Shu Dan, Zhang Long, Bai Xuefeng, Yu Jianhua, Guo Peixuan
Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA.
College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Mol Ther Nucleic Acids. 2021 Mar 13;24:426-435. doi: 10.1016/j.omtn.2021.03.007. eCollection 2021 Jun 4.
Immunotherapy has become a revolutionary subject in cancer therapy during the past few years. Immune checkpoint-targeting antibodies (Abs) could boost anticancer immune responses. However, certain protein-based immunotherapies revealed side effects and unfavorable biodistribution, so effective non-protein options with lower side effects are highly sought after. RNA's ability to form various three-dimensional configurations allows for the creation of a variety of ligands to bind different cell receptors. The rubber-like properties of RNA nanoparticles (NPs) allow for swift lodging to cancer vasculature with little accumulation in vital organs, resulting in a favorable pharmacokinetic/pharmacodynamic (PK/PD) profile and safe pharmacological parameters. Multi-specific drugs are expected to be the fourth wave of biopharmaceutical innovation. Herein, we report the development of multi-specific Ab-like RNA NPs carrying multiple ligands for immunotherapy. The stoichiometries and stereo conformations of the checkpoint-activating RNA NPs were optimized for T cell activation. When compared to mono- and bi-specific RNA NPs, the tri-specific Ab-like RNA NPs bound to the trimeric T cell receptor with the highest efficiency, showed the optimal T cell activation, and promoted the strongest anti-tumor function of immune cells. Animal trials demonstrated that the tri-specific RNA NPs inhibited cancer growth. This Ab-like RNA NP platform represents an alternative to protein Abs for tumor immunotherapy.
在过去几年中，免疫疗法已成为癌症治疗领域的一个革命性课题。免疫检查点靶向抗体（Abs）能够增强抗癌免疫反应。然而，某些基于蛋白质的免疫疗法显示出副作用和不良的生物分布，因此人们迫切需要副作用更低的有效非蛋白质选择。RNA形成各种三维结构的能力使得能够创建多种配体以结合不同的细胞受体。RNA纳米颗粒（NPs）类似橡胶的特性使其能够迅速附着于癌血管，而在重要器官中积累很少，从而产生良好的药代动力学/药效学（PK/PD）特征和安全的药理学参数。多特异性药物有望成为生物制药创新的第四波浪潮。在此，我们报告了用于免疫治疗的携带多种配体的多特异性类抗体RNA纳米颗粒的研发情况。对检查点激活RNA纳米颗粒的化学计量和立体构象进行了优化以激活T细胞。与单特异性和双特异性RNA纳米颗粒相比，三特异性类抗体RNA纳米颗粒以最高效率与三聚体T细胞受体结合，表现出最佳的T细胞激活，并促进免疫细胞最强的抗肿瘤功能。动物试验表明，三特异性RNA纳米颗粒可抑制肿瘤生长。这种类抗体RNA纳米颗粒平台代表了用于肿瘤免疫治疗的蛋白质抗体的一种替代方案。
