A Homodimeric Aptamer Variant Generated from Ligand-Guided Selection Activates the T Cell Receptor Cluster of Differentiation 3 Complex
A Homodimeric Aptamer Variant Generated from Ligand-Guided Selection Activates the T Cell Receptor Cluster of Differentiation 3 Complex
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DOI：
10.1016/j.omtn.2020.08.016
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
Mallikaratchy, Prabodhika R.
中科院分区：
文献类型：
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作者：
Freage, Lina;Jamal, Deana;Mallikaratchy, Prabodhika R.
最近，利用基因工程细胞和单抗的免疫治疗方法已经在治疗几种恶性肿瘤方面取得了有效的效果。核酸适配子可以作为替代分子设计具有高度功能多样性的免疫治疗剂。在这里，我们报道了一个由DNA适配子组成的合成原型，它可以激活培养的T细胞中的T细胞分化受体簇3(TCR-CD3)复合体。我们发现其激活潜能与抗TCR-CD3的单抗相似，提示适配子具有开发有效的合成免疫调节剂的潜力。本文所述的抗TCRCD3 epsilon的合成原型是利用配体引导选择(LIGS)产生的针对TCR-CD3 epsilon的适体ZUCH1来设计的。适体ZUCH-1被截短并用抗核酸酶的RNA类似物修饰以提高稳定性。几个带有截短和修饰变体的二聚体类似物被设计成具有可变连接子长度的二聚体类似物，以研究每个构建体的激活潜力。其中，尺寸与抗体相似的二聚体适配子表现出最高的T细胞活性，这表明在工程功能适配子中优化接头长度的重要性。观察到的二聚体适配子的激活潜力表明，适配子在设计具有可调药代动力学特性的合成多功能免疫调节剂、通过使用核酸配体(如适配子)来扩大免疫治疗设计方面具有巨大的潜力。
Recently, immunotherapeutic modalities with engineered cells and monoclonal antibodies have been effective in treating several malignancies. Nucleic acid aptamers can serve as alternative molecules to design immunotherapeutic agents with high functional diversity. Here we report a synthetic prototype consisting of DNA aptamers that can activate the T cell receptor cluster of differentiation 3 (TCR-CD3) complex in cultured T cells. We show that the activation potential is similar to that of a monoclonal antibody (mAb) against TCR-CD3, suggesting potential for aptamers in developing efficacious synthetic immunomodulators. The synthetic prototype of anti-TCRCD3 epsilon, as described here, was designed using aptamer ZUCH1 against TCR-CD3 epsilon, generated by ligand-guided selection (LIGS). Aptamer ZUCH-1 was truncated and modified with nuclease-resistant RNA analogs to enhance stability. Several dimeric analogs with truncated and modified variants were designed with variable linker lengths to investigate the activation potential of each construct. Among them, a dimeric aptamer with dimensions approximately similar to those of an antibody showed the highest T cell activation, suggesting the importance of optimizing linker lengths in engineering functional aptamers. The observed activation potential of dimeric aptamers shows the vast potential of aptamers in designing synthetically versatile immunomodulators with tunable pharmacokinetic properties, expanding immunotherapeutic designs by using nucleic acid-based ligands such as aptamers.