Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies

The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration in vivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aβ reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies. •Limited antibody uptake in brain for low-expressing targets at the BBB•Proteomic analysis reveal highly expressed proteins at the BBB•Brain uptake of antibodies against highly abundant BBB targets follows in vivo dosing•CD98hc is a robust and novel BBB target for antibody therapeutics for CNS diseases Receptor-mediated transcytosis is a promising approach for delivering therapeutics across the blood-brain barrier. However, only a limited number of receptors have demonstrated success. Zuchero et al. describe novel receptor pathways that can be exploited for brain transport of antibody drugs.