Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

• DOI: 10.1016/j.celrep.2014.06.038
• Publication Date: 2014-07-17T15:51:36Z
• Authors: Sophie E. Broughton; Timothy R. Hercus; Matthew P. Hardy; Barbara J. McClure; Tracy L. Nero; Mara Dottore; Huy Huynh; Hal Braley; Emma F. Barry; Winnie L. Kan; Urmi Dhagat; Pierre Scotney; Dallas Hartman; Samantha J. Busfield; Catherine M. Owcz...; Andrew D. Nash; Nicholas J. Wilson; Michael W. Parker; Angel F. Lopez
• Keywords: Common gamma chain; Interleukin-4 receptor

Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity contributes to several immunopathologies. Here, we report the crystal structure of IL-3 receptor α chain (IL3Rα) in complex with anti-leukemia antibody CSL362 reveals N-terminal domain (NTD), a also present granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, IL-13 receptors, adopting unique "open" classical "closed" conformations. Although extensive mutational analyses NTD epitope show minor overlap binding site, only inhibits closed conformation, indicating alternative mechanisms for blocking signaling. Significantly, whereas "open-like" IL3Rα mutants can simultaneously bind CSL362, still prevents assembly higher-order receptor-signaling complex. The discovery open forms cytokine receptors provides framework development potent antibodies achieve "double hit" blockade.