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 conjugates to target and reduce DRR/FAM107A expression. Specifically, we used antibodies against antigens expressed on the glioblastoma stem cells, such as CD44 and EphA2, conjugated to chemically modified antisense oligonucleotides (AONs) against DRR/FAM107A, which were designed as chimeras of DNA and 2ʹ-deoxy-2ʹ-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.

胶质母细胞瘤干细胞（GSC）是侵袭性，具有治疗抗性的脑癌细胞，在肾细胞癌（DRR）中表达下调，而肾细胞癌（DRR）也称为FAM107A，它是GSC侵袭的遗传驱动力。我们开发了抗体反义寡核苷酸偶联物，以靶向和减少DRR / FAM107A表达。具体而言，我们使用了针对胶质母细胞瘤干细胞表达的抗原（例如CD44和EphA2）的抗体，该抗体与针对DRR / FAM107A的化学修饰的反义寡核苷酸（AON）偶联，这些寡核苷酸被设计为DNA和2′-脱氧-2′-氟-荧光素的嵌合体。 β-D-阿拉伯糖核酸（FANA）可增加核酸酶的稳定性和mRNA亲和力。我们证明这些治疗共轭物成功地内在化，积累，并减少患者来源的GSCs中的DRR / FAM107A表达。