From "no one cares" to "people in the world", how mRNA drugs become the new darlings

“”“”，20，mRNA，mRNA，
。

mRNA、
。

mRNA

（1）CureVac

CureVac AG2000，mRNA
。CureVacRNARNActive^®、RNAntigen^®、RNArt^®、RNAdjuvant^®RNAntibody^®
。

CureVac“mRNA”（“mRNA”Moderna，BioNTechCureVac），20206，CureVacIPO；721，CureVac6.

2011，CureVac，2014，mRNA，CureVacRNActive
。

2013，CureVac，mRNA
。

2014，CureVac（BI），BICureVacmRNA
。

201710，CureVac，CureVac5；11，CureVacCRISPRCas9 mRNA
。

2018，CureVacArcturus，、mRNA
。

2019，CureVacGenmab，CureVacmRNAGenmab，mRNA
。

20207，CureVacGSK8.

　　，CureVacAcuitasAcuitasLNP
。

　　CureVac10mRNA，RNActive®，mRNA
。 CV8102、CV9202、CV7202mRNAⅠ
。

　　1 CureVac，：CureVachttps://#

　　（2）BioNTech

　　BioNTech AG2008，、
。mRNA，BioNTech，，CAR-TTCR-TmRNA、、
。

　　“mRNA”，BioNTech，2019，，、、、
。

　　2015511，BioNTech，TCR，36；519，BioNTechGenmab，1500；11，BioNTech，BioNTechmRNAmRNA，15；2019，BioNTech201511，BioNTech8000，mRNA，
。

　　2016，BioNTech，mRNA；9，BioNTechGenentech，mRNA
。

　　In July 2018, BioNTech and Genevant announced that they would cooperate to develop 5 mRNA treatments for the treatment of rare diseases with high medical demand, and reached a series of exclusive licenses to apply Genevant’s delivery technology to BioNTech’s 5 oncology Project; In October of the same year, BioNTech and Pfizer reached a strategic cooperation to develop an mRNA-based influenza vaccine
.

　　In 2020, BioNTech has reached cooperation with Pfizer and Fosun Pharma to jointly develop an mRNA COVID-19 vaccine.

　　BioNTech's clinical pipeline focuses on oncology products.

　　BioNTech is currently carrying out 1 clinical phase II study and 11 clinical phase I studies
.

　　Figure 2 BioNTech product pipeline, from: BioNTech official website https://biontech.

　　(3) Moderna

　　Moderna Therapeutics was established in 2010 and is dedicated to the development of mRNA therapy.

　　Most of Moderna's cooperation partners are pharmaceutical giants.

　　In 2015, Moderna and Merck reached a partnership on mRNA vaccines for infectious diseases, and Merck will obtain the commercialization rights of Moderna’s 5 candidate products; in 2016, Moderna and Merck again reached a partnership to provide new personalized vaccine technology based on mRNA.

　　In 2016, Moderna and Vertex signed a research and development license agreement totaling more than 300 million U.

　　Moderna has 23 mRNA drug product pipelines, including 9 preventive vaccines, 4 systemic secretion & cell surface therapies, 2 cancer vaccines, 3 intratumoral injection products, 1 local regenerative therapy and 4 systemic intracellular therapies
.
A total of 15 projects have entered the clinical development stage.
Among them, mRNA-1647, mRNA-4157 and AZD8601 have made the fastest progress.
They target cytomegalovirus (CMV) infection, tumors, heart failure, and heart attack, respectively.
All have entered phase II clinical trials Stage
.

　　Figure 3 Moderna product pipeline, from: Moderna official website https://　　(4) eTheRNA

　　eTheRNA Immunotherapies was established in 2013 as a Belgian biotechnology company.
It was founded by Professor Kris Thielemans, a famous immunologist at the Free University of Brussels, and other partners.
It relies on its proprietary mRNA TriMix platform to develop immunotherapies to treat cancer and infectious diseases.

.
eTheRNA's TriMix technology includes three mRNA fragments that express caTLR4, CD40L and CD70 respectively
.
At present, its product pipeline for melanoma has entered phase II clinical phase, and its products for breast cancer have also entered phase I clinical phase
.

　　eTheRNA received 24 million euros in Series A financing in 2016 and 34 million euros in Series B financing in 2020
.

