{"doi":"10.3389/fimmu.2021.779100","title":"Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor","abstract":"Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors - IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ - after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.","journal":"Frontiers in Immunology","year":2021,"id":175024,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":356048,"name":"Kyle C. Kihn","orcid":"0000-0002-0502-1332","position":1,"is_corresponding":false},{"id":715329,"name":"Gabriel Svensson Birkedal","orcid":"0000-0003-3647-1659","position":2,"is_corresponding":false},{"id":356047,"name":"Erik H. Klontz","orcid":"0000-0002-1923-972X","position":3,"is_corresponding":false},{"id":715330,"name":"Kjell Sjöström","orcid":"0000-0003-2306-4384","position":4,"is_corresponding":false},{"id":716099,"name":"Sebastian Günther","orcid":null,"position":5,"is_corresponding":false},{"id":716100,"name":"Robert Beadenkopf","orcid":null,"position":6,"is_corresponding":false},{"id":716101,"name":"G. Forsberg","orcid":null,"position":7,"is_corresponding":false},{"id":715331,"name":"David Liberg","orcid":"0009-0009-0645-746X","position":8,"is_corresponding":false},{"id":356051,"name":"Greg A. Snyder","orcid":"0000-0002-4409-0453","position":9,"is_corresponding":false},{"id":335143,"name":"Daniel Deredge","orcid":"0000-0002-6897-6523","position":10,"is_corresponding":false},{"id":356052,"name":"Eric J. Sundberg","orcid":"0000-0003-0478-3033","position":11,"is_corresponding":false},{"id":356049,"name":"James K. Fields","orcid":"0000-0001-5923-108X","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"35003094","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}