# Current and future therapeutics targeting mast cells in disease

William P M Worrall, Laurent L Reber

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William P M Worrall, Laurent L Reber. Current and future therapeutics targeting mast cells in disease. Pharmacology & Therapeutics, 2025, 273, pp.108892. 10.1016/j.pharmthera.2025.108892. hal-05537878

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# Current and future therapeutics targeting mast cells in disease

William P.M. Worrall, Laurent L. Reber *

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, Université de Toulouse, 31024 Toulouse, France

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## ARTICLE INFO

Available online 30 May 2025

Associate editor: M. Curtis

**Keywords:**

Allergy
Asthma
Urticaria
Antibody
Small molecule
Mastocytosis
MRGPRX2
KIT
IgE

## ABSTRACT

Mast cells (MCs) are tissue resident immune cells which are best known for their detrimental role in allergy. Increasing evidence indicates that MCs are also central to the pathogenesis of chronic urticaria. Abnormal increase in MC burden, in most cases driven by gain-of-function mutations in the receptor KIT, can also lead to mastocytosis, a potentially severe malignant disease. Thus, MCs represent important therapeutic targets in all these diseases, and likely in a number of additional inflammatory conditions. In recent years, several monoclonal antibodies (mAbs) and small molecule inhibitors have been developed to directly target MCs or their mediators. Some of these therapeutics, including antagonists of the receptor MRGPRX2, tyrosine kinase inhibitors, anti-Siglec-6 and anti-KIT mAbs are now undergoing clinical evaluation. In this review, we describe the main mechanisms leading to MC activation, and their known functions in allergic diseases, chronic urticaria and mastocytosis. We then discuss recent preclinical and clinical data obtained with novel biologics aimed at targeting MCs in these diseases.

© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Contents

<table><tr><td>1.</td><td>Introduction</td><td>2</td></tr><tr><td>2.</td><td>Mast cells</td><td>2</td></tr><tr><td>3.</td><td>Main mast cell-dependent diseases</td><td>4</td></tr><tr><td>4.</td><td>Main strategies approved or in clinical development for the treatment of MC-dependent diseases.</td><td>5</td></tr><tr><td>5.</td><td>Concluding remarks</td><td>12</td></tr><tr><td colspan="2">CRCliT authorship contribution statement</td><td>12</td></tr><tr><td colspan="2">Declaration of competing interest</td><td>12</td></tr><tr><td colspan="2">Acknowledgments</td><td>12</td></tr><tr><td colspan="2">References.</td><td>12</td></tr></table>

**Abbreviations:** AMP, antimicrobial peptide; AD, atopic dermatitis; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ASM, advanced systemic mastocytosis; BTK, Bruton's tyrosine kinase; BTKi, Bruton's tyrosine kinase inhibitor; CD, Cluster of differentiation; CDC, complement dependent cytotoxicity; CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; CM, cutaneous mastocytosis; CSP, Competence-stimulating peptide; CST-14, Corticostatin-14; CTMC, connective-tissue mast cells; DC, dendritic cells; ECP, eosinophilic cationic protein; GOF, gain-of-function; GPCR, G-protein-coupled receptor; HDC, Histidine decarboxylase; i.v., intravenous; Ig, immunoglobulin; IL, interleukin; ISM, Indolent systemic mastocytosis; ITAM, Immunoreceptor tyrosine-based activation motifs; ITIMs, immunoreceptor tyrosine-based inhibitory motifs; mAbs, monoclonal antibodies; MBP, major basic protein; MC, mast cell; MMC, mucosal mast cells; MRGPR, mas-related G-protein-coupled receptor; NMBAs, neuromuscular blocking agents; PACAP, pituitary adenylate cyclase-activating polypeptide; PAMP, proadrenomedullin N-terminal peptides; PCA, passive cutaneous anaphylaxis; PD, Pharmacodynamics; PDGFR, platelet-derived growth factor receptor; PK, pharmacodynamics; PKC, protein kinase C; PSA, passive systemic anaphylaxis; SCF, stem cell factor; Siglecs, sialic acid-binding immunoglobulin-type lectins; SM, systemic mastocytosis; SP, substance P; Tac1, Tachykinin precursor 1; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor; TPO, thyroid peroxidase; TRAPV1, transient receptor potential vanilloid type 1; VIP, vasoactive intestinal polypeptide; WHO, world health organization.

<footnote>* Corresponding author at: Team "Asthma, Allergy & Immunotherapy", Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), CHU Purpan - BP 3028, 31024 Toulouse, Cedex 3, France.</footnote>

<footnote>E-mail address: laurent.reber@inserm.fr (L.L. Reber).</footnote>
# 1. Introduction

Mast Cells (MCs) are long-lived tissue resident innate immune cells that contain abundant cytoplasmic granules in which preformed proteases, histamine and heparin are stored. Data in mice indicate that mast cells are among the first immune cells present in embryonic development, arising from primitive hematopoiesis in the yolk sac. Fate mapping studies indicate that these initial yolk sac-derived mast cells are then replaced by those arising from definitive hematopoiesis in the bone marrow (Gentek et al., 2018; St John et al., 2023). Upon activation, MCs can rapidly release these mediators in a process called “degranulation” (Galli et al., 2005). MCs are strategically positioned throughout the body, but are particularly numerous in sites where the body meets the environment, such as the skin, gastrointestinal tract and respiratory tract (Galli et al., 2005). This aligns MCs to be potent regulators of the immune system, in both innate and adaptive arms. Indeed, several studies in mice indicate that MCs can play important protective functions in host defense against parasites, bacteria, fungi and viruses (Abraham & St John, 2010; Dileepan et al., 2023; Piliponsky & Romani, 2018), as well as various toxins and venoms (Galli et al., 2017; Galli et al., 2020).

However, MCs are most famous for their detrimental role in allergic diseases, such as allergic asthma, rhinitis, atopic dermatitis or food allergy (Gulen & Akin, 2022). MC activation also plays a key role in the physiopathology of chronic urticaria, a common inflammatory skin disease characterized in most patients by the presence of autoantibodies which have the potential to activate MCs (Charles et al., 2023). Accumulation of abnormal MCs in different organs, caused in most cases by mutations in the receptor KIT, can also lead to a rare malignant disease called mastocytosis (J. Y. Li et al., 2023). Clinical data have now ascertained the important role of MCs in all these diseases. Increasing evidence, mostly derived from mouse models, strongly suggest that MCs are involved in a much broader range of diseases, but the extent to which their functions are unique and central to these pathologies remains to be fully evaluated.

This review presents an overview of the biology of MCs, and their known functions in allergic diseases, chronic urticaria and mastocytosis. We then discuss some of the main therapeutic strategies that have been developed to target MCs and their products in these disorders.

# 2. Mast cells

## 2.1. Origins, phenotypes and tissue distribution

MCs reside in most tissues, and are particularly abundant at sites exposed to the external environment, such as airways, the skin, and the gastrointestinal tract (Galli et al., 2005). MCs have been long classified as either connective tissue MCs (CTMCs) or mucosal MCs (MMCs), based on their anatomical location and protease content (Katz et al., 1985; Miller & Schwartz, 1989). The skin (among other connective tissues) is particularly rich in CTMCs containing granules which contain preformed chymases, tryptases, carboxypeptidases, heparin proteoglycan, as well as histamine. MMCs are present primarily in the respiratory and gastrointestinal tracts. They contain a different mixture of proteases in their granules, as well as lower levels of histamine and no heparin proteoglycans (Dwyer et al., 2016). This dichotomy particularly applies to laboratory mice. However, recent advances in high-throughput OMICs analyses, including proteomics and bulk and single cell RNA sequencing have revealed that human MCs present with much more diverse phenotypes (Dwyer, et al., 2016; Gentek et al., 2018; Z. Li et al., 2018; Tauber et al., 2023). In particular, an unbiased analysis of the human MC transcriptomes identified six different MC populations distributed across 12 organs (Tauber et al., 2023). It is now clear that MC are functionally and phenotypically heterogeneous depending on the microenvironment in which they mature. While this is a clear challenge for the development of drugs targeting MCs, it also might permit

to identify genes selectively expressed in particular MC populations and/or organs, in order to develop more targeted therapies in the future.

## 2.2. Mast cell activation

MCs express a wide range of receptors and can thus be activated in a plethora of manners, by danger signals, cytokines/alarmins, growth factors, neuropeptides, toxins and allergens (Galli et al., 2017; Gaudenzio et al., 2016; Krystel-Whittemore et al., 2015; Mi et al., 2021; Nagata & Suzuki, 2022). This highlights the plurality of roles that MCs can play in health and disease. Among these receptors, the high affinity IgE receptor FcεRI has been extensively studied for more than 30 years (Balbino et al., 2018; Eggel et al., 2024; McDonnell et al., 2023), and omalizumab, a mAb which blocks binding of IgE to the receptor is approved for the treatment of allergic asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic urticaria and food allergy (please see part 3.1.1 for more detail). Drugs targeting two additional activating receptors on MCs, the stem cell factor (SCF) receptor KIT and the more recently described receptor MRGPRX2, have also now reached the clinic for several MC-dependent disease.

### 2.2.1. IgE-FcεRI

The high-affinity IgE receptor FcεRI is expressed at high level as a tetramer on MCs and basophils, consisting of one alpha subunit (FcεRIα), one beta subunit (FcεRIβ, also known as MS4A2) and two gamma chain subunits (FcεRIγ, also called FcRγ (αβγγ) (Gould & Sutton, 2008) (Fig. 1A). FcεRI is also expressed as a trimer (αγγ) lacking the β subunit on a number of other cell types, including monocytes, macrophages and dendritic cells (DCs). The role of trimeric FcεRI is still debated. It has been hypothesized that constitutive internalization of IgE by FcεRI trimers on DCs and monocytes contributes to serum IgE clearance (Greer et al., 2014).