　　In June 2020, eTheRNA and Broad Group established a strategic partnership.
Broad Group will make an equity investment of 9 million euros in eTheRNA after the relevant conditions stipulated in the investment agreement are met.
After the equity investment is completed, Broad Group will receive eTheRNA approximately 13.
% Of Class B preferred shares and one director seat
.

　　(5) Translate Bio

　　Founded in 2011, Translate Bio is an mRNA therapy company dedicated to transforming mRNA into therapeutic drugs
.
Translate Bio is headquartered in Massachusetts, USA.
It was incorporated in November 2016 under the name of RaNA Therapeutics and was renamed Translate Bio in June 2017.
It utilizes a proprietary MRTTM platform (originally developed by Shire and acquired by Translate Bio in 2016) Develop candidate products for mRNA therapy
.

　　In 2018, Translate Bio was listed on the Nasdaq.
In the same year, Translate Bio and Sanofi established a cooperative relationship to use breakthrough mRNA platform technology to develop mRNA vaccines against a variety of infectious diseases; in March 2020, both parties The agreement reached in 2018 will continue to cooperate in the development of an mRNA vaccine for the new coronavirus pneumonia
.

　　However, from the perspective of pipeline, Translate Bio's main product layout is still dominated by therapeutic products, of which the product MRT5005 for the treatment of cystic fibrosis has made the fastest progress and has now entered the clinical stage
.

　　Figure 4 Translate Bio product pipeline, from: Translate Bio official website https://translate.
bio/pipeline/

　　(6) Ethris

　　Established in 2009, Ethris is an mRNA therapy development company focusing on respiratory diseases
.
Ethris uses its pioneering SNIM ^® RNA technology platform to directly introduce mRNA into the lesion
.
At present, all Ethris pipeline products are in the pre-clinical stage, of which ETH42 has the fastest progress and is used for the treatment of Primary Ciliary Dyskinesia (PCD)
.

　　In 2017, Ethris and AstraZeneca reached a five-year mRNA research cooperation.
AstraZeneca’s MedImmune and Innovative Medicines (IMED) units will obtain exclusive rights to SNIM®RNA technology to develop respiratory drug products for the treatment of asthma.
, COPD and idiopathic pulmonary fibrosis
.

　　Figure 5 Ethris product pipeline, from: Ethris official website https://ethris.
com/pipeline/

　　(7) Argos

　　Argos Therapeutics was established in 1997 by Nobel Prize winner Ralph Steinman.
Its core technology platform Arcelis ^® is a precise immunotherapy technology that can use mRNA isolated from patient tumors to gene-edit the patient’s antigen-presenting cells , To make antigen-presenting cells produce tumor-specific antibodies to activate the body's immune response to tumors, which is suitable for the treatment of a variety of cancers and infectious diseases
.

　　Argos planned to list on the Nasdaq as early as 2012, but due to market conditions and other reasons, it announced its withdrawal from the IPO in March.
Until 2014, Argos was listed on the Nasdaq
.

　　In April 2015, Argos and Laimei (Hong Kong) Co.
, Ltd.
signed a licensing agreement.
Laimei Pharmaceuticals will obtain the right to produce, develop and commercialize AGS-003 in mainland China, Hong Kong, Taiwan and Macau
.
However, there are unpredictable circumstances.
In 2017, Laimei Pharmaceuticals issued an announcement saying that the collective assets of its Argos shares were impaired, which caused the company's performance to decline sharply.
This led to the fact that the effect of Argos' heavy research product AGS-003 is not optimistic, and then Argos The stock price plummeted
.

　　In April 2018, Argos was listed on Nasdaq's OTCQB, but the stock price situation is still not optimistic; in August, Argos shut down another AIDS immunotherapy candidate drug AGS-004 phase II clinical trial; November When Argos filed for bankruptcy
.

　　At present, according to the official website of Argos, its drug candidate AGS-003 for the treatment of metastatic renal cell carcinoma (mRCC) is still in phase 3 clinical trials
.
According to the clinical trial plan, Argos predicted that the product will complete Phase III clinical studies in mid-2016 and obtain FDA approval in mid-2017
.

　　Figure 6 Argos product pipeline, from: Argos official website

　　http://　　(8) Tiba Biotech

　　Founded in 2017, Tiba Biotech is an emerging mRNA vaccine company based on more than five-year experimental research projects of the Koch Institute of MIT, the Whitehead Institute and Boston Children's Hospital
.
Tiba Biotech is committed to using the replicon RNA technology platform to develop safer and more affordable vaccines and related diagnostic equipment for human and animal health
.

