Source of this article: Times Finance Author: Li Aohua
Picture source: Tuchuang Creative
When founded Shenzhen Houcun Nano Pharmaceutical Co., Ltd. (hereinafter referred to as "Houcun Nano") in 2018, Zhang Longgui did not expect that the mRNA industry would undergo tremendous changes in two years due to a global pandemic.
thick storage nanometers are the earliest start-up in China to focus on mRNA drug delivery. The company's delivery technology is mainly used in preventive vaccines, therapeutic tumor vaccines, protein replacement therapy and other directions. Founder Dr. Zhang Longgui recalled to Times Finance that at the beginning of Houcun Nano, almost no investors were optimistic about this track, and the sudden outbreak of the new crown pneumonia epidemic has become a turning point in the fate of the mRNA industry.
With the rapid emergence of two mRNA new crown vaccines, in 2021, various capitals and outstanding talents flocked to us, making homogeneous competition in this field extremely fierce. "As many R&D pipelines that use LNP delivery technology at home and abroad have been removed from the shelves, to a certain extent, it shows that the toxicity of LNP dose does not adapt to indications that require large-scale administration or long-term administration. This also means that the delivery problem in the mRNA field will be the focus of competition in the entire industry in the future." Zhang Longgui told Times Finance.
In mid-October this year, the remarks of the German biotech company Şahin and Türeci, co-founders of German biotechnology company BioNTech, added another fire to the hot mRNA track. In an interview with BBC, they said that BioTech has made a major breakthrough in mRNA technology and that the mRNA cancer vaccine may be launched by 2030.
Although many interviewees told Times Finance that it is not easy to successfully launch mRNA cancer vaccine, it may be the next hot spot for competition in the mRNA industry, and related companies have already made arrangements in advance.
As of March 31, 2022, a total of 56 mRNA drugs around the world have entered the clinical research stage, mainly focusing on the vaccine field. Smart Ba Global New Drug Intelligence Database Pharmsnap Data Platform shows that in the field of mRNA cancer vaccines, BioNTech and Moderna, a well-known American biopharmaceutical company, are still two companies at the forefront. The under-research indications such as colorectal cancer and melanoma have entered the second phase of clinical research.
"In the short term, tumor vaccines are likely to become the main research direction in the field of mRNA, which is due to the dose toxicity of LNP to a certain extent, but the future of mRNA will definitely not be limited to the field of tumors." Zhang Longgui told Times Finance.
mRNA or cancer nemesis
mRNA, full name is messenger ribonucleic acid, which guides the production of protein through "translation" and is also called "master key". Minsheng Securities research report points out that the basic principle of mRNA drugs is to inject modified mRNA templates into the cytoplasm, produce corresponding protein products in the cell, and after being secreted to the cell, it can stimulate the human immune system and thus produce an immune response. This immune response is mainly achieved by introducing secretory signals into the coding sequence of mRAN, and conventional proteins cannot cause similar reactions.
In theory, mRNA can express any protein, meaning it has the possibility of treating all protein-based diseases, including cancer. In recent years, protein maps have become one of the popular directions in cancer research.
According to the research report of Zhongtai Securities, mRNA can currently be used in infectious disease prevention, tumor immunotherapy , protein replacement, CAR-T, gene editing , etc., and can be divided into three categories, namely preventive vaccines, therapeutic vaccines, and therapeutic drugs. At present, the research direction of mRNA cancer vaccine is still mainly therapeutic vaccines.
Zhang Longgui pointed out to Times Finance that the tumor vaccine commonly referred to at present is actually a therapeutic tumor vaccine. It is different from the preventive vaccine of viruses that can cause tumor diseases through immunity and is used for tumor patients. For example, BNT113, which is being developed by BioNTech, is an mRNA cancer vaccine encoding two oncoproteins E6 and E7. These two oncoproteins are often found in HPV16+ solid cancers and are designed to trigger strong and precise immune responses in patients with HPV16+ head and neck squamous cell carcinoma (HNSCC).
tumor vaccine usually treats cancer in conjunction with other therapies, while preventive vaccines are vaccinated with normal and healthy people. For example, Merck recently announced that it has been approved by the China National Medical Products Administration to expand the nine-valent human papillomavirus vaccine (commonly known as the "nine-valent HPV vaccine") that will be used to expand the age of 9 to 45 years old. It is a preventive vaccine, which targets antigen , which is the relevant viral antigen that causes cancer, rather than the antigen expressed directly by cancer cells.
