Design of a potent interleukin-21 mimic for cancer immunotherapy

Jung-Ho Chun^{1

2

3}, Birkley S Lim^{4

5}, Suyasha Roy⁶, Michael J Walsh^{4

5}, Gita C Abhiraman⁷, Kevin Zhangxu^{4

5}, Tavus Atajanova^{4

5}, Or-Yam Revach^{8

9}, Elisa C Clark¹⁰, Peng Li⁶, Claire A Palin⁸, Asheema Khanna¹¹, Samantha Tower¹¹, Rakeeb Kureshi^{5

12}, Megan T Hoffman^{5

12}, Tatyana Sharova^{13

14}, Aleigha Lawless^{13

14}, Sonia Cohen^{13

14}, Genevieve M Boland^{9

13

14}, Tina Nguyen¹, Frank Peprah^{4

5}, Julissa G Tello^{4

5}, Samantha Y Liu⁵, Chan Johng Kim^{1

2}, Hojeong Shin^{1

2}, Alfredo Quijano-Rubio¹, Kevin M Jude⁷, Stacey Gerben¹, Analisa Murray¹, Piper Heine¹, Michelle DeWitt¹, Umut Y Ulge¹, Lauren Carter¹, Neil P King^{1

2}, Daniel-Adriano Silva¹, Hao Yuan Kueh¹⁰, Vandana Kalia^{11

15}, Surojit Sarkar^{11

15

16}, Russell W Jenkins^{8

9}, K Christopher Garcia^{7

17}, Warren J Leonard⁶, Michael Dougan^{4

18}, Stephanie K Dougan^{5

12}, David Baker^{1

2

19}

Affiliations

¹ Institute for Protein Design, University of Washington, Seattle, WA, USA.
² Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA.
³ Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
⁴ Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Bioengineering and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
¹¹ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹² Department of Immunology, Harvard Medical School, Boston, MA, USA.
¹³ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
¹⁶ Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁷ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁹ Howard Hughes Medical Institute, University of Washington, Seattle, MA, USA.

PMID: 41004565
DOI: 10.1126/sciimmunol.adx1582

Design of a potent interleukin-21 mimic for cancer immunotherapy

Jung-Ho Chun et al. Sci Immunol. 2025.

. 2025 Sep 26;10(111):eadx1582.

doi: 10.1126/sciimmunol.adx1582. Epub 2025 Sep 26.

Authors

Affiliations

¹ Institute for Protein Design, University of Washington, Seattle, WA, USA.
² Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA.
³ Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
⁴ Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Bioengineering and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
¹¹ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹² Department of Immunology, Harvard Medical School, Boston, MA, USA.
¹³ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
¹⁶ Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹⁷ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁹ Howard Hughes Medical Institute, University of Washington, Seattle, MA, USA.

PMID: 41004565
DOI: 10.1126/sciimmunol.adx1582

Abstract

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a range of affinities for tumor antigens while suppressing regulatory T cells. Computational protein design has enabled the precise tailoring of proteins to meet specific needs. Here, we report a de novo designed IL-21 mimic, 21h10, with high stability and signaling potency in humans and mice. 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-γ and granzyme B compared with native IL-21, while increasing the frequency of IFN-γ⁺ 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.

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Design of a potent interleukin-21 mimic for cancer immunotherapy

Affiliations

Design of a potent interleukin-21 mimic for cancer immunotherapy

Authors

Affiliations

Abstract

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical