mRNA药物制造的现状与未来展望,Molecular Pharmaceutics

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mRNA药物制造的现状与未来展望
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2022-03-03 , DOI: 10.1021/acs.molpharmaceut.2c00010
Cameron Webb ₁ , Shell Ip ₂ , Nuthan V Bathula ₃ , Petya Popova ₃ , Shekinah K V Soriano ₃ , Han Han Ly ₃ , Burcu Eryilmaz ₁ , Viet Anh Nguyen Huu ₂ , Richard Broadhead ₂ , Martin Rabel ₂ , Ian Villamagna ₂ , Suraj Abraham ₂ , Vahid Raeesi ₂ , Anitha Thomas ₂ , Samuel Clarke ₂ , Euan C Ramsay ₂ , Yvonne Perrie ₁ , Anna K Blakney ₃

Affiliation

2019 年冠状病毒病 (COVID-19) 大流行引发了前所未有的全球努力，以快速开发疫苗以阻止新型严重急性呼吸系统综合症冠状病毒 (SARS-CoV-2) 的传播。信使核糖核酸 (mRNA) 疫苗由那些积极开发 mRNA 疗法和其他适应症疫苗的公司迅速开发出来，导致两种 mRNA 疫苗不仅成为第一个被批准用于紧急使用的 SARS-CoV-2 疫苗，而且也是第一个mRNA药物获得紧急使用授权并最终获得全面批准。这是可能的，部分原因是 mRNA 序列可以被改变以编码几乎任何蛋白质，而不会显着改变其化学性质，从而使药物物质成为药品的模块化成分。保护核糖核酸 (RNA) 并介导递送到细胞细胞质中所需的脂质纳米颗粒 (LNP) 技术同样是模块化的，将 RNA 封装到 LNP 中所需的技术和基础设施也是模块化的。这使得该技术能够快速适应新的目标。在 mRNA 疫苗临床成功的带动下，这种模块化将为未来用于癌症、基因治疗和 RNA 工程细胞治疗的 RNA 药物铺平道路。在这篇综述中，对发表记录和临床试验注册的趋势进行了统计，以显示 RNA 药物临床前和临床研究的急剧加强。RNA原料药（DS）和LNP药品（DP）的生产需求已经紧张，导致疫苗短缺，未来几年其他mRNA药物开发和翻译的增加将加剧这种情况拉紧。为了估计 DP 生产的需求，对两种已批准的 mRNA 疫苗的临床前和临床研究的剂量要求进行了检查。为了了解 mRNA-LNP 生产的现状，我们回顾了当前的方法和技术，以及当前和宣布的全球商业制造能力。最后，对自放大 mRNA、微流体生产以及集成和分布式制造趋势等新兴技术将如何塑造 RNA 制造的未来并释放 RNA 医学革命的潜力的愿景进行了合理化。

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Current Status and Future Perspectives on MRNA Drug Manufacturing

The coronavirus disease of 2019 (COVID-19) pandemic launched an unprecedented global effort to rapidly develop vaccines to stem the spread of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Messenger ribonucleic acid (mRNA) vaccines were developed quickly by companies that were actively developing mRNA therapeutics and vaccines for other indications, leading to two mRNA vaccines being not only the first SARS-CoV-2 vaccines to be approved for emergency use but also the first mRNA drugs to gain emergency use authorization and to eventually gain full approval. This was possible partly because mRNA sequences can be altered to encode nearly any protein without significantly altering its chemical properties, allowing the drug substance to be a modular component of the drug product. Lipid nanoparticle (LNP) technology required to protect the ribonucleic acid (RNA) and mediate delivery into the cytoplasm of cells is likewise modular, as are technologies and infrastructure required to encapsulate the RNA into the LNP. This enabled the rapid adaptation of the technology to a new target. Upon the coattails of the clinical success of mRNA vaccines, this modularity will pave the way for future RNA medicines for cancer, gene therapy, and RNA engineered cell therapies. In this review, trends in the publication records and clinical trial registrations are tallied to show the sharp intensification in preclinical and clinical research for RNA medicines. Demand for the manufacturing of both the RNA drug substance (DS) and the LNP drug product (DP) has already been strained, causing shortages of the vaccine, and the rise in development and translation of other mRNA drugs in the coming years will exacerbate this strain. To estimate demand for DP manufacturing, the dosing requirements for the preclinical and clinical studies of the two approved mRNA vaccines were examined. To understand the current state of mRNA-LNP production, current methods and technologies are reviewed, as are current and announced global capacities for commercial manufacturing. Finally, a vision is rationalized for how emerging technologies such as self-amplifying mRNA, microfluidic production, and trends toward integrated and distributed manufacturing will shape the future of RNA manufacturing and unlock the potential for an RNA medicine revolution.

更新日期：2022-03-03

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