Activated ADAM10 targeting antibody 1H5 suppresses NOTCH-driven glioma progenitors
- 1Department of Neurosurgery, and Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Abstract
Background: High-grade gliomas (HGGs) remain associated with high morbidity, mortality, and invariable recurrence after neurosurgical resection and chemoradiation. A major contributor to treatment failure is a population of stem-like glioma progenitor cells (GPCs) that depend on NOTCH-signaling for self-renewal and survival; clinical attempts to inhibit NOTCH with {gamma}-secretase inhibitors failed due to systemic toxicity. Methods: Here, we investigate the anti-HGG therapeutic potential of a fully-human monoclonal antibody, 1H5, that selectively targets activated-ADAM10, an -secretase required for NOTCH receptor processing, with high tumor specificity. We show that ADAM10 is markedly overexpressed and highly activated in primary and recurrent HGGs, using patient tissue, RNA-sequencing data, and early-passage HGG cell lines. Results: Across a panel of patient-derived HGG lines, sensitivity to 1H5 correlates with the cell-surface levels of activated-ADAM10, and shRNA-mediated ADAM10 knockdown recapitulates the growth-inhibitory effects of 1H5. ADAM10 inhibition suppresses NOTCH-pathway components and target genes, reduces expression of GPC markers, and impairs neurosphere formation while depleting Sox2- and Ki67-positive cells. We further find that 1H5 induces HGG cell death predominantly via necroptosis, characterized by survivin loss and increased phosphorylated MLKL and by transcriptional changes in necroptosis-related genes. In three-dimensional explants derived from primary HGG, 1H5 reduces growth and GPC marker expression while increasing TUNEL staining. Finally, convection-enhanced delivery of 1H5 in orthotopic xenograft models achieves high local intracranial concentrations, slows tumor growth, and prolongs survival, with regional pharmacodynamic effects consistent with NOTCH pathway suppression and necroptosis.
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BibTeX
@misc{tosi2026activated,
title = {{Activated ADAM10 targeting antibody 1H5 suppresses NOTCH-driven glioma progenitors}},
author = {U. Tosi and G. Ghita and N. Saha and A. Giantini-Larsen and K. K. H. Yu and J. Jungverdorben and D. B. Nikolov and V. Tabar},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762427},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762427v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Activated ADAM10 targeting antibody 1H5 suppresses NOTCH-driven glioma progenitors
AU - U. Tosi
AU - G. Ghita
AU - N. Saha
AU - A. Giantini-Larsen
AU - K. K. H. Yu
AU - J. Jungverdorben
AU - D. B. Nikolov
AU - V. Tabar
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762427
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762427v1
AB - Background: High-grade gliomas (HGGs) remain associated with high morbidity, mortality, and invariable recurrence after neurosurgical resection and chemoradiation. A major contributor to treatment failure is a population of stem-like glioma progenitor cells (GPCs) that depend on NOTCH-signaling for self-renewal and survival; clinical attempts to inhibit NOTCH with {gamma}-secretase inhibitors failed due to systemic toxicity. Methods: Here, we investigate the anti-HGG therapeutic potential of a fully-human monoclonal antibody, 1H5, that selectively targets activated-ADAM10, an -secretase required for NOTCH receptor processing, with high tumor specificity. We show that ADAM10 is markedly overexpressed and highly activated in primary and recurrent HGGs, using patient tissue, RNA-sequencing data, and early-passage HGG cell lines. Results: Across a panel of patient-derived HGG lines, sensitivity to 1H5 correlates with the cell-surface levels of activated-ADAM10, and shRNA-mediated ADAM10 knockdown recapitulates the growth-inhibitory effects of 1H5. ADAM10 inhibition suppresses NOTCH-pathway components and target genes, reduces expression of GPC markers, and impairs neurosphere formation while depleting Sox2- and Ki67-positive cells. We further find that 1H5 induces HGG cell death predominantly via necroptosis, characterized by survivin loss and increased phosphorylated MLKL and by transcriptional changes in necroptosis-related genes. In three-dimensional explants derived from primary HGG, 1H5 reduces growth and GPC marker expression while increasing TUNEL staining. Finally, convection-enhanced delivery of 1H5 in orthotopic xenograft models achieves high local intracranial concentrations, slows tumor growth, and prolongs survival, with regional pharmacodynamic effects consistent with NOTCH pathway suppression and necroptosis.
ER -