{"doi":"10.1016/j.jtha.2025.02.032","title":"An engineered Treg selective immunocytokine induces sustained immune modulation in a preclinical model of hemophilia A","abstract":"BACKGROUND: The development of inhibitory antibodies (inhibitors) is a serious complication in the treatment of hemophilia A with clotting factor (F)VIII replacement therapy. Inhibitor formation critically depends on T cell help and modulation by regulatory T cells (Tregs). OBJECTIVES: In this study, we evaluated the F5111 immunocytokine (IC), a single-chain fusion between the human interleukin (IL)-2 cytokine and an IL-2 antibody that biases cytokine activity toward cells with high IL-2 receptor (IL-2R)α expression, leading to extended IL-2 half-life and selective expansion of Tregs. METHODS: A transient F5111 IC administration regimen was applied to a hemophilia A murine model of FVIII replacement therapy. Inhibitory antibody development to FVIII was monitored longitudinally by Bethesda assay and ELISA. RESULTS: F5111 IC failed to stimulate cell types that predominantly express the dimeric IL2Rβγ receptor complex such as effector T and natural killer cells. Potent and highly transient Treg expansion was associated with suppression of effector T cells and in vivo conversion into Tregs. When tested in the hemophilia A mouse model, F5111 IC completely prevented the formation of inhibitors against FVIII for up to 4 months, long after Treg numbers returned to baseline levels. CONCLUSION: These results demonstrate that F5111 IC induces a superior and prolonged tolerogenic response compared with an unbiased control IC. Overall, this study presents a novel and effective strategy for preventing inhibitory antibodies that hinder the effectiveness of FVIII replacement therapy in hemophilia A.","journal":"Journal of Thrombosis and Haemostasis","year":2025,"id":533360,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":868916,"name":"Derek VanDyke","orcid":"0000-0002-0494-7184","position":1,"is_corresponding":false},{"id":663956,"name":"Maite Muñoz-Melero","orcid":null,"position":2,"is_corresponding":false},{"id":1052337,"name":"Charina S. Fabilane","orcid":null,"position":3,"is_corresponding":false},{"id":1396663,"name":"Senthilkumar Thirumurugan","orcid":"0009-0005-9601-956X","position":4,"is_corresponding":false},{"id":1058907,"name":"Sreevani Arisa","orcid":null,"position":5,"is_corresponding":false},{"id":355871,"name":"Baohua Zhou","orcid":"0000-0003-1156-4517","position":6,"is_corresponding":false},{"id":530310,"name":"Jamie B. Spangler","orcid":"0000-0001-8187-3732","position":7,"is_corresponding":false},{"id":290763,"name":"Moanaro Biswas","orcid":"0000-0002-2889-5905","position":8,"is_corresponding":false},{"id":393005,"name":"Jyoti Rana","orcid":"0000-0001-9683-4592","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:51:32.301795Z","pmid":"40056981","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":[]}