Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity
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Helena C. Christianson1,*, Julien A. Menard1,*, Vineesh Indira Chandran1, Erika Bourseau-Guilmain2, Dmitry Shevela3, Jon Lidfeldt1, Ann-Sofie Månsson1, Silvia Pastorekova4, Johannes Messinger3,5 and Mattias Belting1,6
1Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden
2CNRS UMR 5237 CRBM, Montpellier University, Montpellier, France
3Department of Chemistry, Chemical Biological Centre, Umeå University, Umeå, Sweden
4Biomedical Research Centre, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
5Department of Chemistry – Ångström, Molecular Biomimetics, Uppsala University, Uppsala, Sweden
6Department of Oncology, Skåne University Hospital, Lund, Sweden
*These authors have contributed equally to this work
Mattias Belting, email: [email protected]
Keywords: tumor antigen, glycosylation, hypoxia, immunotherapy, proteoglycan
Received: February 14, 2017 Accepted: March 19, 2017 Published: April 07, 2017
Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.
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