A Human Blood-Brain Barrier Transcytosis Assay Reveals Antibody Transcytosis Influenced by pH-Dependent Receptor Binding

被引：106

作者：

Sade, Hadassah ^{[1
]}

Baumgartner, Claudia ^{[1
]}

Hugenmatter, Adrian ^{[2
]}

Moessner, Ekkehard ^{[2
]}

Freskgard, Per-Ola ^{[3
]}

Niewoehner, Jens ^{[1
]}

机构：

[1] Roche, Large Mol Res, Pharma Res & Early Dev pRED, Penzberg, Germany

[2] Roche, Large Mol Res, Pharma Res & Early Dev pRED, Schlieren, Switzerland

[3] F Hoffmann La Roche & Co Ltd, Neurosci Discovery & Translat Area, Pharma Res & Early Dev pRED, CH-4002 Basel, Switzerland

来源：

PLOS ONE | 2014年 / 9卷 / 04期

关键词：

HUMAN TRANSFERRIN RECEPTOR; ENDOTHELIAL-CELL LINE; IN-VITRO; MEDIATED ENDOCYTOSIS; CRYSTAL-STRUCTURE; TRANSPORT; EXPRESSION; PERMEABILITY; CAPILLARIES; HCMEC/D3;

D O I：

10.1371/journal.pone.0096340

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We have adapted an in vitro model of the human blood-brain barrier, the immortalized human cerebral microvascular endothelial cells (hCMEC/D3), to quantitatively measure protein transcytosis. After validating the receptor-mediated transport using transferrin, the system was used to measure transcytosis rates of antibodies directed against potential brain shuttle receptors. While an antibody to the insulin-like growth factor 1 receptor (IGF1R) was exclusively recycled to the apical compartment, the fate of antibodies to the transferrin receptor (TfR) was determined by their relative affinities at extracellular and endosomal pH. An antibody with reduced affinity at pH5.5 showed significant transcytosis, while pH-independent antibodies of comparable affinities at pH 7.4 remained associated with intracellular vesicular compartments and were finally targeted for degradation.

引用

页数：11

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