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In murine and ex vivo human organotypic tumor models, 21h10 showed robust antitumor activity, with more prolonged signaling and stronger antitumor activity than native IL-21. 21h10 induced pancreatitis that could be mitigated by TNF blockade without compromising antitumor efficacy. Although antidrug antibodies to 21h10 formed, they were not neutralizing. 21h10 induced highly cytotoxic T cells with a range of affinities, robustly expanding intratumoral low-affinity cytotoxic T cells and driving high expression of IFN-\u03b3 and granzyme B compared with native IL-21, while increasing the frequency of IFN-\u03b3\n            <jats:sup>+<\/jats:sup>\n            T helper 1 cells and reducing regulatory T cells. The full human-mouse cross-reactivity, high stability and potency, and low-affinity antitumor responses support the translational potential of 21h10.\n          <\/jats:p>","DOI":"10.1126\/sciimmunol.adx1582","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T17:58:23Z","timestamp":1758909503000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Design of a potent interleukin-21 mimic for cancer immunotherapy"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4778-4175","authenticated-orcid":true,"given":"Jung-Ho","family":"Chun","sequence":"first","affiliation":[{"name":"Institute for Protein Design, University of Washington, Seattle, WA, USA."},{"name":"Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA."},{"name":"Graduate Program in Biological Physics, Structure and Design, University of Washington, 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