An anti‐siglec‐8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells

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Abstract
Background: Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐8 is expressed on mast cells and eosinophils, but information about Siglec‐8 expression and function in the lung is limited. A humanized antibody, AK002, targeting Siglec‐8 is undergoing development for treatment of diseases associated with mast cell and eosinophil‐driven inflammation.Objective: To characterize Siglec‐8 expression in the airway in asthma and determine whether antibodies that target Siglec‐8 (S8mAbs) can decrease airway eosinophils in asthma or inhibit lung mast cell activation.Methods: Gene expression profiling and flow cytometry were used to characterize Siglec‐8 expression in sputum cells from stable asthma. An antibody‐dependent cellular cytotoxicity (ADCC) assay was used to determine whether an S8mAb can decrease eosinophils in sputum from asthma patients ex vivo. A mast cell activation assay was used to determine whether an S8mAb can inhibit mast cell activation in human lung tissue ex vivo.Results: Gene expression for Siglec‐8 is increased in sputum cells in asthma and correlates with gene expression for eosinophils and mast cells. Gene expression for Siglec‐8 is inversely and significantly correlated with measures of airflow obstruction in asthma patients. Siglec‐8 is prominently expressed on the surface of eosinophils and mast cells in sputum. S8mAbs decrease eosinophils in sputum from patients with asthma and inhibit FcεR1‐activated mast cells in lung tissues.Conclusions and Clinical Relevance: Siglec‐8 is highly expressed on eosinophils and mast cells in asthmatic sputum and targeting Siglec‐8 with an antibody is a plausible strategy to decrease sputum eosinophils and inhibit lung mast cells in asthma.
Funding Information
  • National Heart, Lung, and Blood Institute (HL107201)

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