HomeENGLISH MAGAZINEIRF5 as a specific target in systemic lupus: the innovational drug discovery...

IRF5 as a specific target in systemic lupus: the innovational drug discovery is on the way

Systemic lupus erythematosus (SLE) is an chronic autoimmune disease characterized by a breakdown of immune tolerance to nuclear self-antigens. Current standard therapies for SLE include steroids, immunosuppressants, DMARDs and biologics among which the most recently approved is a monoclonal antibody against the cytokine BAFF. Owing to these therapies, the 10-year survival rate has improved from 60 to 90% in the past 50 years. However, SLE patients still have unmet medical needs. First of all, the immune suppressing agents employed are also used in other autoimmune conditions, which implies a lack of specificity to treat the disease. Second, in case of a relapse, high doses of steroids or immunosuppressants are often required, and therefore relapsing–remitting inflammation results in not only further tissue damage but also severer adverse effects of the drugs.

One of the highly anticipated new drugs currently in clinical trials is an anti-type I interferon (IFN) receptor monoclonal antibody that blocks the action of type I IFNs (IFN-α and -β). SLE patients display high expression of IFN-stimulated genes (ISGs) called the IFN signature, and animal experiments have revealed that blocking of type I IFN signaling inhibits SLE-like symptoms. Recently, it was announced that phase III trials of anifrolumab, an antagonist antibody for IFN-α and -β receptor subunit 1 (IFNAR1), reached their primary endpoint. The percentage of responders was higher in the anifrolumab group (47.8%) than in the placebo group (31.5%). Nevertheless, the annualized relapse rate was still as high as 43% in the anifrolumab group. Thus, the development of additional therapies other than (or in addition to) blocking of type I IFN signaling is desirable.

Multiple genome-wide association studies have identified IRF5 as one of the genes whose genetic variants are highly associated with SLE risk. IRF5 encodes a transcription factor that has been shown to be activated in monocytes of most SLE patients, and its expression is further induced by estrogens (the biological trigger of the disease in women). Scientists from the Advanced Medical Research Center of Yokohama City University think that targeting specifically this protein instead the whole interferon complex might give better chances to control the disease. First of all, they deminstrated that the proportion of individuals displaying IRF5 nuclear translocation in ≥5% of monocytes was 4% in healthy donors and 52% in SLE patients. Apparently, the levels of the protein remained significantly elevated in both patients with active disease and in remission, compared to healthy individuals.

They then demonstrated that the drugs currently used to treat the disease are unable to counteract the activation of IRF5 through the process of protein phosphorylation. In fact, when IRF5 is de-phosphorylated, its activity is practically absent. For example, regardless of the administration of prednisolone, hydroxychloroquine or mycophenolate mofetil, the percentage of monocytes with IRF5 nuclear translocation as well as the expression levels of interferon-stimulated genes remained high. In the next step of the research, scientist proved that blocking the acticirty on the IFNAR1 alone is not enough to block the progression of the disease in experimental models and that IRF5 regulates the energetic availability of immune cells. Specifically, it enhances mitochondrial energy by upregulating components of the phosphorylative chain and its genetic ablation (conditional dominant negative protein) reduced the disease in sick animals.

However, genetic conditioning is not practical in clinical practice; this is why scientists moved on and reasone that a chemical inhibitor of IRF5 could be a better choice. Therefore, they performed an high-throughput screening of a huge chembank to identify selective inhibitors of IRF5 transcriptional activity. Only one small-molecule compound, named YE6144 substantially inhibited the nuclear translocation of IRF5 in activated monocytes and dendritic cells. This substance was quite specific and did not almost at all interfere with NF-kB, another transcription factor involved in some inflammatory aspects of SLE. Both IRF-5 and NF-kB share some upstream activating mechanisms; but whereas an NF-kB pathway inhibitor (TCPA-1) affected both transcription factors, YE6144 did only interfered with IRF5 nuclear activity. The drug molecule impaired most of the IFN-regulated responses and SLE animals showed an improvement of proteinuria, kidney damage, spleen enlargement and autoreactive immune population in the blood.

And this remission markers lasted longer than conventional immune suppressants or proteasome inhibitors (bortezomid) able to induce the recycling of intracellular proteins. Researchers believe that a long-term remission induced by the IRF5 inhibitor together with standard drugs may eventually result in the disappearance of autoantibodies and their producing cells, plasmacells. If the autoantibody levels remain high, then anti-plasmacells drugs such as atacicept are administered for a short period to induce a deep remission. Eventually, the combination therapy could be replaced by the IRF5 inhibitor monotherapy for remission maintenance.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

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Scientific references

Ban T, Kikuchi M et al. Nat Commun 2021; 12:4379.

Song, S. et al. J. Clin. Investig. 2020; 130, 6700–6717

Malkiel S, Barlev AN et al. Front. Immunol. 2018; 9:427.

Tsokos GC et al. Nat Rev Rheumatol. 2016; 12:716.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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