{"doi":"10.1126/scisignal.adg0699","title":"Multivalent, asymmetric IL-2–Fc fusions show enhanced selectivity for regulatory T cells","abstract":"The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (T reg ) cells. IL-2 receptors consist of combinations of α, β, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively T reg -selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor. However, we found that refining the designs to focus on targeting the high-affinity receptor through avidity effects is key to optimizing T reg selectivity. We profiled the dynamics and dose dependency of signaling responses in primary human immune cells induced by engineered fusions composed of either wild-type IL-2 or mutant forms with altered affinity, valency, and fusion to the antibody Fc region for stability. T reg selectivity and signaling response variations were explained by a model of multivalent binding and dimer-enhanced avidity—a combined measure of the strength, number, and conformation of interaction sites—from which we designed tetravalent IL-2–Fc fusions that had greater T reg selectivity in culture than do current designs. Biasing avidity toward IL2Rα with an asymmetrical multivalent design consisting of one α/β chain–binding and one α chain–binding mutant further enhanced T reg selectivity. Comparative analysis revealed that IL2Rα was the optimal cell surface target for T reg selectivity, indicating that avidity for IL2Rα may be the optimal route to producing IL-2 variants that selectively target T regs .","journal":"Science Signaling","year":2023,"id":353138,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":814560,"name":"Peter C. Emmel","orcid":"0000-0002-8878-6145","position":1,"is_corresponding":false},{"id":814561,"name":"Eli M. Snyder","orcid":"0000-0002-1725-0087","position":2,"is_corresponding":false},{"id":714439,"name":"Scott D. Taylor","orcid":"0000-0001-6767-864X","position":3,"is_corresponding":false},{"id":405318,"name":"Aaron S. Meyer","orcid":"0000-0003-4513-1840","position":4,"is_corresponding":false},{"id":568625,"name":"Brian Orcutt-Jahns","orcid":"0000-0002-1436-1224","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:12:58.542950Z","pmid":"37847758","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":[]}