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The role of IL-5 in the endotyping of CRS patients and the development of monoclonal antibodies (Master thesis)

Σταμκοπούλου, Παναγιώτα/ Stamkopoulou, Panagiota

Introduction: One hundred years after eosinophils were first associated with symptomatic asthma, molecular cloning enabled the identification of IL-5 as a cytokine that stimulates the functions of eosinophils. Since the identification of IL-5 in the 1980s, it has become increasingly clear that in contrast to other cytokines thought to be involved in allergic inflammation, such as GM-CSF and IL-3, the biological activity of IL-5 is very specifically focused on the development, differentiation, recruitment, activation, and survival of a single cell type, the eosinophil. Since then, a body of evidence has firmly established the role of IL-5 in airway eosinophilia. In recent years, the understanding of chronic rhinosinusitis (CRS) has evolved significantly, prompting an exploration of distinct phenotypes and endotypes to better tailor therapeutic approaches. This shift underscores the importance of immunologic factors in the disease’s pathophysiology, particularly the role of interleukin-5 (IL-5). As a key cytokine, IL-5 predominantly drives eosinophilic inflammation, a characteristic feature of a specific endotype of CRS. By differentiating patients based on IL-5 levels and eosinophil activity, clinicians can enhance diagnostic precision and improve treatment strategies. Consequently, the study of IL-5 not only illuminates the underlying mechanisms of CRS but also paves the way for novel interventions, such as targeted biologics, that specifically address eosinophil-mediated inflammation. This shift toward a more personalized medicine approach signifies a crucial advancement in the management of rhinosinusitis, offering hope for better outcomes in affected populations. Aim of the study: This systematic review synthesizes historical and current research and traces the initial discovery and characterization of Interleukin-5 (IL-5), detailing its biochemical properties, explores its role in endotyping rhinosinusitis, examines the development of IL-5-targeting monoclonal antibodies, such as mepolizumab, reslizumab, and benralizumab, and their clinical efficacy. Materials and methods: A comprehensive literature search was conducted across multiple databases, including Pubmed, Μedline/ National Library of Medicine (NLM), Cochrane Database and Wiley Online Library. All papers published between January 1993 and December 31st, 2022, with an English title, were included in the initial stage of this study. The final number of initially identified papers was 898 (n=898). The search was limited to peer-reviewed articles published in English. The studies/papers/journals finally included in the present analysis were 33 (24 clinical trials or clinical studies and 9 systematic reviews /meta-analyses). Results: IL-5 was first identified in the early 1980s as a T-cell-derived cytokine involved in B-cell differentiation and eosinophil activation. Pioneering work highlighted IL-5's role in promoting the growth and differentiation of B cells and eosinophils, establishing its significance in immune response modulation. In rhinosinusitis, IL-5 plays a central role in the recruitment and activation of eosinophils in the nasal and sinus mucosa, contributing to persistent inflammation and polyp formation. Studies have shown a strong correlation between IL-5 levels and the severity of eosinophilic inflammation in CRSwNP patients. IL-5 serves as a key biomarker for the eosinophilic endotype of CRSwNP. Identifying patients with elevated IL-5 levels aids in tailoring personalized treatment strategies, particularly with the use of biologics targeting IL-5. Monoclonal antibodies designed to neutralize IL-5 or block its receptor can effectively reduce eosinophil-mediated inflammation. Conclusions: The discovery and characterization of IL-5 has been pivotal in advancing our understanding of eosinophilic inflammation and its role in rhinosinusitis. Endotyping based on IL-5 and other cytokines has led to a more precise understanding of rhinosinusitis and improved therapeutic outcomes. The development of monoclonal antibodies targeting IL-5 has transformed the treatment landscape, providing effective options for patients with severe and refractory CRSwNP. Continued research and clinical advancements will further refine these therapeutic strategies, enhancing their efficacy and ensuring long-term safety.