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Title: Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma.
Austin Authors: Gilabert-Oriol, Roger;Furness, Sebastian G B;Stringer, Brett W;Weng, Alexander;Fuchs, Hendrik;Day, Bryan W;Kourakis, Angela;Boyd, Andrew W;Hare, David L ;Thakur, Mayank;Johns, Terrance G;Wookey, Peter J 
Affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Cardiology, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Department of Experimental Therapeutics, BC Cancer Research Centre, 675 W 10th Ave, Vancouver, BC, V5Z IL3, Canada
Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University (Parkville), Parkville, Victoria, Australia
QIMR-Berghofer Medical Research Institute, Brisbane, QLD, Australia
Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
Institute of Pharmacy, Königin-Luise-Str. 2+4, 14195, Berlin, Germany
Hudson Institute of Medical Research, Monash University (Clayton), Clayton, Victoria, Australia
Issue Date: Sep-2017 2017-05-13
Publication information: Cancer immunology, immunotherapy : CII 2017; 66(9): 1217-1228
Abstract: We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC50for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC50for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.
DOI: 10.1007/s00262-017-2013-z
ORCID: 0000-0002-3937-1621
Journal: Cancer immunology, immunotherapy : CII
PubMed URL: 28501939
Type: Journal Article
Subjects: Calcitonin receptor
High-grade glioma cell lines
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