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dc.contributor.authorSharma, Ankuren_US
dc.contributor.authorGadkari, Rupali Aen_US
dc.contributor.authorRamakanth, Satthenapalli Ven_US
dc.contributor.authorPadmanabhan, Krishnananden_US
dc.contributor.authorMadhumathi, Davanam Sen_US
dc.contributor.authorDevi, Lakshmien_US
dc.contributor.authorAppaji, Lingappaen_US
dc.contributor.authorAster, Jon Cen_US
dc.contributor.authorRangarajan, Annapoornien_US
dc.contributor.authorDighe, Rajan Ren_US
dc.date.accessioned2015-07-13T18:47:07Z
dc.date.issued2015en_US
dc.identifier.citationSharma, Ankur, Rupali A Gadkari, Satthenapalli V Ramakanth, Krishnanand Padmanabhan, Davanam S Madhumathi, Lakshmi Devi, Lingappa Appaji, Jon C Aster, Annapoorni Rangarajan, and Rajan R Dighe. 2015. “A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors.” Scientific Reports 5 (1): 11012. doi:10.1038/srep11012. http://dx.doi.org/10.1038/srep11012.en
dc.identifier.issn2045-2322en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17295664
dc.description.abstractHigher Notch signaling is known to be associated with hematological and solid cancers. We developed a potential immunotherapeutic monoclonal antibody (MAb) specific for the Negative Regulatory Region of Notch1 (NRR). The MAb604.107 exhibited higher affinity for the “Gain-of-function” mutants of Notch1 NRR associated with T Acute lymphoblastic Leukemia (T-ALL). Modeling of the mutant NRR with 12 amino-acid insertion demonstrated “opening” resulting in exposure of the S2-cleavage site leading to activated Notch1 signaling. The MAb, at low concentrations (1–2 μg/ml), inhibited elevated ligand-independent Notch1 signaling of NRR mutants, augmented effect of Thapsigargin, an inhibitor of mutant Notch1, but had no effect on the wild-type Notch1. The antibody decreased proliferation of the primary T-ALL cells and depleted leukemia initiating CD34/CD44 high population. At relatively high concentrations, (10–20 μg/ml), the MAb affected Notch1 signaling in the breast and colon cancer cell lines. The Notch-high cells sorted from solid-tumor cell lines exhibited characteristics of cancer stem cells, which were inhibited by the MAb. The antibody also increased the sensitivity to Doxorubucinirubicin. Further, the MAb impeded the growth of xenografts from breast and colon cancer cells potentiated regression of the tumors along with Doxorubucin. Thus, this antibody is potential immunotherapeutic tool for different cancers.en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.relation.isversionofdoi:10.1038/srep11012en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457015/pdf/en
dash.licenseLAAen_US
dc.titleA novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumorsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalScientific Reportsen
dash.depositing.authorAster, Jon Cen_US
dc.date.available2015-07-13T18:47:07Z
dc.identifier.doi10.1038/srep11012*
dash.contributor.affiliatedAster, Jon


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