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mRNA cancer vaccine presses the accelerator button, how is the progress of domestic enterprises catching up with learning?

 Last Update: 2023-01-01
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From the first successful extraction of mRNA in 1960, and the epoch-making mRNA new crown vaccine obtained by modifying mRNA more than 60 years later, mRNA technology has really played a huge role
.
If it weren't for the insistence of a female scientist, the technology might have come a long time to notice
.

But while known for its vaccine products, the future of mRNA technology goes far beyond that
.

In October, the two founders of BioNTech said in an interview with the BBC that cancer vaccine research based on the mRNA vaccine technology route has made breakthroughs and is expected to come out
before 2030.
If mRNA technology can go well, then humanity may not be far from curing cancer
.

▲Source: http://biosmedi.
com/index.
php?m=home&c=View&a=index&aid=65

From the edge to the center of the stage

In 1985, Hungarian biological researcher Katalin Kaliko was fired
from the Center for Biological Research of the Hungarian Academy of Sciences for delaying the results of her research.
Infatuated with mRNA, she originally wanted to find a job in Europe to continue research, but she was frustrated one after another
.
In desperation, Katarin Karico moved to the United States, but still ran into a wall
repeatedly.

In 1995, after six years in Pennsylvania, Katarin Kaliko was demoted and missed out on becoming a full professor at the university
.
It wasn't until 1997, when he joined the team of immunologist Drew Weissmann, who also believed in mRNA technology, that Katalin Kaliko's research began to take a turn for
the better.

Drew Weissman and Katalin Karikó,

Source: Reference 1

The biggest bottleneck encountered in Katarin Kaliko's previous research process was that both natural RNA and RNA synthesized in vitro invariably activated the response of human immune cells, resulting in the degradation of RNA before it could be translated into protein
.
In 2005, with the assistance of Drew Weissmann, Katalin Kaliko discovered that the modified mRNA of uridine, one of the components of RNA, can evade the signal recognition of immune sensors, thus solving the biggest problem
in RNA application research.
This groundbreaking study, published in the journal Immunity, also marked the birth of RNA therapeutics
.

In 2007, Derek Rossi, an assistant professor at Harvard Medical School, attempted to reprogram somatic cells into embryo-like stem cells by using Katalin Karico and Drew Weissmann to modify mRNA uridine in stem
cells.
After more than a year of exploration, they succeeded
.
In 2010, the study was named one of
the top ten medical breakthroughs of the year by Time magazine.

Soon, Derek Rossi founded Moderna
.

In Germany, a Turkish scientist couple, Ugur Saheen and Ozran Tourelli, paid early attention to the research of Katalin Kaliko and Drew Weissmann, and quickly founded BioNTech
, a biotechnology company based on mRNA therapy.

▲BioNTech founders Ugur Saheen and Ozlang Tourelli Source: Reference 4

The story of the future is already familiar to everyone
.
Under the epidemic, mRNA vaccines have become the world's largest pharmaceutical category
.
In 2021, BioNTech's BNT162b2 vaccine and Moderna's mRNA-1273 vaccine generated revenues of $40.
4 billion and $17.
675 billion, respectively, making them the world's first and third largest medical products
by sales.

However, mRNA vaccines still face many challenges in treating cancer, such as identifying tumor-specific epitopes is still a long-term problem that needs to be explored, such as how to verify the most feasible delivery method
.

Challenges that must be broken

mRNA cancer vaccines can be divided into two categories, including dendritic cell (DC)-based mRNA vaccines and direct injection mRNA vaccines
.

DC vaccine obtains mRNA through in vitro transcription, and after transfection to DC, mRNA is translated into the cytoplasm to form antigens to activate DC, and the activated DC is injected into the human body to stimulate the immune system response and achieve the purpose of killing tumor cells; The mRNA vaccine injected directly uses granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to inject mRNA encoding relevant antigens into the patient's body, thereby stimulating the body to produce antibodies and inhibit the growth of
tumor cells.

▲ mRNA-based vaccine mode of action Source: Reference 3

In 1996, the first mRNA-based cancer vaccine research was first conducted in vitro experiments
in DC.
Nowadays, the advancement of science and technology has optimized the structure, stability and injection method of mRNA
.
mRNA can be administered
intradermally, subcutaneously, intranasally, intranodularly, intramuscularly, intratumorally, and intravenously.
How to successfully deliver it to the human body has become the biggest challenge
in the development of mRNA technology.

mRNA is composed of single strands and is easily degraded in the human body; At the same time, mRNA must enter the cell membrane to achieve translation function, but because both mRNA and the cell membrane are negatively charged, a rejection reaction will occur, making it difficult for mRNA to enter
.
Due to these factors, even if mRNA does not cause an immune response, it is still difficult to play a safe and stable therapeutic purpose
.

