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

Autor:	Rattray Z; Department of Therapeutic Radiology and., Deng G; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA., Zhang S; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA., Shirali A; Department of Therapeutic Radiology and., May CK; Department of Therapeutic Radiology and., Chen X; Department of Therapeutic Radiology and., Cuffari BJ; Department of Therapeutic Radiology and., Liu J; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA., Zou P; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA., Rattray NJ; Yale School of Public Health, New Haven, Connecticut, USA., Johnson CH; Yale School of Public Health, New Haven, Connecticut, USA.; Yale Cancer Center, New Haven, Connecticut, USA., Dubljevic V; Patrys Ltd., Melbourne, Australia., Campbell JA; Patrys Ltd., Melbourne, Australia., Huttner A; Yale Cancer Center, New Haven, Connecticut, USA.; Department of Pathology and., Baehring JM; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.; Yale Cancer Center, New Haven, Connecticut, USA.; Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA., Zhou J; Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.; Yale Cancer Center, New Haven, Connecticut, USA., Hansen JE; Department of Therapeutic Radiology and.; Yale Cancer Center, New Haven, Connecticut, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2021 Jul 22; Vol. 6 (14). Date of Electronic Publication: 2021 Jul 22.
DOI:	10.1172/jci.insight.145875
Abstrakt:	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.
Databáze:	MEDLINE
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