Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody.
Cell Rep
; 8(2): 410-9, 2014 Jul 24.
Article
em En
| MEDLINE
| ID: mdl-25043189
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Subunidade alfa de Receptor de Interleucina-3
/
Anticorpos Monoclonais Humanizados
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article