　　The products it is developing have proven protection against Ebola virus, H1N1 virus and other fatal infections in a series of animal models
.
Currently, Tiba Biotech's early production lines are focused on vaccines
.

　　Figure 7 Tiba vaccine, from: Tiba Biotech official website

　　http://tiba.
bio/technology/

　　(9) Arcturus

　　Founded in 2013 and headquartered in San Diego, California, Arcturus Therapeutics is an RNA pharmaceutical company dedicated to the development of nucleic acid drugs to treat diseases with unmet needs
.
Arcturus uses its proprietary LUNAR ^® delivery system and mRNA design and production capabilities to develop a variety of mRNA drugs, including siRNA, miRNA, ASO, replicon RNA, mRNA, DNA, and gene editing therapies
.

　　Arcturus’ external development partners include Janssen, Ultragenyx, Takeda, CureVac and Synthetic Genomics
.

　　In 2015, Arcturus and Ultragenyx reached an agreement on mRNA treatment of rare diseases.
The agreement involved a total amount of US$1.
57 billion
.

　　In 2016, Arcturus announced a collaboration with Takeda Pharmaceuticals (Takeda) to develop RNA-based treatments for non-alcoholic fatty liver (NASH) and other gastrointestinal (GI)-related diseases
.

　　In 2017, Arcturus signed a research cooperation and global licensing agreement with Janssen, a subsidiary of Johnson & Johnson, to jointly develop new drugs for the treatment of hepatitis B, and formed a strategic alliance with Synthetic Genomics to jointly develop a new generation of vaccine therapies
.

　　In 2018, Arcturus and CureVac established a strategic partnership to jointly discover, develop and commercialize new mRNA therapies
.

　　In April 2020, Arcturus' LUNAR-OTC and LUNAR-COVI19 were approved for clinical use, and the remaining products are still in the preclinical stage
.

　　LUNAR-OTC is a low-dose, systemic mRNA drug that uses Arcturus' innovative messenger RNA construct and proprietary LUNAR® delivery system to deliver OTC messenger RNA to liver cells
.

　　Figure 8 Arcturus vaccine, from: Arcturus official website

　　https://arcturusrx.
com/pipeline/

　　(10) In-Cell-Art

　　Founded in 2005, In-Cell-Art is a biopharmaceutical company that specializes in pre-clinical and drug development solutions (based on DNA/RNA vaccines or therapies), and its business is more biased towards contract R&D companies
.
In-Cell-Art uses its patented core technology, Nanoaxi ^{®, a} biosynthetic delivery system to help deliver drugs to specific parts of the body
.

　　Vaccines and treatments developed by In-Cell-Art have passed infectious disease models (HIV, influenza, dengue fever, dust mites, Mycobacterium abscessus), cancer treatment models (melanoma, liver cancer, breast cancer, and cervical cancer) and treatments The model (muscular dystrophy, renal failure anemia) was confirmed
.
Its product pipeline has 16 Nanotaxi®/DNA/RNA vaccine projects at different stages of development, of which 14 are ongoing Nanoaxis®/DNA vaccines (including 4 therapeutic vaccines and 10 preventive vaccines), 2 Nanotaxi ^® /RNA vaccine in the field of infectious diseases
.

　　In-Cell-Art participated in the cooperation between CureVac and Sanofi.
The US Department of Defense Advanced Research Projects Agency (DARPA) once selected the research project and invested US$33.
1 million
.

　　(11) Acuitas

　　Founded in 2009, Acuitas Therapeuticsc is a biotechnology company dedicated to promoting the clinical development and commercialization of nucleic acid therapies.
The vision is to provide delivery technologies that can fully realize nucleic acid drugs, thereby addressing unmet clinical needs
.

　　The key technology of Acuitas lies in the development of a lipid nanoparticle (LNP)-based nucleic acid therapeutic drug delivery system, which can be applied to the development of vaccines, monoclonal antibodies, genetic disease drugs and gene editing therapies, etc.
, to deliver drugs to the parts of the body needed
.

