Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell‐mediated diseases

Abstract

Chronic urticaria (CU) is a mast cell (MC)‐dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE‐mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid‐binding immunoglobulin‐like lectin8 ‐[Siglec‐8] [lirentelimab/AK002], Siglec‐6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on‐ or off‐target, immunosuppressive adverse effects.

The Alarmin Triad—IL-25, IL-33, and TSLP—Serum Levels and Their Clinical Implications in Chronic Spontaneous Urticaria

“…These observations suggest that IL-33's influence in CSU extends beyond that of a biomarker, acting as a pivotal mediator in the disease's pathogenesis and affecting both clinical outcomes and patient well-being. The significant correlation between IL-33 with the UAS7 and DLQI scores underlines the necessity for developing IL-33-targeted therapeutic approaches, especially for patient subgroups inadequately managed by current treatments, such as omalizumab [26,27]. The findings by Manti et al [28] support this approach, emphasizing the potential of monoclonal antibodies in enhancing CSU management.…”

“…The potential for targeting these cytokines to mitigate the symptoms of CSU represents an intriguing and scientifically promising avenue for exploration. While the effectiveness of such therapeutic interventions has yet to be definitively proven, the development of biologic therapies aimed at these pathways, including tezepelumab (anti-TSLP), etokimab, and itepekimab (both targeting IL-33), as well as astegolimab and GSK3772847 (targeting the ST2 subunit of the IL-33 receptor), are currently undergoing clinical evaluation [26,27]. This innovative therapeutic strategy marks a significant shift in the approach to managing CSU, offering the potential to transform patient outcomes by addressing the underlying mechanisms of the disease directly.…”

“…The total UAS7 score is the sum of these daily assessments, with a maximum potential score of 42. The cumulative score categorizes CSU severity into three levels: mild (0-15), moderate (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), and severe (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), enabling a nuanced understanding of the disease's impact on the patient.…”

Pathophysiological Mechanisms of the Onset, Development, and Disappearance Phases of Skin Eruptions in Chronic Spontaneous Urticaria

“…Mast cells express inhibitory molecules, such as Siglec-8, Siglec-6 and CD200R. The activation of these molecules expressed on mast cells and diminishes histamine release (Metz et al 2023). The low-affinity IgG receptor (Fc γ R2b), which contributes to supra-optimal negative regulation of Fc ε RI-induced mast cell activation is another candidate of a player in the disappearance phase (Gast et al 2018).…”

Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease

“…In children with DCM, who usually display severe MC mediator-related symptoms, new drugs capable of reducing the pathogenic MC activity may turn out to be more effective and less toxic than MC depleters, such as tyrosine kinase inhibitors. MC activation antagonists, including omalizumab, for which only a few uncontrolled studies showing response in children with CM have been reported so far, or other monoclonal antibodies that engage inhibitory receptors (e.g., lirentelimab), might prove to be effective and become true therapeutic options in the near future [ 96 , 108 , 109 ]. Currently, early clinical trials of new drugs believed to reduce pathogenic MC activity are ongoing, which provides hope for patients with various MC disorders.…”