Development of blood–brain barrier transitable anti–amyloid–β oligomer antibodies

Abstract

The development of drug delivery system across the blood–brain barrier (BBB) into the brain is still a challenging problem to introduce an effective molecular–targeted therapy for intractable neurological disorders. We have developed an efficient delivery system utilizing glucose transporter–1 (GLUT1), which is expressed at a remarkably high level in brain microvascular endothelial cells, by adopting a unique biological strategy.

We constructed a 30nm–sized self–assembled supramolecular micelle integrated with glucose on its surface. Intravenously administered glucosylated nanomicelle accumulated highly in the mouse brains (6% dose/g–brain) in response to a glycemic increase after a prior fasting condition. The accumulation of the micelle was considerably decreased by intravenous administration of a GLUT1 inhibitor. We directly observed the transport of the micelle from brain microvessels into brain by intravital real–time confocal laser scanning microscopy, and identified the delivery of the micelle into neurons by immunohistochemistry. In the course of crossing the BBB, the micelle was partially localized at recycling endosomes immunolabelled with anti–Rab11a antibody in the brain microvascular endothelial cells, suggesting GLUT1 intracellularly migrates from the luminal to the abluminal plasma membrane.

For targeting amyloid–β oligomer (AβO), the pathological hallmark of Alzheimer's disease (AD), we start to engineer an anti–AβO antibody, which has been used in a phase 1 clinical trial for AD patients in the United States, and combine the products with the above delivery system. A full–body anti–AβO antibody or its antibody fragments could be used to develop a nanomicelle decorated with GLUT1 ligands to penetrate the BBB. This nanomicelle containing some anti–AβO antibody is going to be used for the analysis of AβO pathophysiology, diagnosis of early AD, and treatment of AD.