选择靶向 CD19 的核酸酶抗性 RNA 适体。,Cancers

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选择靶向 CD19 的核酸酶抗性 RNA 适体。
Cancers ( IF 4.5 ) Pub Date : 2021-10-18 , DOI: 10.3390/cancers13205220
Carla L Esposito ₁ , Katrien Van Roosbroeck ₂ , Gianluca Santamaria ₃ , Deborah Rotoli ₁ , Annamaria Sandomenico ₄ , William G Wierda ₅ , Alessandra Ferrajoli ₅ , Menotti Ruvo ₄ , George A Calin _{5,

6,

7,

8} , Vittorio de Franciscis _{1,

8} , Silvia Catuogno ₁

Affiliation

跨膜分化糖蛋白簇 19 (CD19) 是 B 细胞特异性表面标志物，在大多数肿瘤性 B 细胞上表达，最近已成为非常有吸引力的生物标志物和 B 细胞恶性肿瘤的治疗靶点。开发安全有效的 CD19 配体已成为开发靶向常规疗法和免疫疗法的重要需求。在这方面，适配体代表了一类非常有趣的分子。另外被称为“化学抗体”，它们显示出许多作为治疗剂的优势，包括低毒性和免疫原性。在这里，我们分离了与人 CD19 糖蛋白结合的抗核酸酶 RNA 适配体。为了开发也可用作二级试剂载体的适体，我们采用了基于细胞的 SELEX（指数富集配体系统进化）方案，该方案适用于分离能够在与其细胞表面靶标结合后内化的适体。我们描述了一种名为 B85.T2 的 2'-氟嘧啶修饰适体，它专门与 CD19 结合并在人血清中显示出极好的稳定性。该适配体在纯化的人重组 CD19 (rhCD19) 糖蛋白上显示出 49.9 ± 13 nM 的估计解离常数 (KD)，对表达 CD19 的人 B 细胞慢性淋巴细胞白血病细胞具有良好的结合活性，以及有效且快速的细胞内化，因此代表了一种用于 CD19 靶向以及开发新的 B 细胞恶性肿瘤靶向疗法的有前途的分子。

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Selection of a Nuclease-Resistant RNA Aptamer Targeting CD19.

The transmembrane glycoprotein cluster of differentiation 19 (CD19) is a B cell-specific surface marker, expressed on the majority of neoplastic B cells, and has recently emerged as a very attractive biomarker and therapeutic target for B-cell malignancies. The development of safe and effective ligands for CD19 has become an important need for the development of targeted conventional and immunotherapies. In this regard, aptamers represent a very interesting class of molecules. Additionally referred to as 'chemical antibodies', they show many advantages as therapeutics, including low toxicity and immunogenicity. Here, we isolated a nuclease-resistant RNA aptamer binding to the human CD19 glycoprotein. In order to develop an aptamer also useful as a carrier for secondary reagents, we adopted a cell-based SELEX (Systematic Evolution of Ligands by EXponential Enrichment) protocol adapted to isolate aptamers able to internalise upon binding to their cell surface target. We describe a 2'-fluoro pyrimidine modified aptamer, named B85.T2, which specifically binds to CD19 and shows an exquisite stability in human serum. The aptamer showed an estimated dissociation constant (KD) of 49.9 ± 13 nM on purified human recombinant CD19 (rhCD19) glycoprotein, a good binding activity on human B-cell chronic lymphocytic leukaemia cells expressing CD19, and also an effective and rapid cell internalisation, thus representing a promising molecule for CD19 targeting, as well as for the development of new B-cell malignancy-targeted therapies.

更新日期：2021-10-18

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