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Lipid Nanoparticle Delivery System for mRNA Encoding B7H3-redirected Bispecific Antibody Displays Potent Antitumor Effects on Malignant Tumors
Advanced Science ( IF 14.3 ) Pub Date : 2022-11-20 , DOI: 10.1002/advs.202205532 Cheng Huang 1 , Xing Duan 1 , Jichao Wang 1 , Qingqing Tian 1 , Yangmei Ren 1 , Kepan Chen 1 , Zongliang Zhang 1 , Yuanyou Li 2 , Yunyu Feng 1 , Kunhong Zhong 1 , Yuelong Wang 2 , Liangxue Zhou 2 , Gang Guo 1 , Xiangrong Song 3 , Aiping Tong 1
Advanced Science ( IF 14.3 ) Pub Date : 2022-11-20 , DOI: 10.1002/advs.202205532 Cheng Huang 1 , Xing Duan 1 , Jichao Wang 1 , Qingqing Tian 1 , Yangmei Ren 1 , Kepan Chen 1 , Zongliang Zhang 1 , Yuanyou Li 2 , Yunyu Feng 1 , Kunhong Zhong 1 , Yuelong Wang 2 , Liangxue Zhou 2 , Gang Guo 1 , Xiangrong Song 3 , Aiping Tong 1
Affiliation
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The therapeutic use of bispecific T-cell engaging (BiTE) antibodies has shown great potential for treating malignancies. BiTE can simultaneously engage CD3ε on T cells and tumor antigen on cancer cells, thus exerting an effective antitumor effect. Nevertheless, challenges in production, manufacturing, and short serum half-life of BiTE have dampened some of the promise and impeded the pace of BiTE-based therapeutics to combat diseases. Nowadays, in vitro-transcribed mRNA has achieved programmed production, which is more flexible and cost-effective than the traditional method of producing recombinant antibody. Here, the authors have developed a BiTE-based mRNA treatment by encapsulating mRNA encoding B7H3×CD3 BiTE into a novel ionizable lipid nanoparticles (LNPs). The authors have found that LNPs have high transfection efficiency, and the hepatosplenic targeting capability of produce high concentrations of BiTE. Above all, a single intravenous injection of BiTE mRNA-LNPs could achieve high levels of protein expression in vivo and significantly prolonged the half-life of the BiTE, which can elicit robust and durable antitumor efficacy against hematologic malignancies and melanoma. Therefore, their results suggested that the therapeutic strategy based on mRNA expression of B7H3×CD3 BiTE is of potential research value and has promising clinical application prospects.
中文翻译：
用于编码 B7H3 重定向双特异性抗体 mRNA 的脂质纳米颗粒递送系统对恶性肿瘤显示出有效的抗肿瘤作用
双特异性 T 细胞接合 (BiTE) 抗体的治疗用途已显示出治疗恶性肿瘤的巨大潜力。 BiTE可以同时结合T细胞上的CD3ε和癌细胞上的肿瘤抗原，从而发挥有效的抗肿瘤作用。然而，BiTE 的生产、制造和较短的血清半衰期等方面的挑战削弱了一些前景，并阻碍了基于 BiTE 的疗法对抗疾病的步伐。如今，体外转录的mRNA已经实现了程序化生产，比传统的重组抗体生产方法更加灵活、更具成本效益。在这里，作者通过将编码 B7H3×CD3 BiTE 的 mRNA 封装到新型可电离脂质纳米颗粒 (LNP) 中，开发了一种基于 BiTE 的 mRNA 治疗方法。作者发现LNPs具有高转染效率，并且具有产生高浓度BiTE的肝脾靶向能力。最重要的是，单次静脉注射 BiTE mRNA-LNP 可以在体内实现高水平的蛋白质表达，并显着延长 BiTE 的半衰期，从而对血液恶性肿瘤和黑色素瘤产生强大而持久的抗肿瘤功效。因此，他们的结果表明，基于B7H3×CD3 BiTE mRNA表达的治疗策略具有潜在的研究价值和良好的临床应用前景。
更新日期：2022-11-20
中文翻译：
用于编码 B7H3 重定向双特异性抗体 mRNA 的脂质纳米颗粒递送系统对恶性肿瘤显示出有效的抗肿瘤作用
双特异性 T 细胞接合 (BiTE) 抗体的治疗用途已显示出治疗恶性肿瘤的巨大潜力。 BiTE可以同时结合T细胞上的CD3ε和癌细胞上的肿瘤抗原，从而发挥有效的抗肿瘤作用。然而，BiTE 的生产、制造和较短的血清半衰期等方面的挑战削弱了一些前景，并阻碍了基于 BiTE 的疗法对抗疾病的步伐。如今，体外转录的mRNA已经实现了程序化生产，比传统的重组抗体生产方法更加灵活、更具成本效益。在这里，作者通过将编码 B7H3×CD3 BiTE 的 mRNA 封装到新型可电离脂质纳米颗粒 (LNP) 中，开发了一种基于 BiTE 的 mRNA 治疗方法。作者发现LNPs具有高转染效率，并且具有产生高浓度BiTE的肝脾靶向能力。最重要的是，单次静脉注射 BiTE mRNA-LNP 可以在体内实现高水平的蛋白质表达，并显着延长 BiTE 的半衰期，从而对血液恶性肿瘤和黑色素瘤产生强大而持久的抗肿瘤功效。因此，他们的结果表明，基于B7H3×CD3 BiTE mRNA表达的治疗策略具有潜在的研究价值和良好的临床应用前景。
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