The α chain binds the Cε3 domain of IgE with a very high affinity ($K_d$ of $10^{-9}$ to $10^{-10}$ M) (Garman et al., 2000). In addition, the IgE-FcεRIα complex has an extremely low dissociation rate ($k_{off} \approx 10^{-5}$ s⁻¹) (Geha et al., 1985; McDonnell et al., 2001). As a result, MCs and basophils are constantly saturated with surface IgE. The two Cε3 domains of IgE bind two distinct sites on FcεRIα, which explains the 1:1 stoichiometry of the IgE-FcεRIα complex (Garman et al., 2000). The β chain stabilizes the expression of the receptor at the cell surface, and both the β and γ chains contain immunoreceptor tyrosine-based activation motives (ITAMs) and are responsible for signal transduction upon receptor activation (Garman et al., 2000) (Fig. 1A). Very recently, two publications reported the cryogenic electron microscopy structure of the IgE-FcεRI tetramer complex (Chen et al., 2025; Deng et al., 2024). Importantly, it was demonstrated that prior to IgE binding, FcεRI exists as an (αβγγ)₂ dimer on MC membranes, and that such dimeric organization might represent an inactive state of the receptor. Upon IgE binding, this complex dissociates into αβγγ tetramers, each of which can bind one IgE, representing the active state of the receptor in which conformational changes allows intracellular ITAMs to engage downstream signaling kinases (Chen et al., 2025).

In allergic subjects, binding of the allergen to FcεRI-bound specific IgE at the surface of MCs (and basophils) induces crosslinking of FcεRI, leading to the fast activation of a complex signaling cascade involving multiple kinases (Blank et al., 2021). Among these, Lyn, Syk and Bruton's tyrosine kinase (BTK) were found to play a particularly important role, and are thus considered potential targets for the treatment of MC-related diseases. Indeed, small molecules BTK inhibitors have now been tested in different clinical trials for peanut allergy and CSU (please see part 3.1.4). This signaling pathway leads to the rapid exocytosis of cytoplasmic granules (a process called MC degranulation) containing preformed inflammatory mediators, including histamine and tryptase. MC degranulation is a key event in the allergic cascade, and can even lead to a potentially lethal systemic shock reaction called anaphylaxis (Reber et al., 2017). FcεRI crosslinking also leads to the *de novo* synthesis
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Structure of IgE bound to its high-affinity receptor FcεRI. A. Representation of the Fc portion of IgE (Cε2–3–4) (grey and yellow) bound to FcεRI tetramer on MCs. IgE makes direct binding with FcεRIα D1 and D2 extracellular domains (pink), while the beta chain (MS4A2) (cyan) and two gamma chains (FcRγ) (light and dark green) are responsible for signaling upon crosslinking of the receptor. Adapted from ref. Deng et al. (Deng et al., 2024) (PDB ID: 87GS). B. Close-up the interaction of IgE Fc portion with FcεRIα (PDB ID: 2Y7Q). Residues represented in blue (molecular surface) correspond to the main epitope of the anti-IgE mAb Omalizumab (Eggel et al., 2014), while those represented in red (molecular surface) are residues making direct contacts with the anti-IgE mAb Ligelizumab (Gasser et al., 2020).</figcaption></figure>

of lipid mediators (prostaglandins, leukotrienes), and various cytokines and chemokines (Blank et al., 2021).

### 2.2.2. SCF-KIT

KIT is a class III tyrosine kinase receptor composed of five extracellular IgG-like domains (D1-D5), a transmembrane domain (TM), a juxtamembrane domain (JM), and two intracellular tyrosine kinase domains (TK1 and TK2) (Yuzawa et al., 2007). Upon binding to its ligand stem cell factor (SCF), via the D1-D3 domains, the receptor homodimerizes, which leads to conformational changes that allow for the activation of the tyrosine kinase (Yuzawa et al., 2007) (Fig. 2). Activation of KIT induces a complex signaling cascade which has been reviewed in detail elsewhere (Reber et al., 2006; Tsai et al., 2022).

KIT signaling is essential for MC development, proliferation, maturation and survival (Tsai et al., 2022). This is best exemplified by the fact that mice which lack SCF or KIT have, among many other phenotypical abnormalities, a profound deficiency in MCs (Reber et al., 2012). Both *in vitro* and *in vivo* studies in mice indicate that activation of KIT by high doses of SCF can lead to MC degranulation and anaphylaxis (Lewis et al., 2013; Taylor et al., 1995). Such high doses are most likely non-physiological. However, it has been reported that KIT signaling can act synergistically with IgE-FcεRI complexes to increase degranulation (Hundley et al., 2004). Given its key role in MC activation and survival, KIT is an important pharmacological target in MC-related diseases, as detailed in part 3.4. However, it is important to keep in mind that KIT expression is by far not restricted to MCs, as it is also expressed by many other cells types such as hematopoietic progenitors, melanocytes, interstitial cells of Cajal, innate lymphoid cells (ILCs) and even gamete cells (Hines et al., 1995; Lasota & Miettinen, 2006; Montone et al., 1997; Rossi et al., 2000; Tsai et al., 2022).

### 2.2.3. MRGPRX2

Mas-Related G couple Protein Receptors (MRGPRs) are part of a large family of orphan receptors with more than 50 members identified in human and rodents (Serhan et al., 2021). Many of these receptors are expressed on neurons and specialized immune cells, including on MCs (Serhan et al., 2021). Among these, the expression of MRGPRX2 (and that of its mouse orthologue Mrgprb2) seems to be highly restricted to connective tissue-type MCs, with a particularly high expression in skin MCs (McNeil et al., 2015). However, it has been reported that human basophils can also express lower levels of MRGPRX2, and that such levels might be increased in CSU patients or upon basophil activation (Bartko et al., 2023; Toscano et al., 2022).

MRGPRX2 has endogenous ligands, including substance P which is produced by peripheral Tac1⁺TRPV⁺ sensory neurons. Multiple lines of evidence suggest that the receptor is a mediator of itch, neurogenic inflammation and associated pain (Cao et al., 2021; Green et al., 2019). In addition, the receptor can be activated by a number of pharmaceutical compounds commonly used in the clinic, including vancomycin (antibiotic), ciprofloxacin (antibiotic), rocuronium

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Structure of the receptor KIT and its interaction with SCF. The KIT receptor is composed of five extracellular Ig-like domains (D1-D5 [purple, magenta, violet, teal and blue respectively]; PDB: 2CE8), a transmembrane domain (TM [black]), and an intracellular part composed of two tyrosine domains (TK1–2 [orange and red respectively]; PDB: 1T45). Aspartate at position 816 in TK2 is mutated to a valine (D816V) in >90 % of patients with systemic mastocytosis. SCF homodimers [yellow] bind to D1–3 which promotes the homodimerization of the receptor, followed by and conformational changes that enable interactions between membrane proximal Ig-like domains D4 and D5 and activation of the TK domains leading to downstream signal transduction. The D816V mutation and additional mutations found in mastocytosis patients can promote the activation of the tyrosine kinase domains and signal transduction independently on SCF. Abbreviations: Ig, immunoglobulin; SCF, stem cell factor.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** MRGPRX2 endogenous and exogenous agonists. Endogenous ligands that have been shown to activate the MRGPRX2 receptor (Left). Exogenous ligands demonstrated to have MRGPRX2 activation capacity, especially pharmaceuticals but also microbial and venom toxins (Right) (Kuhn et al., 2021; Kumar et al., 2021; Serhan et al., 2021). Activation of the MRGPRX2 receptor leads to activation of both Gi and Gq signaling, Ca²⁺ mobilization and PKA signaling, and ultimately MC activation and degranulation. Figure created in https://BioRender.com. Abbreviations: BAM, bovine adrenal medulla; cAMP, cyclic adenosine monophosphate; CSP, competence-stimulating peptide; ECP, eosinophilic cationic protein; GnRH, gonadotropin releasing hormone; IP3, inositol trisphosphate; MBP, major basic protein; NMBA, neuromuscular blocking agents; PACAP, Pituitary adenylate cyclase activating polypeptide; PAMP (1–20), proadrenomedullin N-terminal peptides; PKA, protein kinase A; SP, substance P; vasoactive intestinal polypeptide,</figcaption></figure>

(neuromuscular blocking agent [NMBA]) and morphine (analgesic) among others (Kolkhir et al., 2023; McNeil, 2021; Mi et al., 2021) (Fig. 3). Engagement of MRGPRX2 by these medications can induce injection site reactions due to IgE-independent MC degranulation, a process called “pseudo-allergic” reactions (Che et al., 2018; McNeil et al., 2015; Zhang et al., 2018). MRGPRX2 is a class A G-protein-coupled receptor (GPCR), with a typical seven-transmembrane helices domain, an extracellular ligand binding pocket and intracellular G-protein-binding region (Cao & Roth, 2023). It has been reported that MRGPRX2 activation leads to both Gi and Gq signaling pathways, and that synergistic activation of both pathways might be required for optimal MRGPRX2-mediated MC degranulation (Cao & Roth, 2023; Chompunud Na Ayudhya et al., 2019; Lansu et al., 2017; Subramanian et al., 2011) (Fig. 3).

# 3. Main mast cell-dependent diseases

## 3.1. Allergic diseases

The incidence of allergies has dramatically increased over the last three decades in industrialized countries (Pawankar et al., 2011). Among all allergies, allergic asthma and food allergy are major public health problems now each affecting more than 220 million people worldwide (Busse & Lemanske Jr., 2001; Turner & Campbell, 2016). Allergies are considered to result from a breakdown of tolerance to typically non-infectious environmental factors, resulting in type 2 immune responses characterized by the production of T_H2 cytokines such as IL-4, IL-5 and IL-13, and high levels of IgE antibodies. Upon exposure to an allergen in allergic subjects, such allergen is recognized by allergen-specific IgE bound to their high-affinity receptor FcεRI on the surface of tissue MCs and blood basophils, which promotes the degranulation of these cells, and the release of both preformed and newly synthesized mediators, including histamine and tryptase (Reber et al., 2015). This reaction can even lead to anaphylaxis, a severe and potentially fatal systemic allergic reaction (Finkelman, 2010). For these reasons, clinical

diagnoses of allergies are largely based on measurements of allergen-specific IgE (Sicherer & Sampson, 2010). Quantification of serum (or plasma) levels of total and mature tryptase (as a readout of MC degranulation) is also recommended in the diagnostic evaluation of systemic anaphylaxis (Schwartz, 2006).