　　In the field of nucleic acid drugs, the biggest challenge is the delivery system.
LNP technology is currently the most widely used type of delivery technology in the field of nucleic acid
.
Both Moderna and CureVac have cooperated with Acuitas to obtain licenses for their LNP technology, but this cooperation has also caused patent disputes
.
Acuitas' LNP technology license was obtained from Arbutus.
After Arbutus discovered that Acuitas licensed the technology to Moderna, it plans to terminate the previous license agreement for Acuitas.
The final result is that Moderna cannot use the LNP technology to develop other products
.
And CureVac also cooperated with Arbutus and obtained the authorization of Arbutus' LUNAR delivery technology platform
.

　　(12) RNAimmune

　　Sirnaomics, Inc.
, a biopharmaceutical company focused on RNAi drug research and development, announced on June 11, 2020, the establishment of an independent biopharmaceutical company RNAimmune, Inc
.
.
RNAimmune will conduct mRNA therapy and vaccine research and development based on its exclusive authorized peptide lipid nanoparticle (PLNP) delivery technology, Sirnaomics' large-scale GMP technology, and a proprietary artificial intelligence algorithm (ALEPVA) for epitope prediction and verification
.

　　RNAimmune is a biopharmaceutical company in the field of mRNA therapy and vaccines.
It uses mRNA as a data carrier to instruct the human body to produce its own proteins that can resist a variety of diseases
.
RNAimmune mRNA-based COVID-19 vaccine candidates have been approved by the World Health Organization (WHO), and are currently working with the National Institute of Allergy and Infectious Diseases (NIAID) to evaluate anti-COVID-19 in animal modelsactivity
.
RNAimmune believes that its technology can be applied to a variety of diseases, such as preventive and therapeutic vaccines against SARS-CoV-2 and influenza, cancer treatments for neoantigen vaccines and antibodies, and treatments for rare diseases
.

　　China mRNA Pharmaceutical Company

　　Looking back at China, since the establishment of China's first mRNA pharmaceutical company Simicrobiology in 2016 (Note: Although Minuo Hengkang was established in 2013, the company was originally established as an outsourcing service company, and started to develop mRNA tumor vaccines in 2018) , China Pharmaceuticals closely follows the international trend, and progress in this segment is surging.
The Yangtze River Delta and the Pearl River Delta have once again become gathering places for new technology companies
.

　　(1) Microbes

　　Siwei (Shanghai) Biotechnology Co.
, Ltd.
("Smicrobiology" for short) was established in May 2016.
It is a platform-based enterprise that carried out the research and development and production of mRNA drugs earlier in China.
It was established by a team of doctors returned from the United States in Shanghai Zhangjiang Pharmaceutical Valley.
, Is committed to building a leading mRNA drug platform and product pipeline in China
.

　　Since its establishment in 2016, Siwei has completed the angel round and the A round of financing totaling hundreds of millions of yuan
.
In February 2020, Sri Microbiology received a strategic investment of up to 351 million RMB from Tibet Pharmaceutical
.

　　Based on its advantageous mRNA synthesis platform and LPP nano-delivery platform, S.
Microbiology has carried out the development of multiple pipelines.
The products involve mRNA personalized cancer vaccines, mRNA infectious disease vaccines, protein defect diseases mRNA drugs and genetic disease mRNA drugs, etc.
immune therapeutic areas including cancer, infectious disease prevention, the mRNA of the induced stem cells and the like
.

　　Figure 9: Si Microbiology product pipeline, from: Si Microbiology official website

　　http://　　(2) Blue magpie creature

　　Shanghai Blue Magpie Bio-Pharmaceutical Co.
, Ltd.
("Blue Magpie Bio") was established in April 2019, focusing on early innovative research on mRNA drugs.
The founder team came from Harvard University, Yale University, and Karolinska Institutet in Sweden.
Magpie Bio has laboratories in Shanghai Jiangwan and Houston, USA
.

　　Blue Magpie Bio's RNApeutics platform is a one-step automated mRNA drug development platform.
The platform uses the company's own mRNA core raw materials for screening and optimization, ensuring that each production chain of mRNA drug development requires extremely low costs
.
The RNApeutics platform enables Blue Magpie Bio to expand its own production scale and ensure that the quality of mRNA produced reaches the GMP level of pre-clinical and clinical research
.

