{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:38:17Z","timestamp":1793824697825,"version":"4.6.1"},"reference-count":210,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Interleukin-5 (IL-5) is a central regulator of eosinophil differentiation, maturation, survival, activation, and mobilization, and it contributes to eosinophil recruitment to inflamed tissues. These biological functions have made the IL-5\/IL-5 receptor alpha (IL-5R\u03b1) pathway a key therapeutic target in eosinophil-associated diseases. Four biologics currently target this pathway in clinical practice: mepolizumab, reslizumab, and depemokimab bind soluble IL-5, whereas benralizumab targets IL-5R\u03b1 and induces antibody-dependent cellular cytotoxicity. Clinical development has been successful in severe eosinophilic asthma (SEA), where targeting the IL-5\/IL-5R\u03b1 pathway reduces exacerbation risk and can lower the need for long-term oral corticosteroid use. The therapeutic scope has since expanded to chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic granulomatosis with polyangiitis (EGPA), and idiopathic hypereosinophilic syndrome (iHES). Mepolizumab has shown efficacy across these eosinophilia-associated diseases, reducing asthma exacerbations, nasal polyp burden, EGPA relapse activity, HES flares, and eosinophils in peripheral blood. Mepolizumab is approved by both FDA and EMA for SEA, CRSwNP, EGPA, and HES. Reslizumab improves exacerbation rates and lung function in SEA and is approved by FDA and EMA for this indication. Benralizumab produces rapid and near-complete blood and tissue eosinophil depletion, reduces exacerbation rates and oral corticosteroid use in SEA, and has demonstrated sustained remissions and corticosteroid-sparing efficacy in EGPA; it is approved by FDA and EMA for SEA and EGPA. Depemokimab extends IL-5 inhibition through a long-acting, twice-yearly dosing strategy, reduces exacerbation rates in SEA, and improves nasal polyp burden in CRSwNP; it is approved by FDA and EMA for SEA and by EMA for CRSwNP. Safety data from randomized trials, extension studies, real-world cohorts, and meta-analyses are generally reassuring, with most adverse events being mild to moderate and no consistent major safety signal. This review synthesizes current understanding of IL-5 biology, critically evaluates the clinical trial evidence for IL-5\/IL-5Ra-targeted biologics across major eosinophilia-associated diseases, and highlights remaining evidence gaps and future directions.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1875279","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T04:39:06Z","timestamp":1781152746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Biological functions and clinical efficacy of IL-5\/IL-5R\u03b1-targeted therapies across eosinophilia-associated diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Johannes","family":"L\u00fcbke","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University","place":["Mannheim, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University","place":["Mannheim, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Schwaab","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University","place":["Mannheim, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0969-2126(00)00018-6","article-title":"Structural comparisons among the short-chain helical cytokines","volume":"2","author":"Rozwarski","year":"1994","journal-title":"Structure"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2210\/pdb1hul\/pdb","article-title":"A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5","volume":"363","author":"Milburn","year":"1993","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.144.4.1345","article-title":"Role of carbohydrate moiety of IL-5. 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