MRNA technology: A medical revolution that is giving rise to a new generation of therapies

Therapies based on mRNA technology deliver synthetic mRNA into specific cells in the human body, where it is translated into the desired proteins in the cytoplasm. As vaccines or drugs, mRNA can be used for the prevention of infectious diseases, the treatment of tumors, and protein replacement therapy.

• Preventive vaccines in the field of infectious diseases

Molecularly Modified RNA (mRNA) vaccines for infectious diseases encode antigens related to the pathogen, which can be expressed in the body after injection. These antigens can simultaneously induce cellular and humoral immunity, stimulating the production of corresponding antibodies and immune cells to prevent the infection by the pathogen.

• Tumor therapeutic vaccine

The mRNA encoding tumor-specific antigen targets is delivered to the body in a specific manner, allowing these tumor-specific antigens to be translated and presented on the cell surface. This activates the immune system, enabling it to specifically recognize and kill tumor cells.

• Protein replacement therapy

Normally, protein replacement therapy is used to treat rare single-gene diseases, aiming to restore enzyme function. Protein synthesis is difficult, administration presents many challenges, and it is expensive. However, using mRNA to turn the human body into its own protein factory is theoretically an economical and efficient method.

mRNA drug targets are abundant, not limited by the medicineability of target proteins or intracellular/extracellular constraints. mRNA sequence design is simple; it uses the patient's own cells to produce molecules, bypassing the challenges of chemical synthesis, and the molecules produced by self-induction have stronger pharmacological effects. mRNA production platforms have strong scalability and replicability, making them suitable for large-scale production.

Globally, mRNA technology has become an important track actively pursued by major pharmaceutical companies and biotechnology firms. International companies represented by Moderna, BioNTech, and CureVac, in addition to deploying a variety of preventive vaccines in the field of infectious diseases, are also making related investments in oncology treatment, including universal tumor vaccines, personalized tumor vaccines, and tumor cytokine supplements.

According to statistics, as of March 31, 2022, there were a total of 56 mRNA drugs entering clinical trials worldwide, with research and development mainly concentrated in the vaccine field, accounting for about 84%, while therapeutic drugs accounted for about 16%. Apart from the emergency launch of mRNA COVID-19 vaccines, most of the others are in the early stages, with mRNA research and development mainly in Phase I clinical trials, accounting for about 40% of the total.

Source: Frost & Sullivan

In China, the mRNA market is still in its early stages of development, with several biotechnology companies showing potential in research and development. Seven companies have obtained clinical approval from the Center for Drug Evaluation (CDE) for mRNA drugs, among which Sino Biologics has the most clinical pipeline and the widest range of indications. Sino Biologics' pipeline focuses on two major areas: infectious disease prevention and tumor treatment. The COVID-19 mRNA vaccine product is undergoing Phase II clinical trials globally and Phase I clinical trials domestically. Personalized tumor vaccine products targeting advanced solid tumors (including lung cancer, esophageal cancer, and digestive tract tumors) are currently conducting Phase I clinical trials globally and in China.

At the end of 2020, two mRNA COVID-19 vaccines developed by Pfizer/BioNTech and Moderna, respectively, received emergency use authorization. In 2021, the global sales of these two vaccines reached as high as $58.7 billion.

Compared to traditional vaccines, mRNA vaccines have a shorter development cycle, are easier to modify, and can be rapidly updated and iterated to respond to emerging mutant strains. They are produced based on a common technology platform, providing a flexible, large-scale, fast, and cost-effective production process. Moreover, their production capacity can ramp up extremely quickly, with batch yields reaching hundreds of millions, giving them a clear advantage in dealing with sudden epidemiological crises. mRNA vaccines have broken the immune activation mode of traditional inactivated and attenuated live vaccines. By innovatively using human cells to express antigen proteins, they can induce more extensive and effective cellular and humoral immune responses, resulting in higher protection rates. At the same time, compared to other innovative vaccines (such as DNA vaccines, which are more toxic and require entering the cell nucleus for transcription into mRNA, while mRNA only needs to enter the cytoplasm to be expressed), they have higher safety. The safety of hundreds of millions of doses of mRNA COVID-19 vaccines has been fully verified.The advantages of mRNA technology are evident and it will be the primary choice for the development of new vaccines.

In the short term, the preventive vaccine market mainly stems from COVID-19 products. In the medium and long term, due to the advantages of mRNA vaccines in terms of target number, efficacy, safety, and production process, it will expand to the prevention of more infectious diseases such as influenza virus vaccines, influenza respiratory syncytial virus vaccines, and malaria vaccines. In addition to preventive vaccines, immunotherapy for treating tumors is also a current research hotspot for mRNA technology. Traditional immunotherapy requires injecting antigens into the body, which poses many difficulties in protein delivery, including synthesis difficulties and high costs. Injecting artificially synthesized mRNA into the body to guide the body to synthesize corresponding antigen proteins is an effective and economical method. In the field of tumor treatment, there is a large number of patients and unmet clinical needs, and the market scale of tumor therapeutic vaccines will continue to climb in the future. Overall, with improvements and advancements in delivery technology and stability, mRNA has a very strong competitive advantage and has the potential to become a product across application fields, with broad market development space.

Common delivery methods and vectors for mRNA vaccines

Source: Nature Reviews Drug Discovery

The mainstream mRNA delivery system has evolved from protamine to lipid-based delivery systems. Lipid-based delivery systems include liposomes (liposome), lipid Nanoparticle (LNP), and Lipopolyplex (LPP).

LPP in lipids is a bilayer structure with a polymer-coated mRNA core and a phospholipid envelope. The bilayer lipid bilayer membrane of LPP has a better effect in encapsulating and protecting mRNA, and the core of LPP can gradually release mRNA molecules as the polymer degrades. LPP has excellent targeting effect on dendritic cells, can better activate the immune response of T cells through antigen presentation, and achieve ideal therapeutic effects. Sino Biologics is the only company using a non-LNP delivery system and owns the independent intellectual property rights of LPP.

mRNA technology has shone brightly in the development of COVID-19 vaccines and is expected to expand into broader therapeutic fields such as tumor treatment and regenerative medicine.

In the field of tumor treatment, there is a large number of patients and unmet clinical needs. Compared to other technologies, mRNA has certain advantages in tumor vaccines, especially personalized vaccines. mRNA is capable of expressing more than 20 tumor antigens simultaneously, and its sequence design and production are rapid, making it the most promising technology platform for personalized tumor vaccines.

Personalized therapeutic tumor vaccines are developed by sequencing to identify unique neoantigens on patient tumor cells, and various personalized tumor vaccines targeting these neoantigens are developed using mRNA. BioNTech and Moderna's respective pipelines have entered clinical trials. In China, Sino Biologics is currently the only company with a clinical-stage mRNA personalized tumor vaccine, and its corresponding pipeline has entered Phase I clinical trials.

In the field of regenerative medicine, IPS cells can be generated by transfecting fibroblasts with mRNA encoding reprogramming factors to induce differentiation into functional cells. For example, Somacon has produced iPS cells by transfecting fibroblasts with mRNA encoding reprogramming factors (Oct4, Sox2, c-Myc, Klf4), inducing their differentiation into cardiomyocytes, and is committed to using mRNA to induce stem cells for the treatment of cardiovascular diseases.