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IL-23 Continued research on inflammatory pathways
by Dec 23, 2022 06:05am
Efforts to develop treatments through various studies such as combination therapy and receptor targets. Interleukin (IL) inhibitors used in autoimmune diseases such as psoriasis are evolving as several companies continue to develop them. With the emergence of more effective treatments, psoriasis can expect "PASI 100," which means complete improvement. Interleukin inhibitors are classified according to the mechanism. Stelara, which appeared first, targets IL-12 and IL-23 simultaneously. Cosentyx and Taltz are mechanisms that inhibit IL-17. Recently, drugs that are attracting attention are Tremfya and Skyrizi, which are exclusively targeting IL-23. It is known to have the most powerful effect. As IL-23 pathway research becomes more active, evidence is accumulating that IL-23 inhibitors are inevitably more effective than interleukin inhibitors of other mechanisms. In a recent interview with Dailypharm, Daniel Cua Janssen, vice president of the immune business department, said, "IL-23 inhibitors act on immune cells themselves that activate inflammatory pathways, preventing the underlying cause in the early stages. Recently, it was found that IL-23 reprogrammed a group of T cells that produce IL-17 and found that a fairly strong inhibitor was needed among IL-23 inhibitors, he explained. Daniel Cua is a world-renowned scholar who first discovered the IL-23 pathway 22 years ago. The IL-23 route he discovered was the beginning of the development of IL-23 inhibitors such as Trempier and Skyrich. Studies on the mechanism of how IL-23 causes inflammation are still ongoing. "It is clear that IL-23 is the strongest interleukin associated with autoimmune diseases. Based on this, he added, "In the future, challenges to develop treatments through various studies such as combination therapy and receptor targets will continue." The following is a question-and-answer session with Vice President Cua. -After studying immunology for a long time, we discovered the IL-23 pathway that is the target of autoimmune disease treatment. We are curious about the history. =22 years ago, I was researching a small biotech in Silicon Valley, USA. At that time, research was in full swing to discover substances that control inflammation. The goal was to find an inflammatory control substance, but the IL-23 pathway was found at that time. At that time, not many people believed it because it was an unexpected discovery. It was only a year or two later that the substance that academia wanted to find was IL-23 which we discovered in 2000. It began to be recognized as a very important discovery. Animal models that inhibited IL-23 showed all resistance to several autoimmune diseases. This also affected future research and treatment development. The discovery of the IL-23 pathway is considered to be the starting point of several subsequent studies. - Various interleukin inhibitors such as IL-12/23, IL-17 and IL-23 have been developed as treatments for autoimmune diseases. What differences do differences in mechanisms make? =One of the most frequently asked questions is why blocking only IL-23 works better than blocking IL-12 and 23 together. To put it simply, IL-23 is the standard target we have to hit. Cytokines sometimes cross-regulate each other. Controlling one means that the other rises. IL-12 and IL-23 are. Blocking the two together in a cross-regulation relationship results in a "push and pull" conflict effect of each other's actions at the same time, which reduces the effect. Only IL-23 should be blocked to show the most precise inhibitory effect we want. IL-17 is an interleukin present in a lower stage than IL-23 on the reaction path. It has higher specificity in intestinal epithelial cells and skin epidermal cells. On the other hand, IL-23 acts on immune cells themselves that activate inflammatory pathways. For this reason, IL-23 must be suppressed to prevent the underlying cause of the inflammatory system in a more early stage. In psoriasis, IL-23 shows a clinical improvement effect of 80-90% in more than 90% of patients. - Like immuno-cancer drug combination therapy in cancer, can autoimmune diseases be more effective by combining upper and lower series that suppresses interleukin? = combination therapy is the approach that many researchers and companies in this field are most interested in. The concern is the accumulation of adverse reactions caused by combination therapy. Therefore, research on port therapy is being conducted on the most reasonable and scientific basis. A combination of specific route drugs based on biomarkers is being sought. Although it is still in its early stages, many efforts are being made to find a combination that increases the effectiveness but does not increase the response. So far, it is known that blocking complementary paths may be more effective than targeting only specific paths. For detailed research, the understanding of various paths is improved based on biomarker analysis. -How far has the research on IL-23 progressed? =The level we know is that IL-23 induces the production of receptors called IL-17, IL-22, and GM-CSF. However, it was not clear exactly how IL-23 causes inflammation. It has recently been revealed that IL-23 reprogrammed a group of T cells that produce IL-17. Reprogramming is a fairly powerful action and cannot go back because it is semi-permanent in itself. To prevent this, considerably strong inhibitors among IL-23 inhibitors should be used. In the end, I realized that inhibiting IL-23 has a much stronger effect than inhibiting elsewhere and that it is also effective in preventing lower-level diseases when applying a mechanism that prevents reprogramming at the epigenetic level to new drug development. - What are the targets or pipelines to pay attention to in the subsequent development of interleukin formulations? = First, the receptor. Ligands such as IL-23 bind to receptors, a new drug that blocks the receptor itself to prevent binding. The number of receptors is smaller than that of ligands, so it is easier to block and has precise access, making them a good candidate. The second is the study of RORgamma-t. Many researchers are targeting it, but no one has succeeded yet. Treatments that produce the most accurate and precise effects in this route are expected to be developed in the future.