TY - JOUR
T1 - Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood‒brain barrier
AU - Holst, Mikkel Roland
AU - de Wit, Nienke Marije
AU - Ozgür, Burak
AU - Brachner, Andreas
AU - Hyldig, Kathrine
AU - Appelt-Menzel, Antje
AU - Sleven, Hannah
AU - Cader, Zameel
AU - de Vries, Helga Eveline
AU - Neuhaus, Winfried
AU - Jensen, Allan
AU - Brodin, Birger
AU - Nielsen, Morten Schallburg
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood–brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium. Graphical Abstract: [Figure not available: see fulltext.]
AB - Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood–brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium. Graphical Abstract: [Figure not available: see fulltext.]
KW - Blood‒brain barrier
KW - Brain endothelial cells
KW - Caco-2
KW - Cargo receptor
KW - CD133
KW - Podocalyxin
KW - Receptor-mediated transcytosis
KW - Sortilin
KW - Therapeutic antibodies
KW - Transcytosis
KW - Transferrin receptor
U2 - 10.1186/s12987-023-00480-x
DO - 10.1186/s12987-023-00480-x
M3 - Journal article
C2 - 37932749
AN - SCOPUS:85175824172
VL - 20
JO - Fluids and Barriers of the CNS
JF - Fluids and Barriers of the CNS
SN - 2045-8118
IS - 1
M1 - 82
ER -