　　Figure 10 Blue magpie biological product pipeline, from: Blue magpie biological official website

　　http://cn.
rnacure.
com/yanfaguanxian

　　In the critical period for the prevention and control of the new crown virus pneumonia epidemic, Lanque Biology and the Lin Jinzhong team of the School of Life Sciences of Fudan University and the affiliated Zhongshan Hospital and the Xu Yingjie team of Shanghai Jiaotong University have carried out research on the new crown virus mRNA vaccine, which is currently in the preclinical stage
.

　　Figure 11 The research plan of Blue Magpie Biology and Fudan University on the new crown virus mRNA vaccine, from: Shanghai Blue Magpie official website, http://cn.
rnacure.
com/blog/2020-02-27

　　(3) Minuo Hengkang

　　Taicang Meinuo Hengkang Biotechnology Co.
, Ltd.
("Meinuo Hengkang" for short) was established in 2013.
The founder is Wu Chenyan, who was the senior chief scientist of Pfizer
.
Minuo Hengkang is a tumor vaccine developer and independently researches and develops mRNA tumor vaccine products, which are mainly used in the fields of pancreatic cancer, rectal cancer and liver cancer
.
In addition, Mi Nuo Heng Kang also provides research services such as DNA cloning, DNA extraction, cell culture, recombinant protein and recombinant antibodies
.
Unlike other mRNA research and development companies, Minor Hengkang started outsourcing services.
After tumor vaccines have gradually become a hot field of biotechnology, it began to develop mRNA tumor vaccines in 2018, and only one year later achieved the mRNA tumor vaccine.
Proof of concept
.

　　Minuohengkang seeks targets from Tumor Associated Antigen (TAA), develops universal therapeutic vaccines, and will be comparable to the "mRNA Big Three" in universal therapeutic mRNA vaccines
.
In April 2020, Mingyun and Minuo Hengkang signed an investment framework agreement.
Mingyun will inject more than 50 million yuan into Minor Hengkang's mRNA tumor vaccine research and development project in two batches, the first general-purpose mRNA tumor in China.
The vaccine company Minuo Hengkang officially settled in Xiamen
.

　　During the new crown pneumonia epidemic, Minuo Hengkang Wu Chenyan team also actively participated in the development of new coronary pneumonia preventive mRNA tumor vaccines.
At present, the animal pharmacodynamic experiment of this project is being researched by the Academy of Military Medical Sciences
.

　　(4) Aibo Biological

　　Suzhou Aibo Biotechnology Co.
, Ltd.
(abbreviated as "Abo Bio") was established in January 2019.
The founder is InBev.
He has been engaged in the research and development of mRNA vaccines at Moderna and has many years of senior experience and technical background
.
Aibo Biotech focuses on the technical fields such as mRNA vaccine research and development, molecular design, delivery system, and is committed to building a pharmaceutical technology platform based on mRNA delivery system.
It is currently the only domestic team with experience in the industrialization of mRNA drugs and the US FDA application
.

　　According to Tianyan Check, only more than one year after its establishment, Aibo Bio will complete the first round of equity financing in February 2020, and the investor is Taifu Capital
.

　　Since the outbreak of the new crown pneumonia epidemic, AB Biosciences has relied on its own scientific research advantages, and has joined forces with the Academy of Military Medical Sciences and Watson Bio to actively promote vaccine research and development
.
At present, the new coronavirus mRNA vaccine (ARCoVax) jointly developed by them is the first mRNA vaccine approved for clinical trials in China, achieving a "zero" breakthrough in China's mRNA vaccines.
The vaccine's phase I clinical study was conducted on June 25 Enrolled in the group, phase II clinical trials will be conducted in Guangxi
.

　　(5) Believe in biology

　　Shenzhen Shenxin Biotechnology Co.
, Ltd.
("Shenxin Bio") was established in November 2019.
The founder, Dr.
Linxian Li, studied under Professor Robert Langer, the founder of Moderna.
He has many years of preclinical drug research and development experience in the field of mRNA, especially LNP delivery technology.
In September 2019, together with MIT Professors Daniel Anderson, Robert Langer and others, he published an important research result in Nature Biotechnology, demonstrating a platform technology that can design and prepare mRNA drug delivery vectors.
Through this platform, the technology Researchers have developed a new type of lipid nanoparticle carrier that can be used to deliver mRNA vaccines against cancer
.

