现出异常的酸性物种,具有增强的结合亲和力 (2倍) 和效力 (4倍).
- 多样性质的分析表明,这些酸性物种的质量转移为+80-达尔顿,与Tyr硫化相一致.
- 硫化水平可以通过抑制剂或基因共同表达来控制,并且在CDRL-1中确定了特定的Tyr残留物作为硫化部位.
结论:
- 抗体轻链CDRL-1上的氨酸硫化可以增强结合亲和力和效力.
- 这种PTM提供了一种新的策略,用于设计针对IL-4等细胞因子的改善治疗抗体.
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