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

Rattray, Zahra and Deng, Gang and Zhang, Shenqi and Shirali, Anupama and May, Christopher K. and Chen, Xiaoyong and Cuffari, Benedette J. and Liu, Jun and Zou, Pan and Rattray, Nicholas J.W. and Johnson, Caroline H. and Dubljevic, Valentina and Campbell, James A. and Huttner, Anita and Baehring, Joachim M. and Zhou, Jiangbing and Hansen, James E. (2021) ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody. JCI Insight, 6 (14). e145875. ISSN 2379-3708 (https://doi.org/10.1172/jci.insight.145875)

[thumbnail of Rattray-etal-JCII-2021-ENT2-facilitates-brain-endothelial-cell-penetration-and-blood-brain-barrier]
Preview
 Text. Filename: Rattray_etal_JCII_2021_ENT2_facilitates_brain_endothelial_cell_penetration_and_blood_brain_barrier.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo
Download (22MB)| Preview

Abstract

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.

CORE (COnnecting REpositories)