Abstract
AbstractThe brain uptake of biotherapeutics for brain diseases is hindered by the blood–brain barrier (BBB). The BBB selectively regulates the transport of large molecules into the brain and thereby maintains brain homeostasis. Receptor-mediated transcytosis (RMT) is one mechanism to deliver essential proteins into the brain parenchyma. Receptors expressed in the brain endothelial cells have been explored to ferry therapeutic antibodies across the BBB in bifunctional antibody formats. In this study, we generated and characterized monoclonal antibodies (mAbs) binding to the basigin receptor, which recently has been proposed as a target for RMT across the BBB. Antibody binding properties such as affinity have been demonstrated to be important factors for transcytosis capability and efficiency. Nevertheless, studies of basigin mAb properties' effect on RMT are limited. Here we characterize different basigin mAbs for their ability to associate with and subsequently internalize human brain endothelial cells. The mAbs were profiled to determine whether receptor binding epitope and affinity affected receptor-mediated uptake efficiency. By competitive epitope binning studies, basigin mAbs were categorized into five epitope bins. mAbs from three of the epitope bins demonstrated properties required for RMT candidates judged by binding characteristics and their superior level of internalization in human brain endothelial cells.
Publisher
Springer Science and Business Media LLC
Reference39 articles.
1. Zuchero, Y. J. Y. et al. Discovery of novel blood-brain barrier targets to enhance brain uptake of therapeutic antibodies. Neuron 89, 70–82 (2016).
2. Yu, Y. J. et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Transl. Med. 3, 84ra44 (2011).
3. Fishman, J. B., Rubin, J. B., Handrahan, J. V., Connor, J. R. & Fine, R. E. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J. Neurosci. Res. 18, 299–304 (1987).
4. Couch, J. A. et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci. Transl. Med. 5(183ra57), 1–12 (2013).
5. Pardridge, W. M., Boado, R. J., Patrick, D. J., Ka-Wai Hui, E. & Lu, J. Z. Blood-brain barrier transport, plasma pharmacokinetics, and neuropathology following chronic treatment of the rhesus monkey with a brain penetrating humanized monoclonal antibody against the human transferrin receptor. Mol. Pharm. 15, 5207–5216 (2018).
Cited by
22 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献