对α-Dystroglycanopathies的糖融合双特异抗体的代谢工程
Xiaotian Zhong1, Guoying Grace Yan1, Apurva Chaturvedi1
1BioMedicine Design, Discovery and Early Development, Pfizer Research and Development, 610 Main Street, Cambridge, MA 02139, USA.
Antibodies (Basel, Switzerland)
|October 25, 2024
概括
补充剂增强了一种新型双特异抗体的基甘修饰,改善其与拉米宁的结合,并为治疗α-基甘病变提供了潜在的可能性.
科学领域:
- 生物化学和分子生物学
- 葡萄糖科学 (Glycoscience) 是一种科学.
- 抗体工程 抗体工程
背景情况:
- 阿尔法-双糖病是一种先天性肌肉衰变,与减少或缺失的母糖有关,这是一个关键的O-链接糖.
- 低糖化α-dystroglycan (α-DG) 损害了与拉米宁等细胞外连接体的结合,损害了肌肉细胞的存活.
- 这种缺陷导致肌肉细胞脆弱和功能衰退,特别是在收缩后.
研究的目的:
- 设计一种新型的糖融合双特异性 (GBi) 抗体,以恢复拉米宁和双糖复合体之间的分子联系.
- 调查GBi抗体的代谢工程,以改善α-dystroglycanopathies中的治疗潜力.
主要方法:
- 通过将α-DG粘蛋白样域与抗β-DG抗体轻链融合,开发一个GBi抗体.
- 通过短暂的HEK表达产生GBi抗体,并与LARGE1.1共传输.
- 用尿素,银和离子 (Mn2+) 补充培养基,以评估对抗体修饰和功能的影响.
主要成果:
- 最初的GBi抗体产生显示了有限的马特里格利干修饰和弱的拉米林-211结合.
- 补充尿素,银河糖和Mn2+显著增强了母糖糖的修饰.
- 补充Mn2+的GBi抗体显示显著改善了拉米因结合活性.
结论:
- 离子 (Mn2+) 对于增强GBi抗体上的母糖甘修饰至关重要.
- 增强的母糖甘修饰与改善的双特异抗体功能直接相关.
- 这种工程GBi抗体对向α-dystroglycanopathies的治疗策略具有前途.
相关概念视频
01:24Oligosaccharide Assembly
Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
Multiple sugar molecules that may or may...
01:27Glucose Transporters
Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
01:05Proteoglycans
Glycans, a class of complex heterogeneous molecules, can be covalently attached to proteins to form glycosylated proteins that regulate various physiological and pathological processes. Glycosylated proteins or glycoproteins comprise N-linked and O-linked oligosaccharides. O-glycosylation is the most common type of protein glycosylation. Here, glycans attach to the oxygen atom of the hydroxyl groups of Serine or Threonine residues. O-linked glycosylation occurs later in protein processing,...