Issue link: https://www.e-digitaleditions.com/i/1519174
PharmTech.com Innovations in mRNA eBook April 2024 Pharmaceutical Technology ® 5 Formul ation much faster to reach approva l compared to more conventional therapeutic modalities, [such as] pro- tein-based vaccines or viral vector-based vaccines. T he reason beh ind t hat is t hat m R NA is ent irely produced in vitro, so [there is no] need [for] any cells to produce it. [Their manufacture] is just based on a n in-vitro t ra nscr ipt ion react ion, [wh ich] uses a viral polymerase to amplif y the mRNA. [Moreover, mRNA] only contains four building blocks, and, be- cause of that, it has ver y constant physical/chemi- cal properties. Thus, regardless of the protein [one] wants to encode, [they] would have the same phys- ical/chemical properties. This, [therefore], allows [one] to develop generic manufacturing processes. A third aspect is the abilit y to modulate the im- munogenicity of the platform. This means that the mRNA and the formulation can either be made less (for t herapeutics) or more im munogenic (for vac- cines) based on the application. It really makes the immune system believe that the viral infection is ongoing, and it needs to respond to that infection by mounting a strong immune response. These three things together—the f lexibility, the speed of man- ufacturing, and abilit y to modulate the immuno- genicity of the platform—makes mRNA a versatile platform for vaccines and other uses. Mode of action PharmTech: Can you describe the mode of action by which an mRNA therapy identifies and attacks cancer cells? De Koker (etherna): mRNA is actually being used in multiple ways to treat cancer. Currently, the most advanced [methods] are mRNA-based cancer vac- ci nes. Here, t he goa l of t hat ca ncer vacci ne is to induce a cy toly tic T-cell response against a tumor antigen. What happens is, when a cell gets trans- formed, and it evolves into a cancer cell, it star ts to express aberrant proteins. These are presented at the surface of a cancer cell, and they can be rec- ognized by an immune cell, [such as] a cytolytic T cell. That cytolytic T cell moves throughout the body, and whenever it comes across a mutated cell that expresses these aberrant proteins [i.e., antigens] at its surface, it will react to these antigens and start killing the cancer cell. That's basically how a can- cer vacci ne work s; a n m R NA [is used] to encode t he t umor antigen, it is injected in t he format of an mRNA [enclosed in] a lipid-based nanoparticle, and then the immune system will react against the m RNA encoded antigen by mounting c y toly tic T cells, which will then travel through the body and, whenever they encounter a tumor cell, will kill it, or at least try to kill it. mRNA versus others PharmTech: What advantages does mRNA have over other categories of therapeutics for cancer treatment and as a vaccine? De Koker (etherna): There is, of course, a ver y broad range of cancer therapeutics, so [one] needs to compa re apples w it h apples. If we a re ta l k i ng about the cancer vaccine, the first big advantage is, again, the f lexibility and the speed of manufactur- ing. [In looking] at a tumor, a tumor accumulates mutations, [which] leads to antigens, which can be immunogenic and can be recognized by the immune system. One of the issues is that these antigens are different for each tumor, and they're also different for each patient. This means that the vaccine needs to be adapted [by] encoding [it] with mRNA to the individual tumor of a patient. The tumor is being sequenced, the antigens are being predicted or iden- tified, and … that [gets translated] into a vaccine. Also, in terms of therapeutic benefits, mRNA has big advantages compared to other technologies that have been explored as cancer vaccines. Originally, just peptides were used, or protein antigens, to im- munize patients. But these typically do not lead to the strong cy toly tic T-cell response needed to kill t he cancer cel ls. So, t hese formats have had ver y low efficacy. Only when people were starting to use m R NA, or v i ra l vectors, was ef f icac y seen. T hus, there is an efficacy benefit compared to a peptide, and certainly a production benefit to viral vectors. There is also another benef it compared to viral vectors, and that is that [mRNA] does not induce an- tibodies against itself. If using a viral vector, which encodes a tumor antigen, to vaccinate patients, then the immune system will not only react against the tumor antigen, but also against the viral antigens that are present in that viral vector. That process ac- tually prevents the use [of] that viral vector multiple times, so the same viral vector [cannot be used] to boost the immune response of a patient. LNPs as a standard? PharmTech: Is it too early to say whether LNPs will become standard in the manufacture of mRNA-based therapies, or are there other types of encapsulation mRNA can be produced extremely fast ... nicely exemplified by the COVID crisis.