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ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody
Zahra Rattray, … , Jiangbing Zhou, James E. Hansen
Zahra Rattray, … , Jiangbing Zhou, James E. Hansen
Published June 15, 2021
Citation Information: JCI Insight. 2021;6(14):e145875. https://doi.org/10.1172/jci.insight.145875.
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Research Article Oncology

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

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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.

Authors

Zahra Rattray, Gang Deng, Shenqi Zhang, Anupama Shirali, Christopher K. May, Xiaoyong Chen, Benedette J. Cuffari, Jun Liu, Pan Zou, Nicholas J.W. Rattray, Caroline H. Johnson, Valentina Dubljevic, James A. Campbell, Anita Huttner, Joachim M. Baehring, Jiangbing Zhou, James E. Hansen

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Figure 3

DX1 localizes to orthotopic GBM tumors in a DP-sensitive manner.

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DX1 localizes to orthotopic GBM tumors in a DP-sensitive manner.
Human G...
Human GBM model 1 GSCs engineered to express luciferase were inoculated into the brains of immunodeficient mice (n = 10) to generate orthotopic PDX GBM tumors. (A) Representative IVIS images confirming presence of tumors (upper panel) and comparing DX1 localization to tumors (lower panel). DX1 was labeled with AF750 to facilitate its detection by IVIS. Mice were treated with i.v. and i.p. control buffer (n = 2), i.v. DX1AF750 (20 mg/kg) and i.p. control buffer (n = 4), or i.v. DX1AF750 (20 mg/kg) and i.p. DP (70 mg/kg) (n = 4). IVIS measurements 24 hours after treatment demonstrated DX1 localization into the tumors, and DP significantly suppressed this uptake. (B) Quantification of radiance efficiencies. *P = 0.0142, **P < 0.0001. Tukey’s multiple-comparison test–adjusted P values; numbers of mice evaluated at each point are indicated in the plots.

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