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在中枢神经系统中通过一种穿透血脑屏障的抗体进行Nogo-A的中和

Sandrine Joly¹, Gilles Augusto², Baya Mdzomba³

¹Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Switzerland; Centre de recherche du CHU de Québec-Université Laval and Department of Molecular Medicine, Faculté de médecine, Université Laval, Québec, Québec, Canada; Department of Ophthalmology, Bern University Hospital, University of Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, Switzerland.

Journal of controlled release : official journal of the Controlled Release Society

|December 28, 2023

概括

设计了一种新型抗体片段 (11C7-scFv8D3),可以有效地穿越血脑屏障以准Nogo-A. 这种工程抗体促进中枢神经系统中神经元生长信号传递,用于潜在的神经疾病治疗.

科学领域:

神经科学是一个神经科学.
生物技术是生物技术.
药理学药理学是指药理学的学科.

背景情况:

单克隆抗体 (mAbs) 难以穿透血脑屏障 (BBB),限制神经系统疾病的再生疗法.
中枢神经系统 (CNS) 蛋白质Nogo-A抑制神经元的可塑性,但其中和需要直接向中枢神经系统注射像11C7 mAb.这样的抗体.

研究的目的:

通过将11C7 mAb与8D3.3的转化蛋白受体 (TfR) 结合的单链变量片段 (scFv) 融合,对Nogo-A进行中枢神经系统透抗体的工程.
评估工程抗体 (11C7-scFv8D3) 的结合,BBB转细胞和治疗潜力.

主要方法:

通过结合11C7 mAb和scFv8D3进行工程11C7-scFv8D3以实现TfR介导的BBB转细胞化.
通过捕获ELISA和生物层干扰计验证了与Nogo-A和TfR/CD71的结合.
在小鼠中通过静脉注射和ELISA评估了血清除,脑/脊髓积累和中枢神经系统透.

主要成果:

11C7-scFv8D3证明了对Nogo-A和TfR/CD71的特定结合.
与11C7 mAb相比,工程抗体显示出快速的血清除和显著更高的脑/脊髓积累 (高达19倍).
在大脑外膜中检测到11C7-scFv8D3,证实了血液到中枢神经系统的有效转移.
一次剂量激活了促进生长的Akt/mTOR/S6信号,比对照抗体更强烈.

结论:

BBB交叉11C7-scFv8D3有效地在小鼠中枢神经系统中使用Nogo-A.
工程抗体刺激神经元生长机制,为神经疾病提供了一个有前途的治疗策略.

关键词:

阻断抗体阻断抗体血液-大脑屏障是什么?穿透大脑的抗体进入大脑.神经元的可塑性神经元的可塑性这里是Nogo-A.转移氨酸受体的受体转移氨酸受体

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