"We mentioned above that vaccines targeting tumor-related antigens with higher versatility may have certain 'preventive' vaccine potential, but the actual situation is that tumor patients cannot clearly know whether they will suffer from cancer with certain antigens before being diagnosed; even for the same type of tumor, the differences in tumor antigens between different patients are relatively large." Zhang Longgui said, "It is precisely because of these reasons and practical difficulties that a preventive vaccine commonly used in multiple tumors and different patients have few reports on research at this stage.
Aibo Bio, a clinical innovative biopharmaceutical company focusing on mRNA drug research and development, also pointed out to Times Finance that tumor vaccines often target some mutant tumor antigens, thereby causing antigen specialization.
The heterosexual immune response achieves the purpose of treatment, but because the occurrence of tumors is very complex and has huge differences, it is difficult to develop a preventive tumor vaccine that can cover a large number of tumor antigens at this stage. At present, mRNA tumor vaccine is mainly prepared in a targeted manner by identifying the tumor antigens contained in the tumor that have been formed, and mRNA tumor vaccines can be targeted for treatment.
According to the selection of antigens, there are two main types of mRNA preparations for tumor treatment at this stage. One is mRNA tumor vaccine; the other is to use mRNA to encode tumor immunotherapy-related proteins (such as antibodies). Dr. Li Chuxin, head of the Department of Pharmacy of Houcun Nano, told Times Finance that mRNA tumor vaccines can be divided into two categories, one is to target tumor-related antigens with relatively wide expression (tumor). associated antigens, TAAs), an mRNA vaccine with high versatility and universality. The other is a personalized mRNA vaccine designed for individual tumor neo-antigens in different patients through biopsy sampling and sequencing analysis of patients' tumor tissues.
"The basic principle of these two mRNA vaccines is to use mRNA to encode target tumor antigens, realize the synthesis of corresponding antigens in the patient's body, stimulate the patient's body's immune cells and to produce an immune response to the target tumor antigen, and then attack and eliminate tumor cells. "Li Chuxin explained.
center of gravity returns to the tumor track
Zhang Longgui pointed out that based on tumor patients with clear antigens, therapeutic vaccines can stimulate the body's tumor-specific immunity, which is expected to inhibit tumor growth and prolong survival, and are of equal importance in the field of tumor treatment.
In fact, scientists have long realized the potential of mRNA technology in the treatment of cancer. Before the outbreak of the new crown pneumonia epidemic, cancer has always been the hottest research direction for mRNA. According to future think tank statistics, before 2020, most of the indications targeted for mRNA vaccine clinical trials were cancer, but starting from 2020, the number of mRNA vaccine clinical trials on infectious diseases has surged.
Minsheng Securities statistics point out that preventive vaccines and swelling in immunotherapy Tumor immunization is the current research hotspot. As of April 2022, the three international mRNA giants Moderna, BioNTech and CureVac have been launched and under research pipelines, of which 19 and 14 preventive vaccines and tumor immunotherapy in immunotherapy are respectively.
With the market demand for new crown vaccine As a result, mRNA companies have also chosen to devote more energy to exploration in other fields such as cancer.
Zhang Longgui believes that the focus of research and development in the field of mRNA will gradually shift from the new crown vaccine to other fields. "Foreign research and development of new crown vaccines has basically been saturated, and I guess this is also why the founder of BioNTech was interviewed by the BBC at this time and talked about mRNA cancer vaccines. Everyone will gradually return to the normal pace of drug research and development, and tumor vaccines are one of the key areas.”
