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

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

Neuron

journal_title

Neuron

authors

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 RJ

doi

10.1016/j.neuron.2015.11.024

subject

Has Abstract

pub_date

2016-01-06 00:00:00

pages

70-82

issue

1

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(15)01030-2

journal_volume

89

pub_type

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