Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8