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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapys
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Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapys

机译：LINGO-1-anti-LINGO-1 Li81抗体复合物的结构为LINGO-1的生物学以及抗体疗法的作用机理提供了见识。

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摘要

Multiple sclerosis (MS) is an autoimmune-inflammatory disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunologic response, there is a large unmet eed for treatments that can promote CNS repair. LINGO-1 (leucine-rich repeat and Ig-containing Nogo receptor interacting protein-1) is a membrane protein selectively expressed in the CNS that suppresses myelination, preventing the repair of damaged axons. We are investigating LINGO-1 antagonist antibodies that lead to remyelination as a new paradigm for treatment of individuals with MS. The anti-LINGO-1 Li81 antibody,BIIB033, is currently in clinical trials and is the first MS treatment targeting CNS repair. Here, to elucidate the mechanism of action of the antibody, we solved the crystal structure of the LINGO-1-Li81 Fab complex and used biochemical and functional studies to investigate structurefunction relationships. Li81 binds to the convex surface of the leucine-rich repeat domain of LINGO-1 within repeats 4-8. Fab binding blocks contact points used in the oligomerization of LINGO-1 and produces a stable complex containing two copies each of LINGO-1 and Fab that results from a rearrangement of contacts stabilizing the quaternary structure of LINGO-1. The formation of the LINGO-1-Li81 Fab complex masks functional epitopes within the Ig domain of LINGO-1 that are important for its biologic activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 monoclonal antibody can block its function.
机译：多发性硬化症（MS）是中枢神经系统（CNS）的一种自身免疫性炎症性疾病，伴有明显的脱髓鞘和轴突损伤。尽管大多数MS治疗以免疫反应为目标，但仍存在大量需要促进CNS修复的治疗方法。 LINGO-1（富含亮氨酸的重复序列和含Ig的Nogo受体相互作用蛋白1）是一种在CNS中选择性表达的膜蛋白，可抑制髓鞘形成，从而防止受损轴突的修复。我们正在研究可导致髓鞘再生的LINGO-1拮抗剂抗体，作为治疗MS个体的新范例。目前，抗LINGO-1 Li81抗体BIIB033正在临床试验中，并且是针对CNS修复的首个MS治疗。在这里，为了阐明抗体的作用机理，我们解析了LINGO-1-Li81 Fab复合物的晶体结构，并使用了生化和功能研究来研究结构功能关系。 Li81与重复4-8内的LINGO-1的富含亮氨酸的重复结构域的凸表面结合。 Fab结合可阻断LINGO-1寡聚化中使用的接触点，并产生包含两个拷贝的LINGO-1和Fab的稳定复合物，这是由于稳定LINGO-1的四元结构的接触点重排而产生的。 LINGO-1-Li81 Fab复合物的形成掩盖了LINGO-1 Ig域内的功能性表位，这对于其在少突胶质细胞分化中的生物学活性至关重要。这些研究为LINGO-1的结构和生物学以及Li81单克隆抗体如何阻断其功能提供了新的见识。

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