The equilibrative nucleoside transporters-2 better known as ENT2 may offer an unexpected path to circumventing the blood-brain barrier (BBB), enabling targeted treatment of brain tumors like glioblastoma with a cell-penetrating anti-DNA autoantibody. A study, funded in part by the National Institute of Neurological Diseases and Stroke of the National Institutes of Health and the Australian biotech firm Patrys and others, and led by Yale Cancer Center, researchers was published today online in the Journal of Clinical Investigation – Insight. [1]
The blood-brain barrier tightly regulates the movement of ions, molecules, and cells between the blood and the brain and prevents the uptake of most pharmaceutical agents in the brain. This property is caused by the epithelial-like tight junctions within the brain capillary endothelium. [2]
The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. It has been shown that certain small molecule drugs may cross the BBB via lipid-mediated free diffusion. However, to be successful, these agents need to have a molecular weight <400 – 600 Da and form <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs, ultimately restricting up to 98% of small molecules and almost all biologics. [3]
The results of this study demonstrate that the PAT-Deoxymab-1 (DX1) antibody can cross the blood-brain barrier and inhibit the growth of brain cancers and metastases, showing the potential for tackling these difficult-to-reach-and-treat cancers.
“These findings are very encouraging as the BBB prevents most antibodies from penetrating the central nervous system and limits conventional antibody-based approaches to brain tumors,” explained James E. Hansen, MD, associate professor of therapeutic radiology, radiation oncology chief of the Yale Gamma Knife Center at Smilow Cancer Hospital, and corresponding author of the study.
An unusual cell-penetrating autoantibody
Deoxymab-1 (DX1) is an unusual cell-penetrating autoantibody that localizes into live cell nuclei, inhibits DNA repair, and is synthetically lethal to cancer cells with defects in the DNA damage response (DDR). Researchers have now found that the transporter ENT2 facilitates brain endothelial cell penetration and BBB transport by DX1. In a number of efficacy studies in mice models, DX1 crossed the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases.
“Our data demonstrate the ability of DX1 to cross the BBB and suppress brain tumors in multiple models, and we are particularly impressed that DX1 was able to yield these results as a single agent in these difficult to treat tumor models,” noted Jiangbing Zhou, associate professor of neurosurgery at Yale School of Medicine and co-corresponding author of the study.
“We believe that the ENT2-linked mechanism that transports DX1 across the BBB and into tumors has potential to contribute to multiple new strategies in brain tumor therapy,” added Hansen.
“In addition to establishing proof of concept for single-agent use of DX1 in brain tumor models, we also now recognize the potential for DX1 to target linked cargo molecules to brain tumors or to be useful as a platform for designing additional brain tumor-targeting antibodies, including DX1-based bispecific antibodies,” he concluded.
Reference
Rattray Z, Deng G, Zhang S, Shirali A, May CK, Chen X, Cuffari BJ, Liu J, Zou P, Rattray NJ, Johnson CH, Dubljevic V, Campbell JA, Huttner A, Baehring JM, Zhou J, Hansen JE. ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody. JCI Insight. 2021 Jun 15:145875. doi: 10.1172/jci.insight.145875. Epub ahead of print. PMID: 34128837. [Article]
[2] Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015 Jan 5;7(1):a020412. doi: 10.1101/cshperspect.a020412. PMID: 25561720; PMCID: PMC4292164.
[3] Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012 Nov;32(11):1959-72. doi: 10.1038/jcbfm.2012.126. Epub 2012 Aug 29. PMID: 22929442; PMCID: PMC3494002.
Featured image: Brain scan. Photo courtesy: © 2016 – 2021 Patrys. Used with permission.
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