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Neuron. 2016 Jan 6;89(1):70-82. doi: 10.1016/j.neuron.2015.11.024. Epub 2015 Dec 10.

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

Author information

1
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: joy.yu929@gmail.com.
2
Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
Developmental Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
5
Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
6
Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
7
Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
8
Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
9
Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: chih.ben@gene.com.

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.

PMID:
26687840
DOI:
10.1016/j.neuron.2015.11.024
[Indexed for MEDLINE]
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