Allakos Inc., Redwood City, CA 94065, USA.
Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Cells. 2020 Dec 24;10(1):19. doi: 10.3390/cells10010019.
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.
Siglecs（唾液酸结合免疫球蛋白样凝集素）是单通道细胞表面受体，对免疫细胞具有抑制活性。其中，Siglec-8 是一种 CD33 相关家族成员，选择性表达于人肥大细胞和嗜酸性粒细胞，在嗜碱性粒细胞中低水平表达。这些细胞可以通过释放吸引或激活其他细胞的介质参与炎症反应，有助于过敏和非过敏性疾病的发病机制。自 2000 年发现以来，最初的体外研究发现，Siglec-8 与单克隆抗体或选择性多价唾液酸糖结合配体的结合诱导嗜酸性粒细胞死亡并抑制肥大细胞脱颗粒。体内给予抗 Siglec-8 抗体给人源化和转基因小鼠，这些小鼠在小鼠嗜酸性粒细胞和肥大细胞上选择性表达 Siglec-8，证实了体外发现，并确定了其他抗炎作用。AK002（lirentelimab）是一种临床开发用于肥大细胞和嗜酸性粒细胞介导疾病的针对 Siglec-8 的人源化非岩藻糖基化 IgG1 抗体。AK002 的给药在几项 1 期和 2 期试验中安全地证明了抑制肥大细胞活性和嗜酸性粒细胞耗竭。本文综述了 Siglec-8 的发现和功能，以及针对其治疗靶点治疗嗜酸性粒细胞和肥大细胞相关疾病的策略。
