# Targeting Glioblastoma with a Nuclear-penetrating Anti-DNA Autoantibody

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $366,406

## Abstract

Glioblastoma multiforme (GBM), the most common primary malignancy of the brain, has high rates of relapse
and mortality despite aggressive treatment with surgery, radiation, and chemotherapy. Improved methods to
target and treat GBM are needed, but the blood-brain barrier (BBB) and genetic heterogeneity associated with
GBM are obstacles to drug development. The autoimmune disease systemic lupus erythematosus offers an
unexpected new approach.
We discovered that the lupus anti-DNA autoantibody 3E10 penetrates live cell nuclei and inhibits DNA repair in
a manner that does not kill normal cells but is toxic to cancer cells with genetic defects in repair of DNA double-
strand breaks (DSBs), including PTEN-deficient cancer cells and tumors. 3E10 penetrates cells via a mechanism
that requires both extracellular DNA and the ENT2 nucleoside transporter to be present, which facilitates
preferential penetration of 3E10 into tumors due to their expression of ENT2 and increased DNA in their
environment. ~40% of primary GBM is PTEN-deficient, and we hypothesize that 3E10 will target GBM, have
single agent effects against PTEN-deficient GBM, and can serve as a sensitizing agent for radiation therapy and
as a drug delivery ligand for GBM regardless of PTEN status.
We have re-engineered a 3E10 fragment, hereafter referred to as Deoxymab-1 (DX1), to maximize effect on
cancer cells and minimize risks. In preliminary studies DX1 crosses the BBB to localize into and suppress growth
of PTEN-deficient GBM in an orthotopic patient-derived xenograft (PDX) mouse model, and delivers conjugated
nanocarriers to orthotopic GBM tumors. We now propose studies to help translate DX1 into a novel therapy for
GBM. In Aim 1 we pursue studies to elucidate and enhance the mechanism by which DX1 crosses the BBB in
GBM. In Aim 2 the effects of DX1, alone or in combination with radiation therapy, on viability and DNA damage
accumulation in GBM and normal cells will be determined. DX1 +/- radiation therapy will then be tested in PDX
and syngeneic mouse models of GBM to evaluate efficacy and toxicity. In Aim 3 methods to deliver drug-loaded
nanocarriers by surface conjugation with DX1 are developed and tested in orthotopic GBM models.
We believe use of a modified nuclear-penetrating lupus anti-DNA autoantibody against GBM is an innovative
and compelling new strategy that has potential for significant clinical impact, and the proposed studies will
establish a foundation for advancing the DX1 technology to clinical trials.

## Key facts

- **NIH application ID:** 10130647
- **Project number:** 5R01NS112223-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** James E. Hansen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,406
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130647

## Citation

> US National Institutes of Health, RePORTER application 10130647, Targeting Glioblastoma with a Nuclear-penetrating Anti-DNA Autoantibody (5R01NS112223-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130647. Licensed CC0.

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