Lirentelimab (AK002): A Comprehensive Monograph on a Dual-Action Anti-Siglec-8 Antibody from Mechanistic Promise to Clinical Discontinuation

Executive Summary

Lirentelimab, also known as AK002, is an investigational biotech drug developed by Allakos Inc. as a humanized, afucosylated IgG1 monoclonal antibody designed to target Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8).[1] The therapeutic rationale for Lirentelimab was based on a novel and elegant dual mechanism of action targeting key effector cells in Type 2 inflammation. By binding to Siglec-8, a receptor selectively expressed on eosinophils and mast cells, Lirentelimab was engineered to deplete pathogenic eosinophils through antibody-dependent cell-mediated cytotoxicity (ADCC) and simultaneously inhibit the activation and degranulation of mast cells.[1]

This dual-pronged approach held significant promise for a wide range of allergic and inflammatory conditions where these cells are implicated, including eosinophilic gastrointestinal diseases (EGIDs), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). Early and mid-stage clinical trials showed that Lirentelimab was exceptionally effective at its biological function, consistently demonstrating profound and sustained depletion of eosinophils in both blood and tissue across multiple patient populations.[7]