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

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 5

DX1 suppresses tumor growth and prolongs survival in a 231-BR orthotopic model of breast cancer brain metastases.

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DX1 suppresses tumor growth and prolongs survival in a 231-BR orthotopic...
Formation and growth of brain metastases in mice after intracardiac injection of luciferase-expressing 231-BR cells was followed by monitoring radiance efficiency in the brain. One week after injection, mice began treatment with i.v. control buffer (group 1) or DX1 (20 mg/kg, group 2). Weekly IVIS demonstrated significant suppression of tumor growth by DX1 delivered as 1 or 4 cycles. (A–D) Radiance efficiencies are plotted (A–C), and representative IVIS images from week 5 of the 4 cycle study are shown (D). *P < 0.04, **P ≤ 0.01. Student’s t test; numbers of mice evaluated at each point are indicated in the plots. (E) One cycle of DX1 was associated with a nonsignificant increase in median survival to 35 days, compared with 30 days in control mice (P = 0.42, log-rank test, n = 7). (F) Four cycles of DX1 had a greater effect, with median survival prolonged to 45 days, compared with 31 days in control mice (P < 0.02, log-rank test, n = 7).