{"doi":"10.1172/jci.insight.173469","title":"Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity","abstract":"Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.","journal":"JCI Insight","year":2024,"id":434280,"datarank":0.49465186805760597,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.09879326861531706,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.09879326861531706,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":9,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":true,"deposit_databanks":{"PDB":["IL-2/602 scFv: 8SOZ","IL-2/F10 scFv: 8SOW"],"GEO":["GSM8428011–GSM8428024"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":868917,"name":"Jakub Tomala","orcid":"0000-0002-6315-2832","position":1,"is_corresponding":false},{"id":524944,"name":"Joseph R. Gould","orcid":"0000-0003-1168-6768","position":2,"is_corresponding":false},{"id":1167346,"name":"Michael I. Leff","orcid":null,"position":3,"is_corresponding":false},{"id":1087897,"name":"Jian-Xin Lin","orcid":"0000-0001-5849-9412","position":4,"is_corresponding":false},{"id":228335,"name":"Peng Li","orcid":"0000-0003-4530-2400","position":5,"is_corresponding":false},{"id":1167347,"name":"Mitchell J. Porter","orcid":null,"position":6,"is_corresponding":false},{"id":1167348,"name":"Eric Johansen","orcid":null,"position":7,"is_corresponding":false},{"id":1167349,"name":"Ladaisha Thompson","orcid":null,"position":8,"is_corresponding":false},{"id":1167085,"name":"Shanelle D. Cao","orcid":"0009-0001-5321-2563","position":9,"is_corresponding":false},{"id":1240440,"name":"Shenda Hou","orcid":"0000-0001-5120-2540","position":10,"is_corresponding":false},{"id":869424,"name":"Tereza Henclová","orcid":null,"position":11,"is_corresponding":false},{"id":1167086,"name":"Maroš Huličiak","orcid":"0000-0002-9929-3522","position":12,"is_corresponding":false},{"id":530309,"name":"Paul R. Sargunas","orcid":"0000-0003-4455-9669","position":13,"is_corresponding":false},{"id":1052337,"name":"Charina S. Fabilane","orcid":null,"position":14,"is_corresponding":false},{"id":1167087,"name":"Ondřej Vaněk","orcid":"0000-0003-1190-8535","position":15,"is_corresponding":false},{"id":922805,"name":"Marek Kovář","orcid":"0000-0002-6602-1678","position":16,"is_corresponding":false},{"id":45589,"name":"Bohdan Schneider","orcid":"0000-0001-7855-3690","position":17,"is_corresponding":false},{"id":388909,"name":"Giorgio Raimondi","orcid":"0000-0003-1373-2203","position":18,"is_corresponding":false},{"id":625483,"name":"Warren J. Leonard","orcid":"0000-0002-5740-7448","position":19,"is_corresponding":false},{"id":530310,"name":"Jamie B. Spangler","orcid":"0000-0001-8187-3732","position":20,"is_corresponding":false},{"id":551957,"name":"Elissa K. 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