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

作者：Broughton Sophie E; Hercus Timothy R; Hardy Matthew P; McClure Barbara J; Nero Tracy L; Dottore Mara; Huynh Huy; Braley Hal; Barry Emma F; Kan Winnie L; Dhagat Urmi; Scotney Pierre; Hartman Dallas; Busfield Samantha J; Owczarek Catherine M; Nash Andrew D; Wilson Nicholas J^*; Parker Michael W; Lopez Angel F

来源：Cell Reports, 2014, 8(2): 409-418.

DOI：10.1016/j.celrep.2014.06.038

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 alpha chain (IL3R alpha) 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 %26quot;open%26quot; and classical %26quot;closed%26quot; 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 %26quot;open-like%26quot; IL3R alpha 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 %26quot;double hit%26quot; cytokine receptor blockade.

• 出版日期2014-7-24
• 单位河北医科大学