　　Relying on the internationally leading LNP delivery technology platform, we have built a R&D pipeline in the four major directions of rare diseases, tumor therapeutic vaccines, tumor immunotherapy enhancers, and infectious disease prevention vaccines.
It is one of the few domestic companies that develop mRNA vaccines for rare diseases.
Start-up company
.
At present, the company has a number of simultaneous trials, some of which have entered preclinical studies
.

　　(6) Shenzhen St.
Regis

　　Shenzhen Regis Biotechnology Co.
, Ltd.
("Shenzhen Regis" for short) was established in September 2019.
Based on the field of mRNA gene drugs and therapies, Shenzhen Regis is committed to the development of innovative mRNA drugs and new gene therapies, covering cancer and infectious diseases And rare disease drugs and other therapeutic fields
.
Shenzhen Regis's mRNA vaccine technology has potential advantages in efficacy, development speed, and production scalability and reliability
.
Currently, the company is developing 9 preventive mRNA vaccines and carrying out 7 Ⅰ It also provides customized services in the field of nucleosides and nucleotides
.

　　According to the information from Tianyan Check, Shenzhen Ruiji Biotech and Shenzhen Shenxin Bio jointly established Shenzhen Ruiji Shenxin Biological Technology Co.
, Ltd.
, with Shenzhen Ruiji as the controlling party
.

　　(7) Livanda Bio

　　Zhuhai Livanda Biotechnology Co.
, Ltd.
("Livanda Bio") was established in June 2019 and is an innovative mRNA drug research and development company
.
The company has an internationally advanced mRNA production platform and an in-vivo drug delivery platform, providing treatments that traditional medicine and existing drugs cannot reach, and meeting drug needs
.
Therapeutic fields include infectious disease vaccines, tumor vaccines, rare diseases, and other protein defect diseases; it can also be applied to the fields of beauty and anti-aging
.

　　As early as 2017, the company focused on the research and development of mRNA technology.
It has applied for a number of invention patents in drug design, production and formulation delivery.
It has also introduced Ph.
D.
returnees as the backbone, and the technology platform is relatively solid
.
In January 2020, it received equity financing.
The investors are Tianyou Investment, Hengqin Investment, Kangcheng Investment and Livzon Group
.

　　After the outbreak of the epidemic, Peng Yucai, founder of Livanda Biosciences, led a team to successfully develop a standard sample of mRNA for the new coronavirus vaccine in only 8 days, and passed the cooperation with the Academy of Military Medical Sciences, Guangdong Laboratory Animal Surveillance Institute, and Macau University of Science and Technology.
In-depth cooperation and rapid advancement of project research and development, and delivered to relevant national units for animal testing and drug efficacy verification on February 1
.

　　Figure 12 Livanda's biological product pipeline, from: Tencent News

　　https://xw.
qq.
com/cmsid/20200215A0LHKC00

　　(8) Keep Nano

　　Shenzhen Houcun Nano Pharmaceutical Co.
, Ltd.
("Housun Nano") was established in November 2018.
It is located in the Pioneer Park for Overseas Students in Guangming District, Shenzhen.
It is committed to building three platforms for nano delivery, mRNA synthesis, and vaccine transformation.
An enterprise that has focused on mRNA nano-delivery, mRNA virus vaccine, and mRNA tumor vaccine drug research and development
.
At present, Hocun Nano has accumulatively submitted 4 invention patents and 1 utility model patent
.

　　The key to mRNA drug research and development lies in delivery technology.
The core of the company is to use the LLLRNA nano-delivery technology independently developed and developed independently.
The technology industry is gradually transformed.
The application scenarios of the technology include tumor vaccines, CART therapies, infectious disease vaccines, and rare disease treatments.
, Gene editing, etc.
, has signed a cooperation agreement with Shanghai Cell Therapy Group, and cooperates closely with the University of Hong Kong and Shenzhen Advanced Research Institute
.

　　Figure 13 Hocun Nano Product Line

　　From: Hocun Nano official website, http://　　In the face of the epidemic, Houcun Nano Pharmaceuticals and Shanghai Cell Therapy Group have basically completed the construction of the mRNA nano-delivery research and development platform, figured out the technical route of mRNA synthesis in vitro, and completed the expression effect verification in nude mice
.
In the future, Hocun Nano will use platforms such as the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences and the University of Hong Kong to accelerate the verification of the mRNA synthesis platform, the mRNA delivery platform and the in vivo immune effect of the mRNA vaccine, and further promote the research and development of the new crown mRNA vaccine
.

