An ENT2-dependent, cell-penetrating, and DNA-damaging lupus autoantibody crosses the blood-brain barrier to target brain tumors

Zahra Rattray, Gang Deng, Shenqi Zhang, Anupama Shirali, Christopher May, Jun Liu, Pan Zou, Benedette Cuffari, Nicholas Rattray, Caroline Johnson, Valentina Dubljevic, James Campbell, Anita Huttner, Joachim Baehring, Jiangbing Zhou, James Hansen

Research output: Contribution to journalMeeting abstract

Abstract

The blood-brain barrier (BBB) limits conventional antibody-based approaches to brain tumors. ENT2, an equilibrative nucleoside transporter, facilitates penetration of autoantibodies into live cells and is expressed in the BBB. PAT-DX1 (also known as Deoxymab-1 or DX1) is an ENT2-dependent, cell-penetrating, and DNA-damaging lupus autoantibody that is synthetically lethal to cancer cells with defects in the DNA damage response. PTEN loss renders sensitivity to DX1 and is common in primary and metastatic brain tumors. We show that DX1 is toxic to spheroids derived from primary PTEN-deficient glioblastoma (GBM), and crosses the BBB to suppress the growth of orthotopic GBM and breast cancer brain metastases. Mechanistically, we find the ENT2 inhibitor dipyridamole blocks DX1 penetration into brain endothelial cells and transport across the BBB in vitro and in vivo, consistent with ENT2-mediated uptake of DX1 into brain tumors. Autoantibodies that hijack nucleoside transporters to cross cell membranes may open new frontiers in brain tumor therapy.
Original languageEnglish
Pages (from-to)ii13-ii13
Number of pages1
JournalNeuro-Oncology Advances
Volume2
Issue numberSupplement 2
DOIs
Publication statusPublished - 4 Aug 2020
EventSociety for Neuro-Oncology Virtual Conference on Brain Metastases - Online
Duration: 14 Aug 202014 Aug 2020

Keywords

  • glioblastoma
  • antibody
  • neoplasm metastasis
  • brain tumours
  • lupus

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