Abstract:
: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.
journal_name
Neuronjournal_title
Neuronauthors
Zuchero YJ,Chen X,Bien-Ly N,Bumbaca D,Tong RK,Gao X,Zhang S,Hoyte K,Luk W,Huntley MA,Phu L,Tan C,Kallop D,Weimer RM,Lu Y,Kirkpatrick DS,Ernst JA,Chih B,Dennis MS,Watts RJdoi
10.1016/j.neuron.2015.11.024subject
Has Abstractpub_date
2016-01-06 00:00:00pages
70-82issue
1eissn
0896-6273issn
1097-4199pii
S0896-6273(15)01030-2journal_volume
89pub_type
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