Murer et al. generated ANV419, a bivalent agonist comprising a humanized anti-human IL-2 Ab fused to human IL-2, which bound to IL-2Rβγ, but was sterically hindered from binding to IL-2Rα. ANV419 preferentially stimulated human and mouse CD8+ T and NK cells over Treg cells, and exhibited antitumor efficacy that was enhanced when combined with CTLA-4- or PD-1-specific Abs in syngeneic mouse tumor models and with the ADCC-inducing trastuzumab in a Her2+ xenograft mouse model. In a 4-week/2-dose GLP monkey toxicology study, ANV419 had a 24-hour half life and induced sustained pharmacodynamic effects, without significant high-dose IL-2-associated adverse effects.
Contributed by Paula Hochman
ABSTRACT: 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+ T cells and natural killer (NK) cells over Tregs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2+ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.
Author Info: (1) Anaveon AG, Basel, Switzerland. (2) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (3) Novartis Institutes for Biomedical Research, Basel, Switzerland. (4) An
Author Info: (1) Anaveon AG, Basel, Switzerland. (2) Novartis Institutes for BioMedical Research, Cambridge, MA, USA. (3) Novartis Institutes for Biomedical Research, Basel, Switzerland. (4) Anaveon AG, Basel, Switzerland. (5) Anaveon AG, Basel, Switzerland. (6) Novartis Institutes for Biomedical Research, Basel, Switzerland. (7) Novartis Institutes for Biomedical Research, Basel, Switzerland. (8) Anaveon AG, Basel, Switzerland. (9) Anaveon AG, Basel, Switzerland. (10) Anaveon AG, Basel, Switzerland.