Several groups have ascertained the role of MCs in allergic asthma, food allergy and atopic dermatitis using mouse models of these diseases (Reber et al., 2012). For example, in a mouse model of chronic asthma, MC-deficient mice have markedly reduced airway responses to methacholine or antigen, and reduced eosinophilia and mucus production (Sibilano et al., 2016; Yu et al., 2006). However, it is still unclear how MCs get activated in such models, since subsequent reports indicated that these features of allergic asthma can develop in mice deficient for IgE or FcεRI (McKnight et al., 2017). Similarly, MC-deficient mice also develop reduced inflammation in a model of atopic dermatitis. Interestingly in this model, key features of the pathology, including disruption of the skin barrier architecture and infiltration of eosinophils and neutrophils were also reduced in mice deficient for Mrgprb2, the orthologue of human MRGPRX2 (Serhan et al., 2019a, 2019b). MC-deficient mice are also largely protected from both intestinal symptoms and systemic shock reactions in most (but not all) models of food allergy and anaphylaxis (Reber et al., 2017). Notably, while both basophils and MCs express high levels of FcεRI, IgE-mediated passive anaphylaxis is abrogated in mice deficient for FcεRI (Dombrowicz et al., 1993; Wershil et al., 1987), and in several strains of MC-deficient mice (Dudeck et al., 2011; Feyerabend et al., 2011; Lilla et al., 2011; Sherer et al., 2014; Wershil et al., 1987; Yamaguchi et al., 1997), but still develops in mice deficient for basophils (Ohnmacht et al., 2010).

## 3.2. Chronic urticaria

Chronic urticaria (CU) is characterized by persistent wheal and flare symptoms of the skin, including redness, hives and itchiness for more than six weeks at a time, with or without angioedema (Zuberbier, et al., 2018). The prevalence of CU is 4.4% (Fricke et al., 2020). CU has
been classified in two subtypes: chronic inducible urticaria (CIndU) and chronic spontaneous urticaria (CSU). CIndU is a form of urticaria in which symptoms can be induced by specific triggers such as cold, heat, pressure or scratching. By opposite, wheals and angioedema are induced by unpredictable and unknown triggers in CSU (Elieh-Ali-Komi et al., 2023).

The pathophysiology of CSU still remains elusive. However, it is now clear that CSU has an autoimmune origin in most patients. Two CSU endotypes have been described: type I, also referred to as autoallergy, characterized by the presence of IgE autoantibodies directed against self-antigens (which have been refer to as "autoallergens"), and type IIb characterized by the presence of autoantibodies against IgE or FcεRI. The list of autoallergens which could potentially trigger type I CSU is far from being elucidated. However, IgE antibodies against thyroid peroxidase (TPO) and thyroglobulin have been shown to be elevated in some CSU patients (Altrichter et al., 2011; Cugno et al., 2018; Shin et al., 2015). Other potential autoallergens have also been reported, including IL-24, dsDNA and Tissue Factor (Cugno et al., 2018; Hatada et al., 2013; Mitamura et al., 2020; Sanchez et al., 2020; Schmetzer et al., 2018).

It is largely accepted that the signs and symptoms of CU are mostly caused by the degranulation of skin MCs (Elieh-Ali-Komi et al., 2023). In type I CSU, degranulation might be triggered by autoallergen-mediated crosslinking of IgE/FcεRI. In type IIb CSU, autoantibodies against IgE or FcεRI might directly cause an autoallergen-independent crosslinking of the receptor (Elieh-Ali-Komi et al., 2023). The implication of this IgE/FcεRI-MC axis is best exemplified by the use of antihistamine as first-line therapy (discussed in part 3.2.1), the efficacy of anti-IgE mAbs (discussed in part 3.1.1), and the promising results of ongoing trials with so-called "MC-depleting" anti-KIT mAbs (discussed in part 3.4).

### 3.3. Mast cell activation syndromes (MCASs) and mastocytosis

Mast cell activation syndromes (MCASs) are characterized by recurrent episodes of symptoms during which a transient increase in tryptase (or other MC-derived mediators such as histamine) is observed. MCAS encompass a broad spectrum of diseases, including hereditary α-tryptasemia (a genetic disease leading to elevated alpha tryptase levels) and mastocytosis (Castells et al., 2024). Mastocytosis is a malignant disease characterized by an increase in MC burden. According to the WHO international consensus on mastocytosis, there are three main subtypes: cutaneous mastocytosis (CM), systemic mastocytosis (SM) and MC sarcoma (Leguit et al., 2023; Valent et al., 2021). CM affects solely the skin, and has no evidence of malignant MC infiltration in other organs. This form of the disease effects mostly children, and usually resolves at adolescence. SM effects at least one extracutaneous organ, such as the bone marrow, liver, spleen or gastrointestinal tract. MC sarcoma is a rare form of mastocytosis characterized by the presence of solid tumors comprising malignant MCs, and which can rapidly metastasize. Patients with MC sarcoma have a very poor prognosis, with a median survival time of less than 18 months (Leguit et al., 2023; Monnier et al., 2016; Valent et al., 2021).

It is considered that gain-of-function (GOF) KIT mutations are a key factor in the etiology and progression of mastocytosis (although it should be noted that in rare cases, including in MC sarcoma, KIT mutations can be absent). GOF mutations in KIT allow for the uncontrolled growth of MCs, leading to the symptoms of the disease. While over 50 different KIT mutations have been characterized in mastocytosis, the KITD816V mutation is present in >90 % of mastocytosis patients (Lim et al., 2009; Valent et al., 2021). This mutation is located in exon 17 in the intracellular tyrosine kinase 2 (TK2) domain, and allows for the autophosphorylation of the receptor without the requirement of the receptor's ligand, SCF, or receptor dimerization (Rajan et al., 2023). Elevated serum tryptase levels (>20 ng/mL) is observed in many patients as a result of the increase in MC burden, and is a minor diagnostic

criterion of SM (Leguit et al., 2023; Matsunaga et al., 1989; Valent et al., 2021).

Symptoms of mastocytosis vary greatly, depending on the organs affected (Leguit et al., 2023; Valent et al., 2021). Skin symptoms (pruritis, flushing, blistering or skin lesions) are the most common (Tiryaki et al., 2023). Gastrointestinal involvement is also present in many patients, and include nausea, abdominal pain, bloating and diarrhea (Leguit et al., 2023; Valent et al., 2021). Such symptoms are prevalent in ~60 % of SM patients (Sokol et al., 2013). Liver, spleen and lymph node involvement are present, primarily in advanced SM (ASM). Histopathological analysis finds MC infiltrates in the majority of these cases (Leguit et al., 2023; Mican et al., 1995; Travis & Li, 1988). Reflecting the overall increase in MC numbers and activity, mastocytosis patients also have an increased risk to develop severe anaphylaxis (Brockow et al., 2008).

## 4. Main strategies approved or in clinical development for the treatment of MC-dependent diseases

Many drugs approved or in clinical development are likely to affect MC biological functions. For example, biologics targeting type 2 cytokines or their receptors, which are approved for the treatment of asthma and other diseases likely modulate MC activation, at least in part through their ability to downregulate IgE levels (Barnes, 2018; Guilleminault et al., 2022). MCs are also an important source of leukotrienes, and leukotriene receptor antagonists have been used to treat asthma and other MC-related disorders. However, the extent to which MCs and their products are directly responsible for the clinical efficacy of these drugs is hard to evaluate. This section will thus only focus on drugs which were demonstrated to directly target MCs or MC-derived mediators (summarized in Fig. 4). Some of these drugs are already approved for the treatment of asthma, chronic urticaria and food allergies (summarized in Table 1), and others are at various stages of clinical evaluation (summarized in Table 2).

### 4.1. Blocking activation signals

#### 4.1.1. Anti-IgE mAbs

Drugs targeting IgE have been reviewed extensively elsewhere (Balbino et al., 2018; Blank et al., 2016; Guntern & Eggel, 2020). This section will thus only focus on clinical results obtained with the two most advanced anti-IgE mAbs Omalizumab and Ligelizumab. However, many additional anti-IgE biologics are now undergoing preclinical and clinical development.

##### 4.1.1.1. Omalizumab
Omalizumab is a humanized anti-IgE mAb developed by Novartis and Genentech. Omalizumab neutralizes free IgE by binding to the Cε3 domain of IgE, thereby masking epitopes responsible for binding to both the high affinity IgE receptor FcεRI on MCs and basophils, and to the low affinity receptor CD23 mainly expressed on B cells (Chang et al., 1990; Davies et al., 2017; Pennington et al., 2016; Wright et al., 2015) (Fig. 1B). Importantly, the mAb poorly recognizes IgE already bound to FcεRI. While this avoids crosslinking of the receptor by Omalizumab, it also implies that repeated injections of the drug are required in order to slowly detach IgE from the surface of MCs (Charles et al., 2023). Omalizumab is approved since 2003 for the treatment of moderate-to-severe allergic asthma (Thomson & Chaudhuri, 2012), since 2014 for CSU (Maurer et al., 2018), and since 2020 for chronic rhinosinusitis with nasal polyps (Pedersen et al., 1988). A phase 3 study (NCT03881696) demonstrated that Omalizumab treatment markedly reduces reaction threshold for peanut and other common food allergens upon oral challenge in patients with multiple food allergies (Wood et al., 2024). This has led to the recent FDA US approval for Omalizumab for children and adults with one or more food allergies, making it the first biological therapy approved for this disease. In allergic diseases, Omalizumab is thought to act mainly by trapping allergen-specific IgE, and thereby reducing IgE-mediated MC (and basophil)
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Summary of mast cell targeted therapies. Approved therapies are underlined. *Drugs approved for non-mast cell mediated conditions. **Therapies that have been discontinued. Figure created in https://BioRender.com. Abbreviations: BTK, bruton's tyrosine kinase; FcεRI, high affinity IgE receptor; IgE, Immunoglobulin E; MRGPRX2, mas-related G-coupled-protein receptor X2; SCF, stem cell factor; Siglec, sialic acid- binding immunoglobulin like receptor.</figcaption></figure>

activation. However, Omalizumab could also have MC-independent effects, since the drug can also interfere with the binding of IgE:allergen immune complexes to CD23 (Gasser et al., 2020). In CSU, two types of responders to Omalizumab have been described: early responders (before week 4 of therapy) and late responders (after week 4). It has been postulated that early responses might occur more in patients with autoreactive IgE, while late responses could be more linked to patients with anti-FcεRI or anti-IgE autoantibodies, since longer treatment periods could be required to markedly reduce surface IgE and FcεRI from skin MCs (Charles et al., 2023).

