Basigin Antibodies with Capacity for Drug Delivery Across Brain Endothelial Cells

Abstract

The blood-brain barrier (BBB) poses challenges for delivering antibody-based therapeutics to the brain and is a main obstacle for the successful application of biotherapeutics for the treatment of brain disorders. As only a small fraction of monoclonal antibodies (mAbs) is penetrating the BBB, high doses of therapeutics are required to elicit a pharmacological effect. This limitation has evoked research to improve transport across the BBB through receptor-mediated transcytosis, and several receptors have been explored for mediating this process. A recently suggested candidate is the brain endothelial cells (BECs) expressed basigin. Here, we explore the transcytosis capacity of different basigin mAbs targeting distinct epitopes using the porcine in vitro BBB models and provide data showing the intracellular vesicle sorting of these basigin mAbs in porcine BECs. Our data suggest that basigin mAbs avoid the lysosomal degradation pathway and are internalized to vesicles used by recycling receptors. Engagement of basigin mAbs with basigin led to the translocation of the mAbs across the tight BECs into the astrocytes in our in vitro BBB co-culture model. Although mAbs with higher binding affinity to basigin showed a greater astrocyte internalization, based on our experiments, it is not clear whether the transcytosis is affinity- or epitope-dependent or a combination of both. Overall, this study provides information about the intra- and intercellular fate of basigin mAbs in BECs, which are valuable for the future design of basigin-mediated drug delivery platforms.

Keywords: Basigin; Blood–brain barrier; In vitro models; Microscopy; Receptor-mediated transcytosis.