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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (6): 113-124    DOI: 10.13523/j.cb.2210042
行业分析     
mRNA药物研究进展及市场应用分析
黄可1,李山红2,*()
1 北京医药健康科技发展中心 北京 100035
2 智凤科技(北京)有限公司 北京 100089
Analysis of mRNA Drug Development and Market Application
HUANG Ke1,LI Shan-hong2,*()
1 Beijing Pharma & Biotech Center(BPBC), Beijing 100352, China
2 Zhifeng Technology (Beijing) Co., Ltd., Beijing 100089, China
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摘要：

信使RNA(messenger RNA,mRNA)是一段编码蛋白质的核糖核苷酸序列,因为其进入细胞经翻译修饰后可以表达目的蛋白,所以mRNA分子可以作为药物治疗相应的疾病。mRNA药物用于治疗多种疾病,包括感染性疾病、肿瘤,以及由于缺少某种蛋白质或者某种蛋白质机能异常所引起的疾病,甚至作为基因编辑的工具参与基因治疗。mRNA分子作为疫苗用于预防感染性疾病已经在市场上取得了巨大的成功,因此其应用潜力得到了广泛的关注。由于mRNA药物应用方向广泛,且mRNA药物具有研发生产过程快、生产成本较低等优势,目前多种mRNA药物的相关研究正在进行中。就mRNA的基础结构、mRNA的递送系统、国内外mRNA药物的研究及临床进程进行综述,并对进一步广泛应用mRNA药物所面临的问题进行探讨。
关键词： mRNA药物;  mRNA应用;  国内mRNA疫苗;  mRNA临床进展    
Abstract:

Messenger RNA (mRNA) is a kind of nucleic acid sequence which can express any protein of interest after its translation and modification in cells. Because of its inherent feature of protein of interest production, mRNA has potential to be used as drugs to treat various diseases, including viral infections, tumors, diseases caused by deficiency or abnormality of a certain protein in vivo, as well as genetic diseases by encoding Cas9 protein which is involved in gene editing. With the great success of mRNA vaccines, mRNA drugs have drawn increasing attention for their application potential. In addition, due to their advantages such as rapid research and development cycle, the ease and rapid large-scale production at low cost, and elimination of insertional mutagenesis and integration risk for the host, mRNA drugs have become the third generation of drugs after small molecule and antibody drugs. In this review, the structural properties and the delivery system of mRNA are introduced, the clinical progress of mRNA therapeutics and domestic mRNA vaccine development are summarized, and the remaining problems to be solved in the market application including research, manufacture and logistics of mRNA therapeutics are discussed, hoping to provide a reference for mRNA drug discovery and manufacturing.
Key words: mRNA drugs    mRNA biologicals    Domestic mRNA vaccine    mRNA clinical progress
收稿日期: 2022-10-26 出版日期: 2023-07-04
ZTFLH:  Q522+.2  
通讯作者: *电子信箱:13621149254@139.com   
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引用本文:

黄可, 李山红. mRNA药物研究进展及市场应用分析[J]. 中国生物工程杂志, 2023, 43(6): 113-124.

HUANG Ke, LI Shan-hong. Analysis of mRNA Drug Development and Market Application. China Biotechnology, 2023, 43(6): 113-124.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2210042    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I6/113