On October 13, 2022, Moderna announced that it would cooperate with the well-known pharmaceutical company Merck to jointly develop and sell personalized precision-treatment cancer vaccine (PCV) mRNA-4157/V940 based on mRNA technology, and will use it in combination with Merck's star drug PD-1 inhibitor Keytruda for the treatment of high-risk melanoma patients. At present, the research on this vaccine has entered phase 2 clinical trials, and Moderna and Merck are expected to release the clinical data of the project in the fourth quarter of this year.
In China, mRNA companies have basically also made some arrangements in the field of tumor treatment.
June 24, 2022, Jiahe Biologics (06998 .HK) announced that it has entered into a cooperative development agreement with Aibo Bio. Jiahe Bio's biological antibody development platform will combine with Aibo Bio's mRNA technology platform to jointly develop mRNA drugs for tumor treatment.
Aibo Bio told Times Finance that the above-mentioned tumor mRNA drugs are still in the preclinical proof of concept. At present, Aibo Bio is engaged in drug development cooperation with several domestic biotechnology companies, and its layout in the field of tumor mainly includes tumor vaccine drugs, in vivo protein replacement drugs, cell therapy drugs, etc. "In the future, in the field of tumors, we will continue to carry out different forms of cooperation with various biopharmaceutical companies, including cooperative research and development, authorized introduction, and joint treatment, and jointly promote the process of developing tumor drug products with mRNA technology. "
In addition, the personalized tumor vaccine of mRNA encoding neogenic antigen developed by Si Microbiology has obtained official ethical approval in Australia and has entered the first phase of clinical registration overseas.
cancer vaccine still has a "stumbling block"
Although it is famous for its vaccine products, the future of mRNA technology is far more than this. The core principle of
mRNA technology is the different arrangement sequences of 4 bases AUCG. Through different arrangements of bases , the arrangement of amino acids molecules in proteins can be determined, thereby expressing different proteins, supporting the operation of different human skills, and fighting different diseases.
"This principle is similar to computer programming. There is a saying in the field of mRNA that describes this technology as "hacking the" software of life’, as long as you master this development technology, you can develop any program and any mRNA drug or vaccine. "Aibo Bio said. It is precisely because of this characteristic that mRNA is regarded as a disruptive technology in the biological industry, attracting scientists to invest their energy in research and development, and also attracting many capitals to tirelessly describe the myths it may create in the future.
Pharmaceutical Financing Circle Statistics pointed out that in 2021, there were 29 financing events in the field of nucleic acid drugs in my country, an increase of 17 from 2020, with the investment and financing amount reaching To 12.912 billion yuan, an increase of 8.256 billion yuan from 2020. From 2021 to early 2022, 22 nucleic acid drug companies in my country have completed financing. Among them, Aibo Bio completed three rounds of financing in 2021, with a total financing amount of nearly 8 billion yuan.
With the support of capital, the development speed of mRNA vaccines has increased significantly in the past two years. Southwest Securities research report pointed out that mRNA The average vaccine development cycle is 0.8 years to 1.5 years, and the overall commercialization process is 10 times faster than the traditional path. It is expected that the market size will reach US$32.6 billion in 2025.
Despite this, it is not easy to successfully launch mRNA cancer vaccine.
Aibo Biologics analyzed to Times Finance that the difficulties in the development of cancer vaccines are mainly concentrated in two aspects, namely the diversity of tumors. 4 and drug technology needs to be improved. The heterogeneity of tumors is a major reason for its intractable treatment, because tumors are not entirely composed of the same cell, and it is very difficult for a single drug to remove all tumor cells. Secondly, unlike infectious disease vaccines, cancer vaccines have to face the human body's own cells. The immune systems of different individuals are different. It is very difficult to screen a tumor vaccine that is effective for most tumor patients. This is also an important reason why the previous tumor vaccines were not successful.
"The human immune system is a very complex system, and the history of tumor immunity is relatively short. The academic and industry have not yet fully understood the mechanisms of tumor immunity, including the regulation mechanism of the immune system, how to evaluate the effectiveness of tumor vaccines, and how to predict the safety of tumor vaccines. There is currently no mature solution, which has also brought great difficulties and uncertainties to the development of drugs." Aibo Biologics said.
