Stockmann et al. engineered DF6215, comprised of two truncated IgG1 Fc chains (which bind FcRn, but not FcγR) fused at one Fc C terminus to an IL-2 mutein with reduced IL-2Rα (modest) and IL-2Rαβγ (23-fold) binding, increased IL-2Rβ binding (3.5-fold), and enhanced IL-2Rβγ signaling compared to WT IL-2. DF6215 preferentially expanded murine tumor-infiltrating CD8+ T and NK cells over Tregs, induced robust dose-dependent regression of solid tumors as monotherapy, and synergized with anti-PD-1. In NHPs, DF6215 showed an extended serum half-life and favorable safety and pharmacodynamics relative to aldesleukin. DF6215 is now in Phase 1/2 testing.
Contributed by Paula Hochman
ABSTRACT: DF6215 is a rationally engineered interleukin-2 (IL-2) Fc-fusion protein developed to overcome efficacy and safety limitations of traditional IL-2 cancer immunotherapy. Unlike non-alpha (non-α) IL-2 variants that eliminate CD25 binding and underperform clinically, DF6215 retains moderate IL-2 receptor α (IL-2Rα) affinity while enhancing IL-2Rβγ signaling and extending the half-life via an engineered immunoglobulin (Ig)G1 Fc domain. This design preferentially expands cytotoxic CD8+ T cells and natural killer cells over regulatory T cells, resulting in favorable effector-to-regulatory cell ratios, enhanced immune activation, and robust tumor regression in mouse models. In poorly immunogenic tumors, DF6215 synergized with PD-1 blockade to achieve durable responses without added toxicity. Cynomolgus monkey studies confirm DF6215's pharmacodynamics and favorable safety profile, with no signs of vascular leak syndrome or cytokine release syndrome. These findings position DF6215 as a differentiated IL-2 capable of modulating the tumor microenvironment and achieving potent anti-tumor immunity with improved tolerability, supporting its advancement into clinical trials for solid tumors.
Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dr
Author Info: (1) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (2) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (3) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (4) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (5) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (6) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (7) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (8) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (9) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (10) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (11) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. (12) Dragonfly Therapeutics, Inc., Waltham, MA 02451, USA. Electronic address: ann.cheung@dragonflytx.com.
