by Carrie Taylor, Director of Research & Development of BOCSCI.
Globally, the COVID-19 pandemic has significantly accelerated the development of mRNA technology platforms and mRNA industry chains. The first mRNA drug (BNT162b2 vaccine) was granted emergency use authorization by the FDA in December 2020 and approved for marketing in August 2021.
mRNA drugs encode mRNA based on the selection of targets or antigens and enter the cytoplasm through specific delivery systems (such as LNP) to produce specific protein substances (corresponding to the coding design) within the cell and stimulate the immune system to produce an immune response after being secreted inside the cell or outside the cell. Currently, the development of mRNA drugs mainly focuses on immunotherapy (tumor immunity, preventive vaccines, allergy immunity, etc.), protein replacement therapy, regenerative medicine therapy, etc.
Figure 1. Applications of mRNA technology (Sahin U, et al. 2014)
Advantages of mRNA drugs
- Short R&D cycle, relatively simple production, and preparation. Compared with traditional drugs (including chemical drugs, biological drugs, etc.), mRNA and other novel drugs are given priority evaluation and qualification, so the period from exploratory research to the marketing stage is at least 6.5 years shorter than traditional drugs.
Figure 2. Efficiency comparison between mRNA and traditional technology platforms in the R&D and API production stages (Kis Z, et al. 2020)
(2) Greatly reduced production costs. According to a relevant research report, in the construction of the production process of raw materials, the traditional drug platform needs 6-9 years. In contrast, the evolving technology platform such as mRNA only demands 2-4 years due to more flexibility, smaller scales, and simultaneous multi-product processes. The traditional route costs US $400-700 million to build the raw material production process, while new technology platforms like mRNA only cost US $0.1-50 million.
(3) Flexible applications for different objectives. The front end of mRNA drugs is sequence design and coding, followed by relatively standardized processes such as the LNP delivery system, so it can not only meet the requirements of large-scale general-purpose drug production and preparation (e.g., CAR-T drugs cannot meet the requirements of large-scale production), but also can be personalized for individual conditions, such as the precision treatment of individual tumors.
(4) A tremendous potential for pharmaceutical development. Thanks to the unique pharmacological mechanism of mRNA drugs, as long as the protein structure and sequence of diseases are completely analyzed, the pathogenesis and causes of drug resistance can be fully understood, so as to prevent and treat diseases by changing the corresponding structure and sequence of proteins. Thus, by coding for multiple antigen genes, mRNA platforms can create combined vaccines (Moderna’s lymphoma drug, for example, encodes three proteins simultaneously).
Disadvantages of mRNA drugs
Currently, the only mRNA drugs on the market are mRNA vaccines for COVID-19, so the below shortcomings are analyzed only from this category.
(1) Drugs are difficult to store and are dependent on demanding transportation conditions. BioNTech’s BNT162b2 vaccine can only be stored for five days at 2-8 degrees Celsius and up to six hours after dilution at 2-25 degrees Celsius. Pharmaceutical cold chain logistics requires operation at low temperatures between -80 and -60 degrees Celsius. Moderna’s mRNA-1273 vaccine can be preserved unopened for 30 days at 2-8 degrees Celsius and for up to 12 hours at 8-25 degrees Celsius. Pharmaceutical cold chain logistics require temperatures between -25 and -15 degrees Celsius.
(2) The possibility of third-degree side effects is higher than traditional drugs. BioNTech’s BNT162b2 vaccine has a 3.8 percent chance of fatigue and a 2 percent chance of headaches. Moderna’s mRNA-1273 vaccine has a 15.8 percent rate of fatigue, myalgia, and joint pain. According to a study published in the Journal of Hepatology on April 21, 2022, BioNTech’s BNT162b2 vaccine may cause T cell-mediated autoimmune hepatitis. Safety is the future focus of mRNA drugs.
mRNA technology focuses on sequence design, delivery systems, and scaling production capacity.
(1) The key to mRNA sequence design lies in the construction of a cloud computing mRNA structure platform, cap design, and modified nucleotide design based on bioinformatics algorithms (such as neural network models).
Specifically, the five-prime cap, UTR structure, length and adjusting elements, coding sequence modification, and the design of the 3′ poly(A) tail directly affect mRNA performance.
(2) Lipid Nanoparticles (LNPs) are key to delivery. mRNA encapsulation liposomes/lipid nanoparticles can quickly and safely deliver mRNA into the cell and release it. Therefore, the composition, charge, particle diameter, and particle distribution of synthesized LNPs directly affect their pharmacokinetic characteristics and immune effect.
(3) The key to scaling up production lies in raw material supply chain management. There are hundreds of raw materials for mRNA drugs, but there are very few suppliers of enzymes with synthetic barriers (such as enzymes needed for Clean Cap), modified nucleotides, and liposomes.
Due to their unique mechanism of action, mRNA drugs have broad and far-reaching development prospects in both preventive vaccines and tumor immunotherapy. BOC Sciences, as a member of the raw material supply chain, is working to accelerate mRNA drug achievements.