8RY2

Crystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion protein

Summary for 8RY2

• Entry DOI: 10.2210/pdb8ry2/pdb
• Descriptor: ANV419 heavy-chain, ANV419 light-chain (3 entities in total)
• Functional Keywords: immuno-oncology, cytokine
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 126496.00

Authors

Rondeau, J.M.,Wirth, E. (deposition date: 2024-02-08, release date: 2024-07-31, Last modification date: 2024-10-16)

Primary citation

Murer, P.,Brannetti, B.,Rondeau, J.M.,Petersen, L.,Egli, N.,Popp, S.,Regnier, C.,Richter, K.,Katopodis, A.,Huber, C.
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.
Mabs, 16:2381891-2381891, 2024

PubMed 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 T 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.

PubMed: 39041287
DOI: 10.1080/19420862.2024.2381891

Experimental method

X-RAY DIFFRACTION (2.05 Å)