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
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