图1  mRNA药物研究里程碑
图2  2020年和2021年全球销售量前十药物
图3  mRNA结构[9]
图4  LNP结构示意图[1]
疫苗靶标 临床试验批号 临床进展 制造商
狂犬病毒 NCT02241135 I期 CureVac AG
巨细胞病毒 NCT03382405 I期 ModernaTX, Inc.
人偏肺病毒与副流感病毒3型 NCT03392389 I期 ModernaTX, Inc.
尼帕病毒 NCT05398796 招募中 National Institute of Allergy and Infectious Diseases
(NIAID)& ModernaTX, Inc.
人类免疫缺陷病毒 NCT05217641 招募中 National Institute of Allergy and Infectious Diseases (NIAID)
基孔肯亚病毒 NCT03829384 I期 ModernaTX, Inc.
EB病毒 NCT05164094 招募中 ModernaTX, Inc.
寨卡病毒 NCT03014089 I期 ModernaTX, Inc.
新型冠状病毒 NCT05435027 招募中 Gritstone bio, Inc.
呼吸道合胞病毒 NCT05127434 III期中 ModernaTX, Inc.
流感病毒 NCT05252338 招募中 GSK& CureVac AG
表1  针对感染性疾病的mRNA疫苗临床进展示例
疫苗名称 临床试验批号 临床进展 靶标 厂商
DC-mRNA NCT00846456 I/II Glioblastoma Oslo University Hospital
个体化mRNA疫苗 NCT03908671 未招募 sophageal cancer
Non small cell lung cancer		 Stemirna Therapeutics
个体化新抗原mRNA疫苗 NCT05192460 招募中 Gastric cancer,
Esophageal cancer,
Liver cancer		 NeoCura& The Affiliated Hospital of the Chinese
Academy of Military Medical Sciences
CV9201 NCT00923312 III期 Non small cell lung cancer CureVac AG
BI 1361849 NCT03164772 II期 Non small cell lung cancer Ludwig Institute for Cancer Research;
oehringer Ingelheim MedImmune LLC
CureVac AG
PharmaJet, Inc.
BNT111 NCT04526899 II完成 Melanoma BioNTech SE
TriMix-DC NCT01066390 I期完成 Melanoma Universitair Ziekenhuis Brussel
Melan-A, Mage-A1, Mage-A3
Survivin, gp100, NCT00204516 I/II完成 Melanoma University Hospital Tuebingen
CV9104 NCT02140138 II期终止 Prostate cancer CureVac AG
mRNA- 4157 NCT03313778 招募中 Solid tumor ModernaTX, Inc.
DC-006 (DC-mRNA) NCT01334047 I/II终止 Ovarian Cancer Oslo University Hospital
W_ova1 NCT04163094 招募中 Ovarian Cancer University Medical Center Groningen
表2  mRNA肿瘤疫苗临床进程
治疗方向 抗体形式 靶标或适应证 研究进程 研究团队
肿瘤 双特异性 实体瘤 研究阶段 BioNTech AG
未披露 实体瘤 临床前 BioNTech AG
IgG CD20 研究阶段 CurVac AG
未披露 表面肿瘤 临床前 CurVac AG
感染性疾病 IgG 人类免疫缺陷病毒 研究阶段 University of Pennsylvania
IgG 狂犬病毒 研究阶段 CurVac AG
IgG 乙型流感病毒 研究阶段 CurVac AG
IgG 甲型流感病毒 研究阶段 Moderna Therapeutics
多种形式抗体 呼吸道合胞病毒 研究阶段 Georgia Institution of Technology
and Emory University
未披露(mRNA-1944) 基孔肯亚病毒 临床I期 Moderna Therapeutics/DARPA
毒素 中和抗体 肉毒菌毒素 研究阶段 CurVac AG
中和抗体 志贺毒素 研究阶段 CurVac AG
表3  基于mRNA表达的抗体药物研究进展[34]
靶标 临床试验批号 临床试验进展 技术路线 厂商
病毒性角膜炎 NCT04560790 I/II期 CRISPR/Cas9 Shanghai BDgene Co., Ltd.
遗传性血管水肿 NCT05120830 I/II期 CRISPR/Cas9 Intellia Therapeutics
ZFN修饰的T细胞治疗HIV感染 NCT02388594 I期 ZFN University of Pennsylvania
镰刀状红细胞 NCT03653247 I/II期 ZFN Sangamo Therapeutics
表4  基于mRNA的基因编辑临床试验
名称 研发企业 临床进程 靶标
ARCoV 艾博/沃森 III期 新冠原始毒株
奥密克戎mRNA疫苗 艾博 获得临床批件 新冠奥密克戎变异株
- 斯微生物 II期 新冠原始毒株
LVRNA009 丽凡达/艾美 III期 新冠原始毒株
SYS6006 石药 II期 新冠奥密克戎变异株和德尔塔突变株
- 康希诺 I/II期 新冠原始毒株
R520A 瑞科/瑞吉 I期 新冠原始毒株
- 锐博/阿格纳 I期 新冠原始毒株
- 威斯津 IND申请 新冠奥密克戎变异株和德尔塔突变株
RQ3011/3012/3013 蓝鹊/沃森/复旦 临床前 新冠原始毒株
新冠突变株mRNA疫苗 蓝鹊/沃森 临床前 新冠原始毒株
- 中生复诺健 临床前 新冠奥密克戎变异株和德尔塔突变株
表5  国内mRNA疫苗研发产线进展
图5  mRNA药物生产过程[42]
厂商 冷冻条件下储存稳定性 2-8℃储存稳定性 室温储存稳定性
Moderna -20℃,约6个月 30天 约24 h
Pfizer-BioNTech -80~ -60℃、约6个月,或-20℃、2周 约1个月 约2 h
表6  国外mRNA疫苗储存条件与稳定性
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