　　(9) Other

　　In addition to mRNA drug research and development companies, there are companies based on mRNA sequence design algorithms to assist in the research and development of mRNA drugs
.

　　Shanghai Bendao Gene Technology Co.
, Ltd.
realizes the safe and efficient delivery of CRISPR and other gene editing tools through the leading viroid BDmRNA delivery technology.
Its mRNA delivery and gene editing platform also has important application prospects in the fields of tumor immunity and regenerative medicine
.

　　Compared with conventional mRNA transcriptome sequencing, the Dr.
Tom interactive reporting system independently developed by BGI can also analyze the whole transcriptome to explain biological problems more comprehensively and clearly, and it is mainly aimed at mRNA with coding gene function
.

　　In addition, Baidu Research Institute also launched the world's first mRNA vaccine gene sequence design algorithm LinearDesign, which is an efficient algorithm for optimizing mRNA sequence design
.

　　Pharmaceutical companies deploying mRNA therapy at home and abroad

　　Pfizer, Eli Lilly, Sanofi, GSK, AstraZeneca and other well-known pharmaceutical companies have stepped into the field of mRNA drugs through cooperation with mRNA drug companies such as Moderna, CureVac or BioNTech
.
From the perspective of cooperation, most pharmaceutical companies focus on the deployment of mRNA therapeutic products, and preventive vaccines are mostly new crown vaccines and influenza vaccines
.

　　Table 1 The layout of mRNA drug companies at home and abroad

　　Key technologies and patents of mRNA pharmaceuticals

　　The key technology of mRNA pharmacy mainly lies in two aspects, one is for the active ingredient mRNA itself, and the other is for the delivery system of mRNA
.

　　Figure 14 Schematic diagram of mRNA therapy, (a) the structure of in vitro transcribed mRNA (b) representative mRNA delivery preparation system (c) mRNA cell uptake and protein expression process

　　For the mRNA itself, the main focus is how to increase the stability of the mRNA, extend the half-life, improve translation efficiency, and reduce immunogenicity.
The key technologies related to it include:

　　(1) Synthetic cap structure analogs and capping enzymes can stabilize mRNA and improve protein translation efficiency by binding to eukaryotic translation initiation factor 4E (EIF4E)

　　(2) The regulatory elements located in the 5'-UTR and 3'-UTR untranslated regions can stabilize mRNA and improve protein translation efficiency

　　(3) Poly A tail can stabilize mRNA and improve protein translation efficiency

　　(4) Modified nucleotides can reduce natural immune response and improve translation efficiency

　　(5) Separation/purification technology: RNase III processing and fast protein liquid chromatography purification technology reduces immune activation and improves translation efficiency

　　(6) Sequence and/or codon optimization technology improves translation efficiency

　　Companies are actively deploying patents in the above-mentioned technical fields to improve their position in the field of mRNA pharmaceuticals
.

　　Dr.
Rossi, one of the founders of Moderna, once obtained a patent US8802438, which protects an RNA composition capable of inducing pluripotent stem cells (iPS), in which the cytosine (C) and uracil (U) of the RNA are respectively 5- Replacement of methylcytosine and pseudouracil
.
This modification can improve the stability of mRNA
.
Coincidentally, in the authorized patent "A modified small interfering nucleic acid and its preparation method" by Professor Liang Zicai and Professor Du Quan of Peking University in China, the selected modification sites are also cytosine and uracil, and the modified small interfering nucleic acid Has improved serum stability
.
This indicates that cytosine and uracil at a specific site may play an important role in the stability of RNA
.

　　On the basis of the above-mentioned patents, ModeRNA has further developed a technology to improve mRNA to reduce the immune response caused by exogenous mRNA entering the body.
This technical solution is to use 1-methylpseudouridine to modify RNA.
It has now obtained a US patent.
Approved (US9428535)
.

　　If you look at Translate Bio's patents on mRNA, it is mainly by adding untranslated regions (UTR) to the 5'end and 3'end of the mRNA to improve the stability and translation efficiency of the mRNA in the cell
.

　　For example, WO2012075040 discloses a modified mRNA molecule comprising a coding sequence encoding a target protein and a 5'-UTR sequence, which defines the 5'-UTR sequence
.
The patents of this family are currently mainly authorized in the United States, including US08853377, US09956271, and US09061021, which are expected to expire on November 29, 2031
.