4.1.1.2. **Ligelizumab.** Ligelizumab is a humanized anti-IgE mAb developed by Novartis with a higher affinity for IgE than Omalizumab (Arm et al., 2014). The efficacy of Ligelizumab was compared to that of Omalizumab in a phase 2 study in severe asthma patients (NCT01716754). Not only the drug failed to demonstrate superiority over Omalizumab, but it also did not prove superiority over placebo

(Trischler et al., 2021). These disappointing results points out major differences in the mechanism of action between Omalizumab and Ligelizumab. Ligelizumab and Omalizumab recognize different epitopes in the Cε3 domain of IgE (Fig. 1B). While Ligelizumab shows superior inhibition of IgE binding to FcεRI and inhibition of IgE production by B cells, it is less potent than Omalizumab in inhibiting IgE:CD23 interactions (Gasser et al., 2020). However, the extent to which these differential effects on CD23 vs. FcεRI account for the lack of efficacy of Ligelizumab in asthma still remain to be demonstrated. The interaction of IgE with FcεRI on MCs is thought to play a key role in CSU (Charles et al., 2023). It was hypothesized that, given its higher affinity for IgE, Ligelizumab might demonstrate superiority and/or require lower dose than Omalizumab for this disease. Several trials have been conducted in both CSU and chronic inducible urticaria which overall demonstrated the efficacy of Ligelizumab in chronic urticaria (Charles et al., 2023). However, in 2024, results from two large phase 3 trials in patients with CSU (NCT03580369 and NCT03580356) indicated that

**Table 1**

Main approved therapies known to directly impact mast cell activity or mast cell mediators. Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyps; CSU, chronic spontaneous urticaria.

<table><thead><tr><th>Target</th><th>Drug name</th><th>Indication</th><th>Main use / effects</th><th>Key refs</th></tr></thead><tbody><tr><td rowspan="3">IgE<br>(and other tyrosine kinases)</td><td rowspan="3">Omalizumab</td><td>Asthma</td><td>reduces asthma exacerbations and decreases inhaled corticosteroid</td><td>(Thomson & Chaudhuri, 2012)</td></tr><tr><td>CSU</td><td>diminishes clinical symptoms and signs of CSU in patients who had remained symptomatic despite the use of H1-antihistamines</td><td>(Maurer et al., 2013)</td></tr><tr><td>CRSwNP<br>Food allergy</td><td>improves sleep and self-reported health status</td><td>(Aldinger et al., 2021)</td></tr><tr><td rowspan="3">H1 histamine<br>receptor (H1R)</td><td rowspan="3">Imatinib<br>Midostaurin<br>Avapritinib</td><td>Mastocytosis</td><td>reduces reaction threshold for peanut and other common food allergens upon oral challenge in patients with multiple food allergies</td><td>(Wood et al., 2024)</td></tr><tr><td>CSU, rhinitis</td><td>Does not block mutated KITD816V<br>Preferentially inhibit mutated KIT<br>Preferentially inhibit mutated KIT</td><td>(Pardanani et al., 2003)<br>(Kasamon et al., 2018)<br>(DeAngelo et al., 2021; Gotlib et al., 2021)</td></tr><tr><td>Cetirizine<br>Levocetirizine<br>Bilastine<br>Rupatadine<br>Fexofenadine<br>Several others</td><td>First line therapy in CSU. However, still many non-responders despite high dose of antihistamine</td><td></td></tr></tbody></table>
<caption>**Table 2**</caption>

Main completed and ongoing trials with mast cell-targeted therapies. Abbreviations: AD, atopic dermatitis; BTK, Bruton's tyrosine kinase; CindU, Chronic inducible urticaria; CSU, Chronic spontaneous urticaria; IgE, immunoglobulin E; MRGPRX2, mas-related G-protein-coupled receptor X2; Siglec, sialic acid-binding immunoglobulin-type lectin;

<table><thead><tr><th>Target</th><th>Drug name</th><th>Indication</th><th>Current clinical stage</th><th>Main outcomes</th><th>Key refs or NCT identifier</th></tr></thead><tbody><tr><td rowspan="3">IgE</td><td rowspan="3">Ligelizumab</td><td>Asthma</td><td>Phase 2</td><td>Failed to demonstrate superiority over placebo or the approved anti-IgE mAb omalizumab</td><td>(Trischler et al., 2021)</td></tr><tr><td>CSU</td><td>Phase 3</td><td>Demonstrated superiority over placebo but not omalizumab</td><td>(Maurer, Ensina, et al., 2024)</td></tr><tr><td>Peanut Allergy</td><td>Phase 3 (ongoing)</td><td>Trial terminated prematurely by the sponsor. Long-term safety and efficacy study for participants who had already completed this trial is still ongoing</td><td>NCT04984876 (terminated) &amp; NCT05678959</td></tr><tr><td rowspan="3">BTK</td><td>Acalabrutinib</td><td>Peanut Allergy</td><td>Phase 2</td><td>Oral pretreatment for just two days significantly increased tolerance to peanut during oral exposure</td><td>(Suresh et al., 2023)</td></tr><tr><td>Remibrutinib</td><td>CSU</td><td>Phase 3 (ongoing)</td><td>Met all primary and secondary endpoints at week 12 with significant reduction in urticaria activity as compared to placebo (interim results)</td><td>NCT05030311 &amp; NCT05032157</td></tr><tr><td>INCB000262 (formerly EP262)</td><td>AD</td><td>Phase 2a (ongoing)</td><td>Recruitment completed - no result published yet</td><td>NCT06144424</td></tr><tr><td rowspan="2">MRGPRX2</td><td rowspan="2">EVO756</td><td>CIndU</td><td>Phase 1b (ongoing)</td><td>Recruitment completed - no result published yet</td><td>NCT06050928</td></tr><tr><td>CSU</td><td>Phase 2 (ongoing)</td><td>put on hold at the end of 2024 following the observation of certain in vivo preclinical toxicology findings</td><td>NCT06077773</td></tr><tr><td>Tryptase Siglec-8</td><td>MTPS9579A Lirentelimab (AK002)</td><td>Asthma Eosinophilic gastritis and duodenitis</td><td>Phase 2a (ongoing)</td><td>Enrollment of patients stated in September 2024</td><td>NCT06603220</td></tr><tr><td rowspan="3">Siglec-6</td><td rowspan="3">AK006</td><td>CSU</td><td>Phase 2a (ongoing)</td><td>Did not meet the primary endpoint - development discontinued</td><td>NCT04092582</td></tr><tr><td>AD</td><td>Phase 2</td><td>Met histologic co-primary endpoint but missed symptomatic co-primary endpoint - development discontinued</td><td>NCT04856891, NCT05152563 and NCT04322604</td></tr><tr><td>CSU</td><td>Phase 2</td><td>Failed to meet their primary endpoints - development discontinued</td><td>NCT05528861</td></tr><tr><td rowspan="2">KIT (and other tyrosine kinases)</td><td>Imatinib</td><td>Asthma</td><td>Phase 3</td><td>Failed to meet their primary endpoints - development discontinued</td><td>NCT05155085</td></tr><tr><td>Masitinib</td><td>Mastocytosis</td><td>Phase 3</td><td>Well tolerated in healthy volunteers, and skin biopsies showed high levels of receptor occupancy at day 29. However, AK006 did not demonstrate therapeutic activity in CSU. Development discontinued</td><td>NCT06072157</td></tr><tr><td rowspan="3">Elenestinib</td><td>Bezuclastinib</td><td>Mastocytosis</td><td>Phase 2 (ongoing)</td><td>Effective at reducing airway hyperresponsiveness, MC counts, and tryptase levels in patients with severe refractory asthma</td><td>NCT01097694</td></tr><tr><td>Barzolvolimab</td><td>Mastocytosis</td><td>Phase 2 (ongoing)</td><td>Met primary endpoint. The most frequent adverse events noted were diarrhea and urticaria, but the drug was overall well tolerated</td><td>(Lortholary et al., 2017)</td></tr><tr><td>Prurigo nodularis Eosinophilic esophagitis</td><td>Mastocytosis</td><td>Phase 2 (ongoing)</td><td>Interim results: beneficial effects on disease-related symptoms and dose-dependent reductions in serum tryptase with a promising early benefit-risk profile in indolent systemic mastocytosis</td><td>NCT04910685</td></tr><tr><td rowspan="5">JSP191</td><td rowspan="5">Barzolvolimab</td><td>CSU</td><td>Phase 3 (ongoing)</td><td>Preliminary results suggest that the drug increases quality of life and reduces tryptase levels and bone marrow MCs</td><td>NCT05186753 and NCT04996875</td></tr><tr><td>CSU</td><td>Phase 2 (ongoing)</td><td>Phase 3 still ongoing; Phase 2 trial demonstrated skin mast cell depletion, reduced serum tryptase levels and significant improvement of disease activity</td><td>NCT06455202 and NCT06445023</td></tr><tr><td>CSU</td><td>Phase 2 (ongoing)</td><td>No result published yet</td><td>NCT06366750</td></tr><tr><td>CSU</td><td>Phase 2 (ongoing)</td><td>No result published yet</td><td>NCT05774184</td></tr><tr><td>CSU</td><td>Phase 2 (ongoing)</td><td>No result published yet</td><td>NCT06727552</td></tr><tr><td rowspan="2">JSP191</td><td rowspan="2">Barzolvolimab</td><td>CSU</td><td>Phase 3 (ongoing)</td><td>No result published yet</td><td>NCT06353971, NCT06736262 and NCT06162728</td></tr><tr><td>Asthma</td><td>Phase 1 (ongoing)</td><td>No result published yet</td><td>NCT06592768</td></tr></tbody></table>

Ligelizumab demonstrated superior efficacy versus placebo but not versus Omalizumab (Maurer, Ensina, et al., 2024). A large phase 3 study assessing the efficacy of Ligelizumab as a monotherapy for peanut allergy was initiated in 2021 but terminated prematurely by the sponsor (NCT04984876). However, a long-term safety and efficacy study for participants who had completed the phase 3 trial is still ongoing (NCT05678959).

