Discovery, Function, and Therapeutic Targeting of Siglec-8

Bradford A. Youngblood, John Leung, Rustom Falahati, Jason Williams, Julia Schanin, Emily C. Brock, Bhupinder Singh, Alan T. Chang, Jeremy A. O'Sullivan, Robert P. Schleimer, Nenad Tomasevic, Christopher R. Bebbington, Bruce S. Bochner

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations

Abstract

Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.

Original languageEnglish (US)
JournalCells
Volume10
Issue number1
DOIs
StatePublished - Dec 24 2020

Keywords

  • AK002
  • Siglec-8
  • eosinophils
  • glycan ligands
  • lirentelimab
  • mast cells
  • monoclonal antibodies

ASJC Scopus subject areas

  • Medicine(all)

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