　　For BioNTech RNA Pharmaceuticals, it achieves the effect of reducing the immunogenicity of mRNA by reducing the content of U (uridine acid) in the mRNA molecule.
For example, WO2017036889.
Although the family application is not authorized at present, it should be more important.
A patent layout has entered mainstream countries or regions such as Australia, Canada, the European Union, Japan, and the United States
.

　　BioNTech also improves the stability of mRNA by capping the 5'end and 3'-UTR.
For example, WO2019175356 provides a 5'capped compound, while WO2017059902 defines the sequence of 3'-UTR
.

　　For delivery systems, the main focus is to increase targeted delivery efficiency, improve transfection efficiency, and reduce toxicity
.

　　In order to successfully transport mRNA to target tissues and organs and enter target cells through cell membranes, a specific delivery system is usually needed to help mRNA reach the target organs
.
Because RNA is a biological macromolecule with a negative charge, based on this physical and chemical properties, the mainstream delivery systems in the RNA pharmaceutical field are mostly based on liposomes and cationic polymers, and mRNA pharmaceuticals are no exception
.

　　Figure 15 The main delivery methods of mRNA vaccines

　　ModeRNA initially obtained LNP (lipid nanoparticle) delivery technology from Acuitas, and is also developing its own delivery system
.

　　WO2017049245 is such a patent family related to RNA drug delivery
.
This patent family protects nanoparticle compositions composed of a new lipid and other lipids such as phospholipids, structural lipids and PEG lipids; furthermore, it also protects the composition of RNA molecules that are used for therapeutic or preventive purposes.
Nanoparticle composition is used to mediate the expression of polypeptides, proteins or genes in cells
.

　　WO2017099823 relates to a lipid nanoparticle composition with low toxicity and insensitive to blood clearance, which contains mRNA encoding a protein
.

　　WO2018089540 also relates to a lipid nanoparticle composition, which comprises ionizable lipids and structural lipids, and a stabilizer
.
The lipid nanoparticles can be used to deliver mRNA as therapeutic and preventive agents to mammalian cells or organs to mediate the expression of polypeptides, proteins, RNA or genes, and for the treatment of autoimmune diseases, diabetes, neurodegenerative diseases, and cardiovascular diseases.
And metabolic diseases
.
In addition, a method for preparing the lipid nanoparticle and a method for screening and obtaining a stabilizer are also disclosed
.

　　Translate Bio also mainly uses lipid particles to deliver mRNA
.
For example, WO2016004318 provides an improved method for encapsulating lipid nanoparticle preparations and mRNA
.
WO2011068810 relates to a lipid composition for targeted liver delivery of mRNA, wherein the lipid comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and One or more PEG-modified lipids, and the size of the finally obtained nanoparticles is less than 100nm
.

　　In addition, it also relates to methods of mRNA delivery through polymers such as PEI, such as WO2012170930
.

　　BioNTech's mRNA delivery technology is also mainly based on liposomes and cationic polymers, such as WO2019077053, WO2016045732, WO2018010815, WO2020069718, WO2016155809 and other patent families
.

　　Compared with foreign companies' aggressive patent layout, domestic companies are slightly conservative in the protection of intellectual property rights.
Except for Taicang Minuo Hengkang, Zhuhai Livanda, Hocun Nano, and Kangsino, they have retrieved public patents (applications).
mRNA pharmaceutical companies have not retrieved any published patent (application) information as of the date of writing this article
.

　　In terms of the industrialization of mRNA drugs, companies such as CureVac, ModeRNA, and BioNTech have established GMP-compliant production lines, and these major companies are also expanding their mRNA production scale to meet greater clinical needs
.
In terms of the production process of mRNA drugs, at least from an international perspective, the technology should be mature
.

　　With continuous breakthroughs in mRNA modification and preparation technologies, the mRNA pharmaceutical industry has become increasingly mature; in addition, as mRNA pharmaceuticals, it is still necessary to establish systematic technical solutions for detection, analysis, quality control, and verification
.
As a field based on new technologies, the technical threshold for entering this field is still relatively high, and there are fewer mature talents in the field of nucleic acid drugs.
This is also the reason why most companies are currently hesitant
.