### 4.1.2. BTK inhibitors

Bruton's Tyrosine Kinase (BTK) is expressed broadly, and its function has been extensively studied on B cells (McDonald et al., 2021). However, several *in vitro* studies in human MCs and *in vivo* studies in mice have identified that BTK plays an important role in FceRI-mediated MC degranulation (Kawakami et al., 1994; Kawakami et al., 1998; Kawakami et al., 2000; Setoguchi et al., 1998). This has led to the hypothesis that BTK inhibitors (BTKi) might be used for the treatment of MC-dependent diseases such as food allergy or chronic urticaria. BTKi

were first developed for the treatment of B cell malignancies. Among these, ibrutinib was the first-in-class irreversible BTKi approved by the FDA in 2013. Since then, several other irreversible BTKi have been approved for multiple B cell malignancies, including acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib (Smiljkovic et al., 2017). All these small molecules can be given orally, which makes them particularly attractive for the potential treatment of MC-related diseases.

Dispenza and colleagues demonstrated that BTKi can inhibit IgE-mediated degranulation of primary human MCs and block allergen-induced contraction of isolated human bronchi (Dispenza et al., 2020). In the same study, the authors showed that two oral doses of the BTKi acalabrutinib can prevent IgE-mediated anaphylaxis in a humanized mouse model (Dispenza et al., 2020). The same group reported in a pilot study that two standard doses of ibrutinib can also reduce skin prick test reactivity to peanut and tree nuts in allergic adults (Dispenza et al., 2018). On the basis of these observation, the BTKi acalabrutinib was tested in a phase 2 study in peanut allergic subjects
(NCT05038904). Oral pretreatment with acalabrutinib for just two days significantly increased peanut-allergic patients' tolerance to peanut during oral exposure (Suresh et al., 2023). These results have now to be extended to larger cohorts and longer treatment periods to fully assess the safety and efficacy of BTKi for the treatment of food allergy. In particular, severe adverse event have been observed with "first generation" BTKi such as ibrutinib (Mendes-Bastos et al., 2022). However, "next-generation" BTKi such as remibrutinib seem to have a better safety profile. In a phase 2b study, remibrutinib demonstrated a favorable safety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU (NCT04109313) (Jain et al., 2024). Two large placebo-controlled phase 3 trials have just been completed (REMIX-1 [NCT05030311] and REMIX-2 [NCT05032157]) in a total of more than 900 CSU patients. Although results from these studies have yet to be published, Novartis announced that remibrutinib met all primary and secondary endpoints at week 12 with significant reduction in urticaria activity as compared to the placebo group (AG, 2023; Jain et al., 2024).

### 4.1.3. MRGPRX2 antagonists

The expression of MRGPRX2 seems to be restricted to MCs, and in particular cutaneous MCs (Tatemoto et al., 2006). Several endogenous and exogenous agonists of the receptor can induce MC degranulation (Kolkhir et al., 2023; McNeil, 2021; Mi et al., 2021) (Fig. 3). Moreover, it was shown that the mouse orthologue of MRGPRX2, Mrgrpb2, plays an important role in a model of atopic dermatitis (AD) (Nadine Serhan, et al., 2019). This makes this receptor a particularly attracting target for AD and other MC-driven skin diseases such as chronic urticaria. Several small molecule inhibitors of MRGPRX2 are now at various stages of preclinical and clinical development (Bawazir et al., 2022; Chen, Gurung, et al., 2024; Kumar et al., 2023; Macphee et al., 2024; Ogasawara et al., 2019; Suzuki et al., 2020; Wollam et al., 2024; Wong et al., 2024).

The company Escient Pharmaceuticals (acquired in 2024 by Incyte) developed an antagonist named EP262 (now INCB000262). Preclinical data indicate that oral treatment with INCB000262 potently inhibits MC degranulation and extravasation induced by intradermal injection of various MRGPRX2 agonists in a transgenic mouse line expressing human MRPGRX2. INCB000262 also dose-dependently inhibits histamine release induced by the two MRGPRX2 agonists cortistatin-14 and icatibant in human skin explants (Wollam et al., 2024). INCB000262 is currently being investigated in clinical trials as a once-daily oral therapy for AD (phase 2a, NCT0144424), chronic inducible urticaria (phase 1b, NCT06050928), and CSU (phase 2, NCT06077773). While recruitment of the AD and chronic inducible urticaria trials is completed, that of the CSU trial has been put on hold at the end of 2024 following the observation of certain *in vivo* preclinical toxicology findings (Corporation, 2023).

Another small molecule antagonist of MRGPRX2 developed by Evommune and named EVO756 is now undergoing clinical evaluation. The drug demonstrated a good safety and tolerability profile in a phase 1 study in CSU and otherwise healthy adults (Evommune, 2024). A phase 2 study is now ongoing to evaluate the safety, tolerability and efficacy of daily oral doses of EVO756 in chronic inducible urticaria (NCT06603220).

GE1111 is another MRGPRX2 antagonist in preclinical development (Kumar et al., 2023). *In silico* screening was first carried out to identify possible antagonists to the receptor. Subsequently, *in vitro* testing on the human MC line LAD-2 was carried out to identify GE1111 as the most potent MRGPRX2 antagonist, preventing MC degranulation and reducing MCP-1 and PGD2 production induced by the MRGPRX2 agonist C48/80. The authors further showed that GE1111 can reduce degranulation induced by other MRGPRX2 agonists, including cortistatin-14 (an endogenous ligand) as well as ant venom P17, ala 4 P17 and ciprofloxacin (exogenous ligands) (Kumar et al., 2023). GE1111 also reduced extravasation, epithelial thickening and MC degranulation in a passive cutaneous anaphylaxis (PCA) model, as well as hypothermia in a passive systemic anaphylaxis (PSA) model induced by injections of C48/80 in

mice (Kumar et al., 2023). More recently, GE1111 was found to reduced skin thickening, scaling, erythema and epidermal thickness in a model of DNFB-induced dermatitis in mice (Wong et al., 2024). However, while these results are promising, further work is required to ensure the selectivity and safety of this drug prior to envision its potential use in the clinic.

## 4.2. Neutralizing effector molecules

### 4.2.1. Anti-histamines

MCs are the main producer of histamine in the body. However, MCs are not the sole source of histamine, since it is also produced by basophils and, to a lower extent, by other immune cells and neurons (Huang et al., 2018). Histamine is synthesized by the enzyme histidine decarboxylase (HDC) which, as the name suggests, causes the decarboxylation of L-histidine (Huang et al., 2018). In MCs, histamine is stored in cytoplasmic granules along with proteases, heparin and other inflammatory mediators. Knock-out of HDC and therefore histamine production in MCs has been demonstrated to reduce the capacity of MCs to form mature granules (Nakazawa et al., 2014). Histamine (along with other mediators stored in granules) is rapidly released upon MC degranulation, and is responsible for many symptoms in allergic diseases, including inflammation, pruritus, oedema, and bronchospasm (White, 1990). The key role of histamine in allergic reactions is best exemplified by the fact that HDC-deficient mice are protected from IgE-mediated PSA (Makabe-Kobayashi et al., 2002). Thus, inhibition of histamine mediated reactions is clinically relevant and useful to treat MC-mediated and associated diseases (Castells & Butterfield, 2019).

Histamine mediates its biologic effects through activation of four G-protein-coupled receptors, named H1-H4R (Akdis & Simons, 2006; Thangam et al., 2018; White, 1990). Early studies with histamine receptor antagonists have highlighted that the systemic effects of histamine, including airway obstruction and tachycardia, are mainly mediated by H1R. By contrast, histamine-induced cutaneous flushing and headaches seems to depend on both H1R and H2R (Kaliner et al., 1981). Mice deficient for H1R or H2R are also partially protected from IgE-mediated PSA, with more protection observed in H1R/H2R double-deficient mice (Wechsler et al., 2013).

H1 antihistamines (also called H1 blockers) are inverse agonists of H1R, that have been in the clinic since the 1940s (Simons & Simons, 2011). These molecules preferentially bind the inactivated H1R, stabilizing the receptor in this conformation (Leurs et al., 2002). First generation H1 antihistamines, which include chlorpheniramine, diphenhydramine, doxepin and hydroxyzine, have fast absorption and reduce histamine mediated symptoms such as erythema ("wheal"), itch and pain ("flare") especially in treatment of symptoms in allergic rhinitis, allergic conjunctivitis, and urticaria (Juniper et al., 2005; Plaut & Valentine, 2005; Zuberbier, et al., 2018). However, there are many side effects associated with first generation H1 antihistamines, including effects on the central nervous system (causing drowsiness, fatigue, somnolence, dizziness, headache, dystonia, dyskinesia, agitation, confusion, and hallucinations), the cardiac system (tachycardia and/or arrhythmias) as well as effects on mucosal tissues (dry eyes, dry mouth, urinary retention and hesitancy, decreased gastrointestinal motility, constipation). Thus, first generation antihistamines are not recommended anymore for the treatment of allergic symptoms (Bousquet, et al., 2008; Church, et al., 2010).

