8ry2 | pdb_00008ry2
Crystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion protein
Structural highlights
Publication Abstract from PubMedNovel 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 betagamma (IL-2 Rbetagamma) activation by sterically hindering IL-2 from binding to IL-2 Ralpha. 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 Ralpha. 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(regs) 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. 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.,Murer P, Brannetti B, Rondeau JM, Petersen L, Egli N, Popp S, Regnier C, Richter K, Katopodis A, Huber C MAbs. 2024 Jan-Dec;16(1):2381891. doi: 10.1080/19420862.2024.2381891. Epub 2024 , Jul 23. PMID:39041287[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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