| Title: | Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody. |
| Authors: | Parker, MW Kan, WL Hercus, TR Wilson, NJ Barry, EF Nash, AD Braley, H Owczarek, CM Huynh, H Busfield, SJ Dottore, M Hartman, D McClure, BJ Scotney, PD Broughton, SE Dhagat, U Hardy, MP Lopez, AF |
| Issue Year: | 2014 |
| Publisher | |
| Series | Cell Rep: |
| Abstract | Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique "open" and classical "closed" conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas "open-like" IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a "double hit" cytokine receptor blockade. |
| URI: | https://publications.svi.edu.au/publications/2422 |
| Other Identifiers | 8(2):410-9 |
| Publication type | Article |
| Grant ID | GNT0559001; GNT0565217; GNT1021645 |