Second generation H1 antihistamines, such as cetirizine, levocetirizine, bilastine, rupatadine and fexofenadine, have much reduced side-effects (Chen, Cao, et al., 2024; Podder et al., 2023; Zuberbier, et al., 2018). It has been shown that there are no major adverse reactions with these treatments even when up-dosing to four times the recommended dose. However, cetirizine has been shown to have more sedative effects during up-dosing, compared to the other second-generation antihistamines (Podder et al., 2023). Because the effects of histamine occur extremely fast upon MC degranulation, taking
antihistamine during the onset of an allergic reaction is likely to have lit-
tle effects. However, H1 antihistamines are still commonly used as an
adjuvant therapy in the treatment of anaphylaxis, even though their
efficacy at reducing anaphylaxis symptoms is unclear (Sheikh et al.,
2007). By contrast, there is strong evidence that long-term regular ad-
ministration of H1 antihistamines can decrease symptoms in allergic
rhinitis and CSU (Finn Jr. et al., 1999; Nettis et al., 2006; Ortonne et al.,
2007; Simons, 2001, 2003; Simons, 2007). However, although H1
antihistamine represent first-line therapies for CSU, many patients still
respond poorly to these drugs even at high dose (Guillen-Aguinaga
et al., 2016; Maurer et al., 2017; Maurer et al., 2019; Zuberbier et al.,
2024). It has been postulated that this lack of efficacy might reflect the
vast array of inflammatory mediators released upon MC activation
and/or the heterogenicity of CSU pathogenic mechanisms.

4.2.2. Anti-Tryptase (MTPS9579A)

MCs abundantly and selectively store several proteases in their cyto-
plasmic granules, including tryptases, chymases and carboxypeptidases
(Wernersson & Pejler, 2014). Tryptase is a proteolytic enzyme with two
main subtypes α-tryptase and β-tryptase. Pro-tryptase monomers have
the particularity to be constitutively secreted, whereas mature tryptase
tetramers are stored in granules and secreted only upon degranulation
(Schwartz et al., 2003). Mature tryptase require heparin proteoglycan
for stabilization of their tetrameric structure. Serum tryptase levels are
used as a biomarker for MC activation, anaphylaxis, and as a minor diag-
nostic criterion for mastocytosis (Muraro, et al., 2022; Schwartz et al.,
2003; Valent et al., 2017). The role of tryptase is not fully understood.
It was reported that MC tryptase levels are associated with asthma se-
verity, and that increased active tryptase alleles could be associated
with decreased clinical responses to anti-IgE therapy for asthma.
These results suggested that inhibition of tryptase could have benefit
in asthma.

Genentech has developed a humanized IgG4 mAb (MTPS9579A) that inhibits tryptase activity by dissociating active tryptase tetramers into catalytically inactive monomers (Maun et al., 2019). They demonstrated that the mAb can reduce IgE-mediated PSA in humanized mice, and that subcutaneous injection of the mAb also reduces tryptase activity in bronchoalveolar lavages in cynomolgus monkeys (Maun et al., 2019). A phase 1 trial showed favorable pharmacokinetics (PK) without adverse reactions in healthy individuals. Moreover, treatment with MTPS9579A induced increases in total tryptase in serum and nasosorption samples. However, a dose-dependent reduction in active tryptase levels was observed in nasosorption samples, suggesting that the mAb can inhibit tryptase activity in the upper airways (Rymut et al., 2022). With the aim of treating moderate-to-severe asthma, a phase 2a clinical trial was carried out (NCT04092582). Patients were administered 1800 mg MTPS9579A or placebo i.v every 4 weeks for 48 weeks. Unfortunately, MTPS9579A did not meet the primary endpoint. One potential explanation from such failure came from PK/PD model predictions, since it was suggested that a dose of 3800 mg i.v. (i.e. more than twice higher) would have been required to efficiently suppress airway active tryptase (Rymut et al., 2022). A phase 2 study of MTPS9579A in participants with refractory CSU was initially planned but has since been withdrawn, and the development of this mAb has been discontinued.

4.3. MC "silencers"

The concept of “MC silencing” has been recently introduced and con-
sists on engaging inhibitory receptors at the surface of MCs to block ac-
tivation pathways (Metz et al., 2024). MCs and many other myeloid cells
express inhibitory receptors containing immunoreceptor tyrosine-
based inhibitory motifs (ITIMs) in their cytoplasmic part, including the
IgG receptor FcγRIIB, and sialic acid–binding immunoglobin-like lectins
(Siglecs) which bind sialylated glycans (Angata & Varki, 2023; Macauley
et al., 2014; O’Sullivan et al., 2023). Expression of several Siglecs has

been reported on human MCs, including Siglec-2 (CD22), -3 (CD33),
-5, -6, -7, -8 and -9 (Miralda et al., 2023; Mizrahi et al., 2014;
Yokoi et al., 2006). Among these, a proteomic study found that both
Siglec-6 and Siglec-8 are particularly highly expressed in MCs from dif-
ferent tissues (Plum et al., 2020), and preclinical and clinical develop-
ment has so far mostly focused on these two receptors.

4.3.1. Anti-Siglec-8 mAb Lirentelimab (AK002)

The expression of Siglec-8 was found to be restricted to MCs, baso-
phils and eosinophils (Kikly et al., 2000), making it a particularly attrac-
tive target for allergic diseases (Kiwamoto et al., 2012). Crosslinking of
the receptor with an anti-Siglec-8 antibody induces apoptosis of eosin-
ophils (Nutku et al., 2003). In contrast, Siglec-8 engagement failed to in-
duce human MC apoptosis. However, treatment of human MCs with
anti-Siglec-8 mAbs downregulated IgE-mediated degranulation (Yokoi
et al., 2008). Interestingly, it was reported that anti-Siglec-8 mAbs can
induce apoptosis in primary human skin MCs only if the cells were
pretreated with V. cholera sialidase (an enzyme that removes α2,3-
linked sialic acid from the cell surface). The authors suggested that
Siglec-8 cis ligands, i.e. ligands present on the surface of the same cell,
can constrain Siglec-8 mediated MC death (Cao et al., 2023). The com-
pany Allakos developed a humanized, non-fucosylated IgG1 anti-
Siglec-8 mAb named Lirentelimab (AK002), which selectively binds
MCs, eosinophils and, at a lower level, basophils in human blood and tis-
sue. The mAb demonstrated potent ADCC activity against blood eosino-
phils in the presence of natural killer cells. Furthermore, AK002
prevented anaphylaxis in a model of human IgE-mediated PSA in hu-
manized NSG-SGM3 mice (Youngblood, Brock, Leung, Falahati, Bryce,
et al., 2019). To further study the efficacy of the mAb in vivo, transgenic
mice expressing human Siglec-8 were also generated. The first lines
were generated using Cre-lox approaches and expressed human
Siglec-8 in eosinophils only (O’Sullivan et al., 2018), MCs only, or MCs
and basophils (Wei et al., 2018). However, another transgenic line
was designed to contain a single copy of the human Siglec-8 gene and
the flanking regions containing the putative native promoter and regu-
latory elements. This line demonstrated expression on human Siglec-8
in basophils, eosinophils and in both connective-tissue type MCs and
mucosal MCs (Youngblood, Brock, Leung, Falahati, Bochner, et al.,
2019). Using this line, it was demonstrated that treatment with AK002
reduces eosinophils and MCs in the gastrointestinal tract in a model of
eosinophilic gastroenteritis (Youngblood, Brock, Leung, Falahati,
Bochner, et al., 2019). The mAb was then found to reduce gastrointesti-
nal eosinophils and symptoms in a phase 2 clinical trial in patients with
Eosinophilic Gastritis and Duodenitis (NCT03496571) (Dellon et al.,
2020). However, the subsequent phase 3 studies (NCT04856891,
NCT05152563 and NCT04322604) gave disappointing results. AK002
was also tested in a phase 2a study for antihistamine-resistant chronic
spontaneous and inducible urticaria (NCT03436797), a first-in-human
trial in patients with refractory indolent systemic mastocytosis
(NCT02808793), and a phase 1b trial in patients with allergic conjuncti-
vitis (NCT03379311). In each trial, the drug was well tolerated and pa-
tients reported improvement of symptoms (Altrichter et al., 2022;
Anesi et al., 2022; Siebenhaar et al., 2023). Phase 2 trials were initiated
for both atopic dermatitis (NCT05155085) and CSU (NCT05528861).
However, the company announced in 2024 that both trials failed to
meet their primary endpoints, and the development of AK002 has
been discontinued (Inc., 2023).

4.3.2. Anti-Siglec-6 mAb AK006

Siglec-6 is highly expressed on MCs (Robida et al., 2022). In contrast to Siglec-8, Siglec-6 is not expressed on eosinophils. Its expression has however been reported on basophils, albeit at lower levels than on MCs (Smiljkovic et al., 2023). Importantly, high expression of Siglec-6 has been found on several MC lines harboring gain-of-function KIT mutations (Robida et al., 2022), as well as on bone marrow MCs from patients with mastocytosis, making it an attractive potential target for
this disease (Smiljkovic et al., 2023). Siglec-6 expression has also been reported on acute myeloid leukemia cell lines (Jetani et al., 2021), and subsets of monocytes from AML patients (Smiljkovic et al., 2023), as well as at the surface of trophoblasts in the placenta (Patel et al., 1999), and blood memory B cells (Schmidt et al., 2023). Nevertheless, given its high and relatively restricted expression on MCs, a humanized anti-Siglec-6 mAb (AK006) was developed by Allakos. Preclinical studies indicated that the mAbs can downregulate FcεRI-induced MC activation *in vitro*, and that this inhibitory effect is abolished upon mutation of the ITIM domain of Siglec-6, confirming the agonistic effects of the mAb (Schanin et al., 2022). The authors then tested the efficacy of the mAb in a passive anaphylaxis model induced by injection of an anti-FcεRI mAb (clone CRA-1 which crosslinks the receptor) in humanized mice. A single injection of the anti-Siglec-6 mAb 24 h before challenge with CRA-1 was sufficient to block anaphylaxis in this model. Given the short treatment period in this model, blockade of MC-mediated anaphylaxis was not due to cell depletion but rather to inhibition of MC degranulation. However, the mAb was also found to have potent antibody-dependent phagocytosis (ADCP) activity against human MCs *in vitro*. In line with these results, longer treatment periods (3 injections over 2 weeks) reduced MC numbers in different organs in humanized mice (Schanin et al., 2022). The company then initiated a phase 1 trial in healthy volunteers and in patients with CSU (NCT06072157). According to the company, the mAb was well tolerated in healthy volunteers, and skin biopsies showed high levels of receptor occupancy at day 29, confirming that AK006 reaches skin tissue MCs (Inc., 2024). However, the company announced very recently that AK006 did not demonstrate therapeutic benefit in this phase 1 trial in CSU, and that further development of this mAb is discontinued (Allakos, 2025).