To promote mRNA uptake by cells, scientists began experimenting with delivery systems to help
.
To improve delivery efficiency and minimize therapeutic side effects, researchers have developed a variety of delivery vectors
that encapsulate mRNA.
The means of delivery of mRNA vaccines include physical, viral vector and non-viral vector methods
.
Liposomes and their derivatives have become the most effective non-viral vectors
for delivering mRNA.
The lipid vectors used to deliver mRNA vaccines are mainly divided into the following: liposome complexes (LPs); liposomal polymers (LPR); liposomal nanoparticles (LNP); Cationic nanoemulsion (CNE).

At present, all three mRNA vaccines use the LNP delivery system
.

LNPs typically consist of four components, ionizable/ionizable lipids, cholesterol, cophospholipids/neutral lipids, and PEG-modified lipids, which together encapsulate and protect fragile mRNA
.
Different molecules and composition ratios are the main differences between LNP systems
.

However, mRNA preparations prepared with LNP as carrier will accumulate in the liver and spleen, which is difficult to target other parts and prone to leakage, which greatly limits its application
as a drug carrier.
The industry is also exploring novel delivery vehicles
such as lipid complexes and polymers.

▲LNP delivery carrier structure, source: _msthash="320317" _msttexthash="44557981">Polymers and polymer nanoparticles are not as clinically advanced as LNPs, but polymers have similar advantages to lipids in efficiently delivering mRNA, and cationic polymers concentrate nucleic acids into complexes of different shapes and sizes that can enter cells
through endocytosis.

Polyethyleneimine is the most widely studied nucleic acid transport polymer and, despite its excellent efficacy, limits its application due to its
high charge density and toxicity.

Novel lipid-containing polymers with charge-altering releaseable transporters (CARTs) can effectively target T cells, and manipulation of T cells is very difficult, so CART is an attractive delivery material with great potential
in the field of mRNA vaccines and gene therapy.

Peptides can also deliver mRNA into cells thanks to cations or amphiphilic amine groups in their main and side strands, which bind electrostatically to mRNA and form nanocomposites
.

Squalene cationic nanoemulsions can also deliver mRNA, which consist of oily squalene nuclei, although the mechanism by which squalene cationic nanoemulsions escape from endosomes and deliver mRNA into the cytoplasm is unclear
.

With these maturing delivery technologies, how far have mRNA cancer vaccines been developed?

The age of giants has come

In fact, the three major mRNA giants BioNTech, Moderna, CureVac and some domestic mRNA companies, as early as before the development of new crown vaccines, mainly promoted therapeutic cancer vaccines as core projects of their respective mRNA technologies
.

From the perspective of research and development, mRNA vaccines have been widely tried to be used in the treatment of various types of tumors, including prostate cancer, acute myeloid leukemia, metastatic melanoma, neuroblastoma and so on
.

BioNTech has a pipeline of more than 30 products, about 15 tumor-related, and is developing treatments
for rectal cancer, melanoma and other cancer types.
Among them, BNT111 and BNT113 products for advanced melanoma and HPV16-positive head and neck cancer have entered clinical phase II, and personalized cancer vaccine BNT122 for patient-derived specific antigens has also entered clinical phase
I and II.
In November 2021, BioNTech issued an announcement announcing that the US FDA had granted fast-track status for its mRNA cancer vaccine, BNT111
.

▲BioNTech part of the mRNA R&D pipeline Source: BioNTech official website

Moderna is also in a race
.
Moderna currently has a total of more than 45 product lines, including about 5 related to
tumors.
Among them, there is a personalized cancer vaccine, mRNA-4157, which can hold up to 34 mRNA sequences encoding neoantigens, targets multiple cancers, has a 90% disease control rate in clinical phase I, and is currently undergoing clinical phase II trials
.

In October, Moderna announced a partnership with Merck to jointly develop and market a personalized precision therapy cancer vaccine, advancing Moderna's mRNA technology and Merck's PD-1 Keytruda in combination to explore the treatment of high-risk melanoma patients
.
Currently, the project is in phase II of clinical trials and has enrolled a total of 157 subjects
.

CureVac focuses on developing mRNA therapeutics for tumors, rare diseases, and infectious diseases, with 14 drug candidates, 9 of which are already in clinical stages
.
Among them, CV-8102 is an RNA-based single-stranded non-coding TLR-7/8 and RIG-1 agonist, which has been studied in phase I as early as 2017 for the treatment
of patients with advanced melanoma, cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma or adenoid cystic carcinoma.

However, at present, most of the global mRNA cancer vaccine pipeline research and development is still in the early stage, basic research is not yet fully mature, Chinese companies still have a great opportunity to achieve corner overtaking
.

Can I overtake in a corner?

On November 11, 2022, Wang Hai's research team from the National Center for Nanoscience of the Chinese Academy of Sciences was present at Advanced Functional The journal Materials published a research paper
.
In this study, a hydrogel-LNPs system (HA-mRLNPs) was developed that efficiently delivers mRNA encoding tumor antigens to dendritic cells for antigen presentation, induces antigen-specific CD8+ T cells to kill tumor cells, and can be stored
at room temperature.
This study proves that stable and durable immunohydrogel-LNPs systems can be used for effective tumor immunotherapy
.

