Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity

  • Cell Rep Med. 2025 Aug 19;6(8):102257. doi: 10.1016/j.xcrm.2025.102257.
Julie J Ahn  1 ,  Steven Dudics  1 ,  David P Langan  1 ,  Jeffrey D Smith  1 ,  Alice H Hsu  1 ,  Jacob C McCright  1 ,  Sawyer R Smith  1 ,  Alicia L Castleberry  1 ,  Benjamin I George  1 ,  Javier A Goitía Vázquez  1 ,  Phillip N Kuri  1 ,  Sri Sai Vivek Alla  1 ,  Jennifer Garcia  1 ,  Young Min Haider  1 ,  Fatima W Hamdan  1 ,  Jhonnatan Esquivel Juárez  1 ,  Robert Reddy  1 ,  Aranganathan Shanmuganathan  1 ,  Yuanyuan Wang  1 ,  Arielle Welch  1 ,  David Boclair  1 ,  Pavel A Khrimian  1 ,  Christopher H Yaen  1 ,  John B Mumm  2
Affiliations
  • 1. Deka Biosciences, Inc., Germantown, MD, USA.
  • 2. Deka Biosciences, Inc., Germantown, MD, USA. Electronic address: [email protected].
PMID: 40744022 DOI: 10.1016/j.xcrm.2025.102257
Abstract

Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells, mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK210 epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.

Keywords
EGFR; IFNγ; IL-10; IL-2; T cell exhaustion; cytokine; cytokine release syndrome; immunotherapy; targeted therapy; vascular leak syndrome.
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