title: 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.
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: joy.yu929@gmail.com.
authors.forename: Y Joy Yu
authors.initials: YJ
authors.lastname: Zuchero
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Nga
authors.initials: N
authors.lastname: Bien-Ly
authors.affiliation: Developmental Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Raymond K
authors.initials: RK
authors.lastname: Tong
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Hoyte
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wilman
authors.initials: W
authors.lastname: Luk
authors.affiliation: Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Huntley
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tan
authors.affiliation: Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Kallop
authors.affiliation: Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: chih.ben@gene.com.
authors.forename: Ben
authors.initials: B
authors.lastname: Chih
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001692:Biological Transport / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000276:immunology; D051379:Mice; D040901:Proteomics / Q000379:methods; D011990:Receptors, Transferrin / Q000378:metabolism*; D057900:Transcytosis / Q000502:physiology
chemical_list: D000906:Antibodies; D027282:Fusion Regulatory Protein 1, Heavy Chain; D011990:Receptors, Transferrin