▲Schematic diagram of hydrogel-LNPs system preparation and tumor immunity in vivo Source: Reference 7

The emergence of this study also proves that China is fully capable of making breakthroughs
in the basic research of mRNA.

According to incomplete statistics, there are at least 26 companies focusing on mRNA technology development in China, and this number is increasing
sharply.
Among them, the leading companies with high clinical trial progress include Abogen Biologics, Si Microbios, Lifanda/Emmy Vaccines, Shenxin Biologics, Yaotang Biologics, Jiachen Xihai, St.
Regis Biologics, Lanque Biologics, etc
.

Founded in 2019, Aygen Biologics has an industry-leading mRNA and nano delivery technology platform with independent intellectual property rights, and its self-developed dynamic and precise mixing technology can be applied to the industrial production
of nanolipid spheres 。 At present, the fastest progressing mRNA vaccine is the mRNA new crown vaccine ARCoV jointly developed by Abogen Biosciences, Watson Biologics and the Medical Research Institute of the Academy of Military Sciences, which has been issued an emergency use license by the Indonesian Food and Drug Administration (BPOM) in September 2022, which is the first EUA obtained by Abogen Biosciences overseas and the first mRNA vaccine
approved internationally in China.

However, at present, Abogen Biologics' R&D pipeline is mainly preventive viral vaccines, and no mRNA cancer vaccine has been seen to enter the clinical stage
.
However, in the public introduction of Abogen Biosciences, it said that cancer vaccines are one of the most important aspects of Abogen Biosciences' product development in the field of oncology, and it is also the direction of the largest proportion of the current project
.

▲Abogen Biologics R&D pipeline Source: Abogen Biologics official website

Founded in May 2016 in Zhangjiang, Shanghai, Microbial obtained the exclusive global commercialization rights of the LPP delivery platform authorized by Houston Methodist Hospital in 2017, and built an mRNA production center in 2018 to complete the verification of mRNA synthesis platform and the industrial production of
nanopreparations.
In October this year, Simicrobia announced that the phase III clinical trial of its self-developed mRNA new crown vaccine has been officially launched
in Laos.
Regarding the progress of cancer vaccine research and development, Simicrobi revealed that its mRNA personalized cancer vaccine has been launched in phase I clinical trials in Australia, which is the first personalized cancer vaccine
to enter the clinical clinic in China.

Founded in 2019, Jiachen Xihai is a company with leading industrial experience, especially CMC, in the domestic mRNA industry, with a pipeline covering tumor immunotherapy, infectious disease vaccines, rare diseases and medical cosmetology, among which the self-replicating mRNA cancer vaccine projects JCXH-211 and JCXH-212 have conducted phase I/II clinical trials
in the United States and China respectively.

In general, the domestic mRNA cancer vaccine field cannot constitute competition in terms of quantity, but more in jointly promoting the application and development of mRNA cancer vaccine, and is in the initial stage
of trying to advance the pipeline to clinical application.
And some domestic Big Pharma's entry support, such as CSPC Pharmaceutical Group, may be more about the short-term benefits of mRNA new crown vaccines, rather than really wanting to invest in the development of
mRNA technology.

epilogue

In the future, the results of mRNA technology in cancer vaccine research and development are very worth looking forward to, the new crown epidemic has given mRNA a golden opportunity, after the industry leaders have gained huge benefits, the investment in mRNA will be unprecedented
.
Assuming that the results of mRNA cancer vaccines are seen by 2030, it will be one of the greatest moments in the history of
human medicine.

In the development of mRNA technology in China, we must not be short-sighted, mRNA is not only the only way out for the new crown vaccine
.
Only by really investing in basic research can it be possible
to achieve corner overtaking.
But unfortunately, at present, whether Biotech or Big in China Pharma's current focus is not here, if it does not try to make up for the technical gap, even if the next outlet of mRNA comes, it will be difficult for domestic companies to grasp it
.
How the follow-up development is, Meibai Medical will continue to pay attention
.

【Reference】

【Reference】【Reference】

1.
"Ten years of grinding a sword: the birth history of mRNA vaccines", Bioworld, 2021-1-27

2.
What are the mRNA drugs used in the treatment of tumors and rare diseases? 2020-12-16

3.
"The Lancet Review: Delivery and Clinical Progress of mRNA Cancer Vaccine", GenScript Biologics, 2022-11-7

4.
"Cancer vaccine is coming: can it remove cancer cells with one shot?" Which pharmaceutical companies are in the layout? The Paper, 2022-10-18

5.
"Cancer vaccine available in 8 years? Where is the strength of mRNA, domestic pharmaceutical companies respond to the latest progress", Sina Finance, 2022-10-18

6.
"mRNA Vaccine Industry Analysis Report", Baiaogu, 2022-10-27

7.
"Wang Hai's team of the National Nano Center makes new breakthroughs in tumor nanovaccines", BioWorld, 2022-11-23

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