Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells

Amy E Arnold; Elise Malek-Adamian; Phuong U Le; Anika Meng; Saúl Martínez-Montero; Kevin Petrecca; Masad J Damha; Molly S Shoichet

doi:10.1016/j.omtn.2018.04.004

Antibody-Antisense Oligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma Stem Cells

Mol Ther Nucleic Acids. 2018 Jun 1:11:518-527. doi: 10.1016/j.omtn.2018.04.004. Epub 2018 Apr 19.

Authors

Amy E Arnold¹, Elise Malek-Adamian², Phuong U Le³, Anika Meng⁴, Saúl Martínez-Montero², Kevin Petrecca³, Masad J Damha⁵, Molly S Shoichet⁶

Affiliations

¹ Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada.
² Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
³ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁴ Division of Engineering Science, University of Toronto, 35 St. George Street, Toronto, ON M5S 1A4, Canada.
⁵ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada. Electronic address: [email protected].
⁶ Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada. Electronic address: [email protected].

Abstract

Glioblastoma stem cells (GSCs) are invasive, treatment-resistant brain cancer cells that express downregulated in renal cell carcinoma (DRR), also called FAM107A, a genetic driver of GSC invasion. We developed antibody-antisense oligonucleotide (AON) conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the GSCs, such as CD44 and EphA2, conjugated to chemically modified AONs against DRR/FAM107A, which were designed as chimeras of DNA and 2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid (FANA) for increased nuclease stability and mRNA affinity. We demonstrate that these therapeutic conjugates successfully internalize, accumulate, and reduce DRR/FAM107A expression in patient-derived GSCs. This is the first example of an antibody-antisense strategy against cancer stem cells.

Keywords: FAM107A; antibody conjugates; antisense oligonucleotides; gene therapy; glioblastoma stem cells; targeted therapies.