Design of a potent interleukin-21 mimic for cancer immunotherapy
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<sup>+</sup> 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.
Authors
- Stephanie K. Dougan (ORCID: https://orcid.org/0000-0002-2263-363X)
- Kevin M. Jude (ORCID: https://orcid.org/0000-0002-3675-5136)
- Michelle DeWitt
- Alfredo Quijano‐Rubio (ORCID: https://orcid.org/0000-0003-1567-9530)
- Gita C. Abhiraman (ORCID: https://orcid.org/0000-0002-0546-4133)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Stacey Gerben (ORCID: https://orcid.org/0000-0003-0313-6248)
- Peng Li (ORCID: https://orcid.org/0000-0001-5518-9822)
- Warren J. Leonard (ORCID: https://orcid.org/0000-0002-5740-7448)
- Neil P. King (ORCID: https://orcid.org/0000-0002-2978-4692)
- K. Christopher García (ORCID: https://orcid.org/0000-0001-9273-0278)
- Lauren Carter (ORCID: https://orcid.org/0000-0002-9837-9068)
- Tatyana Sharova (ORCID: https://orcid.org/0000-0003-2123-3906)
- Suyasha Roy (ORCID: https://orcid.org/0000-0002-0332-4962)
- Analisa Murray (ORCID: https://orcid.org/0000-0003-1560-6673)
- Russell W. Jenkins (ORCID: https://orcid.org/0000-0001-6110-2148)
- Jung-Ho Chun (ORCID: https://orcid.org/0000-0003-4778-4175)
- Megan T. Hoffman (ORCID: https://orcid.org/0000-0003-0907-9977)
- Elisa C. Clark (ORCID: https://orcid.org/0000-0003-4267-7215)
- Samantha Tower (ORCID: https://orcid.org/0000-0001-7279-3079)
- Michael J. Walsh (ORCID: https://orcid.org/0000-0002-1283-6847)
- Sonia Cohen (ORCID: https://orcid.org/0000-0003-0172-5620)
- Asheema Khanna
- Michael Dougan (ORCID: https://orcid.org/0000-0001-9266-2009)
- Kevin Zhangxu (ORCID: https://orcid.org/0000-0002-7477-6691)
- Piper Heine
- Or‐Yam Revach (ORCID: https://orcid.org/0000-0002-1606-7467)
- David A. Baker (ORCID: https://orcid.org/0000-0001-7896-6217)
- Hojeong Shin
- Rakeeb Kureshi (ORCID: https://orcid.org/0000-0003-2769-2468)
- Tina K. Nguyen (ORCID: https://orcid.org/0009-0001-8385-0275)
- Daniel‐Adriano Silva (ORCID: https://orcid.org/0000-0002-3195-9009)
- Samantha Y. Liu
- Hao Yuan Kueh (ORCID: https://orcid.org/0000-0001-6272-6673)
- Umut Y. Ulge (ORCID: https://orcid.org/0000-0002-3745-0668)
- Chan Johng Kim (ORCID: https://orcid.org/0000-0002-7256-0205)
- Aleigha Lawless (ORCID: https://orcid.org/0009-0009-3861-3164)
- Tavus Atajanova
- Claire A. Palin
- Vandana Kalia (ORCID: https://orcid.org/0000-0001-6250-2151)
- Surojit Sarkar (ORCID: https://orcid.org/0000-0003-1940-1878)
- Birkley Lim (ORCID: https://orcid.org/0009-0005-7558-9168)
- J. Tello
- Frank Peprah
Institutions
- Broad Institute (US)
- Seattle Children's Hospital (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- California Institute for Regenerative Medicine (US)
- University of Washington (US)
- Massachusetts General Hospital (US)
- National Heart, Lung, and Blood Institute (US)
- Dana-Farber Cancer Institute (US)
- Center for Cancer Research (US)
- Stanford University (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1126/sciimmunol.adx1582
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80