ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting...

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Bibliographic Details
Published in:JCI insight 2021-07, Vol.6 (14)
Main Authors: Rattray, Zahra, Deng, Gang, Zhang, Shenqi, Shirali, Anupama, May, Christopher K, Chen, Xiaoyong, Cuffari, Benedette J, Liu, Jun, Zou, Pan, Rattray, Nicholas Jw, Johnson, Caroline H, Dubljevic, Valentina, Campbell, James A, Huttner, Anita, Baehring, Joachim M, Zhou, Jiangbing, Hansen, James E
Format: Article
Language:English
Subjects:
Animals
Antibodies, Antinuclear - pharmacology
Antibodies, Antinuclear - therapeutic use
Autoantibodies - pharmacology
Autoantibodies - therapeutic use
Autoimmunity
Blood-Brain Barrier - metabolism
Brain Neoplasms - drug therapy
Brain Neoplasms - pathology
Cell Line
CHO Cells
Cricetulus
Endothelial Cells
Equilibrative-Nucleoside Transporter 2 - genetics
Equilibrative-Nucleoside Transporter 2 - metabolism
Gene Knockdown Techniques
Glioblastoma - drug therapy
Glioblastoma - pathology
Humans
Mice
Oncology
Xenograft Model Antitumor Assays
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Summary:The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.145875