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.
Highlights
Antibodies have revolutionized cancer therapy, but the blood-brain barrier (BBB) limits their use against brain tumors [1, 2]
The Fc in 3E10 is not required for cellular penetration or its synthetically lethal effect on PTEN-deficient cancer cells, and in developing DX1, we have intentionally used the di-scFv structure that lacks an Fc in order to minimize risks of Fc-mediated off-target toxicity [8]
Cells treated with control IgG showed minimal uptake of antibody (Figure 1C). These results demonstrate a role of ENT2 in the mechanism of DX1 penetration into hCMEC/D3 brain endothelial cells
Summary
Antibodies have revolutionized cancer therapy, but the blood-brain barrier (BBB) limits their use against brain tumors [1, 2]. The key nucleoside transporter involved in cellular penetration by 3E10, ENT2, is widely expressed in cancer and normal cells. ENT2 in brain endothelial cells contributes to regulating nucleoside flux at the BBB, and a 3E10-heat shock protein fusion was previously shown to localize to and protect the ischemic brain [12,13,14,15]. These findings raised the possibility that ENT2 may facilitate transport of 3E10 across the BBB and that 3E10 could be used to target brain tumors
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