Catuogno Silvia, Di Martino Maria Teresa, Nuzzo Silvia, Esposito Carla Lucia, Tassone Pierfrancesco, de Franciscis Vittorio
IEOS - Istituto per l'endocrinologia e l'oncologia "Gaetano Salvatore," CNR, Naples, Italy.
Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
Mol Ther Nucleic Acids. 2019 Dec 6;18:981-990. doi: 10.1016/j.omtn.2019.10.021. Epub 2019 Oct 28.
B cell maturation antigen is highly expressed on malignant plasma cells in human multiple myeloma and has recently emerged as a very promising target for therapeutic interventions. Nucleic-acid-based aptamers are small oligonucleotides with high selective targeting properties and functional advantages over monoclonal antibodies, as both diagnostic and therapeutic tools. Here, we describe the generation of the first-ever-described nuclease resistant RNA aptamer selectively binding to B cell maturation antigen. We adopted a modified cell-based systematic evolution of ligands by exponential enrichment approach allowing the enrichment for internalizing aptamers. The selected 2'Fluoro-Pyrimidine modified aptamer, named apt69.T, effectively and selectively bound B cell maturation antigen-expressing myeloma cells with rapid and efficient internalization. Interestingly, apt69.T inhibited APRIL-dependent nuclear factor κB (NF-κB) pathway in vitro. Moreover, the aptamer was conjugated to microRNA-137 (miR-137) and anti-miR-222, demonstrating high potential against tumor cells. In conclusion, apt69.T is a novel tool suitable for direct targeting and delivery of therapeutics to B cell maturation antigen-expressing myeloma cells.
B细胞成熟抗原在人类多发性骨髓瘤的恶性浆细胞上高度表达，最近已成为治疗干预的一个非常有前景的靶点。基于核酸的适配体是具有高选择性靶向特性的小寡核苷酸，作为诊断和治疗工具，比单克隆抗体具有功能优势。在此，我们描述了首个被描述的选择性结合B细胞成熟抗原的耐核酸酶RNA适配体的产生。我们采用了一种基于细胞的改进型指数富集配体系统进化方法，以富集内化适配体。所选的2'-氟嘧啶修饰的适配体，命名为apt69.T，能有效且选择性地结合表达B细胞成熟抗原的骨髓瘤细胞，并能快速有效地内化。有趣的是，apt69.T在体外抑制了APRIL依赖的核因子κB（NF-κB）通路。此外，该适配体与微小RNA-137（miR-137）和抗miR-222偶联，显示出对肿瘤细胞的高潜力。总之，apt69.T是一种适用于直接靶向并将治疗剂递送至表达B细胞成熟抗原的骨髓瘤细胞的新型工具。
