具有tigit人源化BALB/c小鼠肿瘤治疗潜力的抗tigit抗体编码mrna的设计与优化

Jingmin Cui, Qiaerxie Gulisaina, Qin Hui, Long Feng, Wang Xi, Zhixin Yang, Du Peng, Cui Yong
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引用次数: 0

摘要

mRNA药物采用无细胞系统合成,无需复杂和严格的制造工艺,制备简单、高效、经济。近年来,编码抗体的mrna已成为抗体药物开发的研究前沿之一。在癌症免疫治疗中,编码免疫检查点抗体的mrna对于患者抗肿瘤免疫反应的抗体持久性和持久性可能是有利的。在我们之前的研究中,报道了一种靶向新型免疫检查点TIGIT的候选抗体aet2010。我们还利用NK-92MI细胞过继转移异种移植小鼠模型来研究其抗肿瘤活性,但该模型的局限性无法进行精确评估。在本研究中,我们进一步研究了AET2010对tigit人源化BALB/c小鼠癌症的治疗潜力。接下来,我们探索了编码AET2010的mRNA的设计、合成和优化,最终获得了一个候选mRNA (mRNA- bu),该mRNA在体外和体内都具有良好的活性AET2010表达水平。特别是,脂质纳米颗粒包裹的mRNA-BU给小鼠产生的AET2010的峰值浓度和表达时间明显高于等效剂量的原始AET2010。该研究为开发靶向TIGIT的新药提供了良好的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design and optimization of mRNAs encoding an Anti-TIGIT antibody with therapeutic potential for cancer in TIGIT-humanized BALB/c Mice
mRNA drugs are synthesized using cell-free systems without complex and stringent manufacturing processes, which makes their preparation simple, efficient, and economical. Over the past few years, mRNAs encoding antibodies have been one of the research frontiers of antibody drug development. In cancer immunotherapy, mRNAs encoding immune checkpoint antibodies may be advantageous regarding antibody persistence and durability of the anti-tumor immune response of patients. In our previous study, a candidate antibody—AET2010—targeting the novel immune checkpoint TIGIT was reported. Its anti-tumor activity was also investigated using adoptive transfer of NK-92MI cells in a xenograft mouse model, but the limitations of the model did not facilitate precise evaluation. In the present study, we further investigated the therapeutic potential of AET2010 for cancer in TIGIT-humanized BALB/c mice. Next, we explored the design, synthesis, and optimization of mRNAs encoding AET2010 and ultimately obtained a candidate mRNA (mRNA-BU) with favorable in vitro and in vivo expression levels of active AET2010. Particularly, lipid-nanoparticle-encapsulated mRNA-BU delivered to mice produced AET2010 with significantly higher peak concentration and expression duration than an equivalent dose of original AET2010. This study provides a sound basis for developing novel drugs targeting TIGIT.
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