Ahn et al. showed in vitro (using human PBMCs) and in mice that IL-10 suppressed IL-2 induction of CRS-associated cytokines by suppressing TNFα production while potentiating IL-2-mediated antitumor activities. DK210(EGFR) – a fusion protein comprising IL-2 coupled to a high-affinity IL-10 mutein targeted by an anti-EGFR scFv scaffold to tumor cells – activated CTLs and NK cells, increased perforin/granzyme B secretion, limited Treg expansion, boosted the CD8+ T cell/Treg ratio within tumors, sustained CTL functions, and enhanced efficacy in murine tumor models. In NHP, at projected therapeutic doses, DK210(EGFR) induced immune activation without inducing CRS or significant organ toxicity.
Contributed by Paula Hochman
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.
Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germa
Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germantown, MD, USA. (5) Deka Biosciences, Inc., Germantown, MD, USA. (6) Deka Biosciences, Inc., Germantown, MD, USA. (7) Deka Biosciences, Inc., Germantown, MD, USA. (8) Deka Biosciences, Inc., Germantown, MD, USA. (9) Deka Biosciences, Inc., Germantown, MD, USA. (10) Deka Biosciences, Inc., Germantown, MD, USA. (11) Deka Biosciences, Inc., Germantown, MD, USA. (12) Deka Biosciences, Inc., Germantown, MD, USA. (13) Deka Biosciences, Inc., Germantown, MD, USA. (14) Deka Biosciences, Inc., Germantown, MD, USA. (15) Deka Biosciences, Inc., Germantown, MD, USA. (16) Deka Biosciences, Inc., Germantown, MD, USA. (17) Deka Biosciences, Inc., Germantown, MD, USA. (18) Deka Biosciences, Inc., Germantown, MD, USA. (19) Deka Biosciences, Inc., Germantown, MD, USA. (20) Deka Biosciences, Inc., Germantown, MD, USA. (21) Deka Biosciences, Inc., Germantown, MD, USA. (22) Deka Biosciences, Inc., Germantown, MD, USA. (23) Deka Biosciences, Inc., Germantown, MD, USA. (24) Deka Biosciences, Inc., Germantown, MD, USA. Electronic address: mummj@dekabiosciences.com.