## 4.4. Depleting mast cells

### 4.4.1. Tyrosine Kinase Inhibitors (TKIs)

A number of small molecule tyrosine kinase inhibitors (TKIs) have been approved for the treatment of mastocytosis, and others are at various stages of clinical development. These TKIs inhibit the KIT receptor, and thereby reduce MC survival and burden (Akin, 2015; Barete et al., 2015; Buonomo, Nucera, & Criscuolo, 2022; Chan et al., 2014; Czarny, Lange, Ługowska-Umer Hanna, & Nowicki, 2018; Gotlib et al., 2016). However, KIT is expressed in several cell populations outside of the MC lineage, including hematopoietic progenitors, melanocytes, innate lymphoid cells, interstitial cells of Cajal and others. In addition, TKIs do not exclusively target KIT but also inhibit other tyrosine kinases (TKs). Thus, these TKIs can induce a large spectrum of side effects, and the extent to which their efficacy can be attributed to direct targeting of MCs must be interpreted with care. Many reviews have covered the mechanisms of action and efficacy of TKIs (Akin et al., 2022; Sabato et al., 2024; Zhao et al., 2022). This section will thus only focus on the TKIs which are approved for mastocytosis, or have demonstrated promising results in trials for MC-related diseases, as well as on preclinical data obtained with a novel highly specific KIT inhibitor.

#### 4.4.1.1. Imatinib.
Imatinib (STI 571, sold under the brand name Gleeved by Novartis) was first developed for its ability to inhibit c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases, and was approved in 2001 for the treatment of patients with chronic myeloid leukemia. Imatinib was then shown to be a potent inhibitor of KIT activity (Heinrich et al., 2000). Imatinib binds and inactivates the tyrosine kinase ATP-binding domain of the receptor, preventing the transfer of a phosphate group and subsequent signaling, ultimately resulting in MC cell apoptosis (Growney et al., 2005; Heinrich et al., 2003; Maekawa, Ashihara, & Kimura, 2007). However, it was soon demonstrated that while imatinib inhibits wild-type KIT, and the growth of the MC line HMC-1.1 bearing the activating KIT mutation G560V, it does not block HMC-1.2 which bear a D816V mutation (found in a great majority of mastocytosis patients) in addition to G560V. Imatinib also

failed to induce killing of neoplastic bone marrow MCs from mastocytosis patients bearing the D816V mutation (Akin et al., 2003). Since then, imatinib has been shown to be effective in some less frequent KIT mutations associated with mastocytosis, including the K509I mutation (Chan et al., 2014). Data from case reports and trials with a limited number of mastocytosis patients treated with imatinib rapidly let to the FDA approval of the drug in 2006 in adults with aggressive systemic mastocytosis and lacking the D816V KIT mutation (Pardanani et al., 2003). This first-generation TKI induces many side effects which greatly limit its potential use for other MC-related disorders. Imatinib was however tested in a phase 3 study in patients with severe refractory asthma (NCT01097694), in which the drug was found to be effective at reducing airway hyperresponsiveness, MC counts, and tryptase levels (Cahill et al., 2017).

#### 4.4.1.2. Masitinib.
Masitinib (AB1010) is an oral TKI developed by the biotech AB Science, and has a greater activity and selectivity against KIT than imatinib *in vitro*. However, masitinib also potently inhibits other TKIs, including PDGFR and the intracellular kinases Lyn and Fyn (Dubreuil et al., 2009). Masitinib is approved for the treatment of grade 2 or 3 MC tumors in dogs (Hahn et al., 2008), and it has been investigated in several trials for multiple diseases, including mastocytosis, asthma, rheumatoid arthritis and multiple sclerosis.

The efficacy of the drug was assessed in a phase 3 study in patients with indolent or smoldering systemic mastocytosis (NCT00814073), in which the primary endpoint was at least 75% improvement in one or more of the following four symptoms: pruritus, flushing, depression, or asthenia. 18.7% of the patients treated with masitinib met this primary endpoint compared with 7.4% for placebo. The most frequent adverse events noted were diarrhea and urticaria, but the drug was overall well tolerated (Lortholary et al., 2017). Importantly, masitinib was effective regardless of KIT mutations. This might appear surprising since masitinib poorly inhibits KIT with the mastocytosis-associated D816V mutation. However, it is thought that its inhibitory activity against Lyn (a kinase involved in MC degranulation) could contribute to the drug's ability to reduce MC activity (Akin et al., 2022).

Masitinib was also tested in patients with corticosteroid-dependent asthma. In a phase 2 trial (NCT00842270), comparable reduction in oral corticosteroids was achieved with masitinib and placebo at 16 weeks of treatment. However, an improved asthma control was observed in masitinib-treated patients, which was reflected by significantly better Asthma Control Questionaire (ACQ) score as compared to the placebo group (Humbert et al., 2009). In a subsequent phase 3 study (NCT01449162), 13 months of oral treatment with masitinib (6 mg/kg/day) led to a 35% reduction in severe asthma exacerbation rate (SAER) relative to placebo (Davidescu et al., 2022). Masitinib also reduced the rate of severe asthma exacerbations compared to placebo in another phase 3 trial in severe asthma patients with >150 eosinophils per µL and not well controlled with oral corticosteroids (NCT03771040).

#### 4.4.1.3. Midostaurin.
Midostaurin (sold under the brand name Rydapt by Novartis) is a broad spectrum anti-neoplastic TKI which has multiple targets, although at first was developed to inhibit protein kinase C (PKC) (Stone et al., 2018). Midostaurin, but not imatinib, was found to inhibit growth of Ba/F3 cells stably transfected with a D816V KIT mutant (Gotlib et al., 2005). Interestingly, midostaurin poorly inhibits wild-type KIT, since it preferentially binds KIT in its activated form (Apsel Winger et al., 2019). This makes the drug particularly attractive for the treatment of mastocytosis and other diseases associated with activating KIT mutations. Indeed, a first case report indicated that the drug was effective in a patient with advanced MC leukemia with the D816V mutation (Gotlib et al., 2005). Following this, two large phase 2 trials were conducted with oral midostaurin at a dose of 100 mg twice daily in patients with advanced systemic mastocytosis (ASM). Midostaurin demonstrated efficacy in 60% (NCT00782067) and 69% (NCT00233454) of
the patients, regardless of the subtype of ASM and KIT D816V mutation status. Serum tryptase levels and bone marrow MC burden decreased by at least 50% in most patients in both trials, confirming that the drug is efficient at depleting malignant MCs (Gotlib et al., 2016; DeAngelo et al., 2018). These studies led to the FDA approval of midostaurin in ASM in 2017 (Kasamon et al., 2018).

4.4.1.4. Avapritinib, Elenestinib and Bezuclastinib. Avapritinib (BLU-285 developed by Blueprint Medicines) is another TKI designed to target the active conformation of KIT and not its wild-type form (Apsel Winger et al., 2019). The drug was found to be effective at inhibiting growth of bone marrow myeloid progenitor cells from patients with KIT D816V positive ASM (Lubke et al., 2019). Avapritinib exhibits increased selectivity for D816V-mutated KIT compared with midostaurin, as well as 10-fold greater potency in vitro, and was found to be active against a spectrum of other clinically observed KIT mutants (Evans et al., 2017). Avapritinib was tested in phase 1 (NCT02561988) and phase 2 trials (NCT03580655) in patients with ASM. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 10⁹/l). In both studies, the overall response rate was 75% with deep and durable responses, including complete remission in 36% of the patients. More than 50% reductions in bone marrow MCs and serum tryptase were observed in almost all patients (DeAngelo et al., 2021; Gotlib et al., 2021). A study comparing the efficacy observed in these two trials to that observed in patients treated with best available therapy concluded that the avapritinib cohort had significantly better survival, and more pronounced decrease in serum tryptase (Reiter et al., 2022). Based on the results of these trials, the drug was approved in 2021 for ASM. Another phase 2 study investigates the efficacy of the drug in patients with indolent systemic mastocytosis (ISM) (NCT03731260). Although the study is still ongoing, a recent interim analysis (week 24) confirmed that the drug is superior to placebo in reducing uncontrolled symptoms and MC burden (Gotlib et al., 2023), leading to its FDA approval in 2023 for ISM. Avapritinib is generally well tolerated, but some patients experienced severe adverse events, including intracranial hemorrhages.

Elenestinib (BLU 263), a next generation TKIs related to avapritinib (also developed by Blueprint Medicines) that demonstrates a more limited central nervous system penetration is now being evaluated in a phase 2 trial in ISM patients (NCT04910685). Interim results from this trial indicate that the drug has beneficial effects on disease-related symptoms and demonstrate dose-dependent reductions in serum tryptase with a promising early benefit-risk profile in ISM (Tashi et al., 2023).

Cogent Bioscience is also developing a next generation TKI, known as Bezuclastinib, which is in clinical trial for indolent and smoldering SM (NCT05186753) as well as in advanced SM (NCT04996875). Preliminary results reported suggest that the drug increases quality of life and reduces MC burden (read by tryptase levels and bone marrow biopsy). Furthermore, treatment-emergent adverse events occurred but were of low grade and reversible without dose modification (Lindsay et al., 2024).

