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

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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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.

Original languageEnglish
Article numbere145875
Number of pages39
JournalJCI Insight
Volume6
Issue number14
Early online date15 Jun 2021
DOIs
Publication statusPublished - 22 Jul 2021

Keywords

  • oncology
  • drug discovery
  • antibody
  • drug delivery
  • BBB
  • brain cancer
  • translational medicine

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