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Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtained, having increased receptor binding ability and improved developability profiles. Selected variants exhibit an accumulation of negatively charged residues at the interface, which provides a better electrostatic complementarity to the beta chain, and faster association kinetics. These findings point to mechanistic differences with the already reported superkines, characterized by a conformational switch due to the rearrangement of the hydrophobic core. The molecular bases of the favourable developability profile were tracked to a single residue: L92. Recombinant Fc-fusion proteins including our variants are superior to those based on H9 superkine in terms of expression levels in mammalian cells, aggregation resistance, stability, in vivo enhancement of immune effector responses, and anti-tumour effect.<\/jats:p>","DOI":"10.1038\/s42003-023-05188-0","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T14:01:58Z","timestamp":1691589718000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6335-6264","authenticated-orcid":false,"given":"Gertrudis","family":"Rojas","sequence":"first","affiliation":[]},{"given":"Ernesto","family":"Relova-Hern\u00e1ndez","sequence":"additional","affiliation":[]},{"given":"Annia","family":"P\u00e9rez-River\u00f3n","sequence":"additional","affiliation":[]},{"given":"Camila","family":"Castro-Mart\u00ednez","sequence":"additional","affiliation":[]},{"given":"Osmany","family":"Diaz-Bravo","sequence":"additional","affiliation":[]},{"given":"Yanelys Cabrera","family":"Infante","sequence":"additional","affiliation":[]},{"given":"Tania","family":"G\u00f3mez","sequence":"additional","affiliation":[]},{"given":"Joaqu\u00edn","family":"Soloz\u00e1bal","sequence":"additional","affiliation":[]},{"given":"Ana Beatriz","family":"D\u00edazBravo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7041-9056","authenticated-orcid":false,"given":"Maren","family":"Schubert","sequence":"additional","affiliation":[]},{"given":"Marlies","family":"Becker","sequence":"additional","affiliation":[]},{"given":"Beatriz","family":"P\u00e9rez-Mass\u00f3n","sequence":"additional","affiliation":[]},{"given":"Dayana","family":"P\u00e9rez-Mart\u00ednez","sequence":"additional","affiliation":[]},{"given":"Rydell","family":"Alvarez-Arzola","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-3394","authenticated-orcid":false,"given":"Osmany","family":"Guirola","sequence":"additional","affiliation":[]},{"given":"Glay","family":"Chinea","sequence":"additional","affiliation":[]},{"given":"Luis","family":"Graca","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8811-7390","authenticated-orcid":false,"given":"Stefan","family":"D\u00fcbel","sequence":"additional","affiliation":[]},{"given":"Kalet","family":"Le\u00f3n","sequence":"additional","affiliation":[]},{"given":"Tania","family":"Carmenate","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"5188_CR1","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/nri1435","volume":"4","author":"TR Malek","year":"2004","unstructured":"Malek, T. 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CIM is the applicant of CU-022-0020 (pending), which claims beta super-binders and their use. G.R., E.R.-H., T.C. and K.L. are the inventors. A.-P.-R. and Y.C.I. were also employed at CIM during this research. O.D.-B., A.B.DB., M.S., M.B., O.G., G.Ch., L.G. and S.D. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The Institutional Committee of Animal Care and Use (CICUAL) at the Center of Molecular Immunology (CIM) approved all the experimental protocols with living animals performed at CIM. Experiments involving animals developed at the Instituto de Medicina Molecular were approved by ORBEA-iMM (the institutional Animal Welfare Body). Permission for animal experimentation was granted by DGAVG (Portuguese competent authority for animal protection). Animal experiments were performed in accordance with the relevant national and international guidelines for using living animals in research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"828"}}