2. Academic Validation
  3. Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity

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

Affiliations

  • 1 Deka Biosciences, Inc., Germantown, MD, USA.
  • 2 Deka Biosciences, Inc., Germantown, MD, USA. Electronic address: mummj@dekabiosciences.com.
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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