4.4.1.5. MDI-0238. A new TKI known as MOD000001 has been recently described by Nakamura and colleagues. The authors tested the interaction of the drug with 468 kinases covering more than 80% of the human catalytic protein kinome, and found that MOD000001 is highly selective for KIT and does not inhibit the closely related class 3 receptor tyrosine kinases PDGFRA and PDGFRB. The drug was found to block SCF-induced mouse and human MC activation in vitro (Nakamura et al., 2024). Short-term (7 days) oral treatment with MOD000001 also inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) reactions in mice. However, histological analysis indicated that the drug blocked skin MC degranulation but did not induce MC depletion. Subsequent

experiments demonstrated that depletion of MCs in multiple organs required much longer (7 weeks) duration of treatment (Nakamura et al., 2024). Whether the drug can also inhibit MC bearing activating KIT mutations has not yet been reported. The company Alivexis has now developed one TKI named MDI-0238, related to MOD000001, which they intend to test in MC-driven inflammatory diseases. It will be interesting to see whether this more targeted TKI induces less side effects as compared to other TKIs, and demonstrates efficacy at depleting MCs in human.

4.4.2. Anti-KIT mAbs

Given the lack of selectivity of most TKIs, several laboratories have developed mAbs to more specifically target and block KIT for MC depletion. Some of these mAbs have now started to be tested in clinical trials, mainly for chronic urticaria, with very promising initial results.

4.4.2.1. Barzolvolimab (CDX-0159). Homotypic interactions between the fourth and fifth Ig-like domains of KIT (D4 and D5) are very important for receptor activation (Yuzawa et al., 2007) (Fig. 2). Several mAbs were designed to target the epitope that mediates D4 dimerization, and were found to inhibit KIT activation and SCF-mediated cell proliferation (Reshetnyak et al., 2013). Among these, CDX-0158 (previously KTN-0158) is a humanized IgG1 anti-KIT mAb that binds the D4 domain of canine, feline, monkey and human (but not rodent) KIT. This mAb was first tested in dogs with spontaneous MC tumors, where it was well tolerated and reduced cutaneous MC numbers in a dose-dependent manner (London et al., 2017). CDX-0158 was then tested in a phase 1 study in patients with KIT⁺ solid tumors (NCT02642016). Unfortunately, significant (grade 2 and grade 3) infusion reactions were observed shortly after mAb infusion. These were clearly related to MC activation, since rapid increases in circulating serum tryptase levels were observed (Alvarado et al., 2022).

In vitro experiments strongly suggested that such adverse events could be link to clustering of IgG Fcγ receptors (FcγRs) by the Fc portion of CDX-0158 (L'Italien et al., 2018). In support to this, engagement of FcγRs by IgG has been shown to induce MC- and histamine-dependent anaphylaxis in mouse models (Khodoun et al., 2025). In order to avoid this, a novel mAb developed by Celldex Therapeutics and named Barzolvolimab (CDX-0159) was engineered from the same CDX-0158 clone. This mAb contained several mutations in its Fc portions: L234A/L235Q/K322Q to reduce binding to both FcγRs and complement C1q, and thus avoid ADCC, ADCP and CDC and the risk of MC activation due to clustering of FcγRs (as observed with CDX-0158); and M252Y/S254T/T256E to enhance affinity for FcRn and thereby reduces clearance of the mAb (since binding of IgG to FcRn leads to antibody recycling and protection from endosomal degradation) (Alvarado et al., 2022). Indeed, no sign of MC activation were observed upon infusion of Barzolvolimab in healthy volunteers, and the half-life for the mAb was approximately five-fold longer than that for CDX-0158 (Alvarado et al., 2022). Importantly, a single i.v. injection of Barzolvolimab markedly reduced tryptase levels for up to 18 weeks at the highest dose tested (9 mg/kg) (Alvarado et al., 2022). In a subsequent phase 1b trial in patients with antihistamine refractory chronic inducible urticaria (CIndU) (NCT04548869), a single i.v. dose of Barzolvolimab (3 mg/kg) also reduced tryptase levels and resulted in significant depletion of skin MCs. Complete responses (negative provocation test) were observed in 19 out of 20 patients, and all patients showed improvement in urticaria control (Terhorst-Molawi et al., 2023). The mAb was well tolerated but induced some side effects consistent with KIT inhibition outside of the MC lineage, including hair depigmentation (most likely due to a blockade of KIT on melanocytes (Grichnik et al., 1996)), taste changes (which could be due to effects of the mAb on KIT⁺ taste cells (Choo & Dando, 2020)), and decreases in hematological parameters that were asymptomatic and reversible (Terhorst-Molawi et al., 2023). Barzolvolimab was then tested in a phase 2 trial in CSU patients and demonstrated significant improvement
of disease activity (Maurer, Kobielusz-Gembala, et al., 2024). Celldex Therapeutics has now initiated two large phase 3 trials for CSU (NCT06455202 and NCT06445023), as well as trials in other diseases in which MCs are thought to play an important role, including prurigo nodularis (NCT06366750), eosinophilic esophagitis (NCT05774184), and atopic dermatitis (NCT06727552).

4.4.2.2. Anti-KIT ADC (LOP628). A KIT targeted antibody drug conjugate (ADC) named LOP628 was developed by Novartis. LOP6288 is formed from the anti-KIT mAb clone LMJ729 in which mertansine was conjugated using a succinimidyl 4-(*N*-maleimidomethyl) cyclohexanecarboxylate (SMCC) linker. LOP628 was shown to be rapidly internalized upon binding to KIT, but does not block the receptor. The mertansine payload, a maytansinoid, binds to tubulin and prevents microtubules formation thus limiting mitosis needed for cell-division and proliferation (Abrams et al., 2018). Although not directly tested for its ability to deplete MCs, LOP628 exhibited potent antiproliferative activity on KIT⁺ cell lines, whereas LMJ729 displayed little to no effect (implying that the effect was due to internalization of the drug payload). LOP628 was also effective at kill tumor cell lines in preclinical exenograft mouse models, and gave a favorable safety profile when tested in non-human primates (cynomolgus monkeys) (Abrams et al., 2018). However, the development of this mAb was discontinued as a result of rapid hypersensitive reactions in three patients with gastrointestinal stromal tumors (GIST) enrolled in phase I clinical trial (NCT02221505). Similarly to the adverse effects observed with CDX-0159 (the parental unmutated version of Barzolvolimab described in part 5.2.1), transient increases in serum tryptase levels were observed shortly after injection of the mAb, indicative of systemic MC degranulation. Indeed, LOP628 and its parental antibody LMJ729 induced dose-dependent degranulation of primary MCs in vitro. Such effects were likely due, at least in part, to engagement of FcγRs, since an Fc silent version of LMJ729 (N297A) displayed reduced (but still significant) MC activation (L'Italien et al., 2018).

4.4.2.3. *Biriquilimab*. Biriquilimab (JSP191 or previously AMG191) is an aglycosylated (Fc silent) anti-KIT antibody that blocks SCF binding to the KIT receptor, developed by Jasper therapeutics. The mAb was initially developed for its ability to deplete endogenous KIT⁺ hematopoietic stem cells and thus create space permitting hematopoietic cell transplantation (Gandhi et al., 2023; Kwon et al., 2019; Pang et al., 2019). However, the mAb is now also regarded as a potential drug for MC-driven diseases. Indeed, it has been shown to deplete MCs in a chimeric human-mouse KIT receptor mouse model, and can protect from IgE mediated anaphylaxis (Chang et al., 2023). Biriquilimab also efficiently depleted MCs in non-human primates (Lee et al., 2024). The mAb is now being tested in several ongoing phase 1/2 trials for chronic inducible or spontaneous urticaria (NCT06353971, NCT06736262 and NCT06162728), and in a phase 1 trial in patients with allergic asthma (NCT06592768).

## 5. Concluding remarks

It is an exciting time for the field of MC biology with several drugs targeting these cells at various stages of preclinical or clinical development. Very encouraging results have already been obtained in early trials with some of these drugs, and will now need to be confirmed in larger studies. However, the lack of clinical efficacy of an anti-tryptase mAb in asthma, or that of an anti-Siglec-8 or anti-Siglec-6 mAbs in atopic dermatitis and chronic urticaria also illustrates once more the difficulty to translate preclinical data into the clinic.

None of the drugs developed to date should be considered entirely MC specific, and thus the extent to which their efficacy reflects direct effects on MC or MC-derived products remains to be fully understood. Recent single-cell RNA sequencing datasets have revealed an unexpected level of transcriptomic heterogeneity among MC populations

within and between organs (Tauber et al., 2023). While such heterogeneity increases the challenge to develop "universal" MC therapies, it also opens new avenues for the development of future drugs targeting specific MC populations.

Clinical results obtained with MC depleting anti-KIT mAbs in chronic urticaria are very encouraging, with rapid and pronounced reduction of symptoms. These mAbs seem to induce a profound MC deficiency, as observed in skin biopsies and further illustrated by a pronounced reduction in serum tryptase. MC depleting mAbs have so far only been evaluated in urticaria. However, it is tempting to speculate that such drugs would likely demonstrate important clinical benefit in other MC-dependent diseases, including asthma and food allergy.

However, while MCs are best known for their detrimental role in allergic diseases and urticaria, results obtained in mice indicate that MCs also play important protective functions, including in host defense against intestinal parasites and various venoms (Mukai et al., 2016). Thus, the impact of long-term MC inactivation or depletion in human will have to be carefully evaluated.

## CRediT authorship contribution statement

**William P.M. Worrall:** Writing – review & editing, Writing – original draft. **Laurent L. Reber:** Writing – review & editing, Writing – original draft, Supervision.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: (William Worrall reports financial support was provided by French foundation for Cancer Research (ARC). Laurent Reber reports a relationship with French National Research Agency that includes: funding grants. Laurent Reber reports a relationship with European Research Council that includes: funding grants. Laurent Reber reports a relationship with Néovacs SA that includes: employment and funding grants. Laurent Reber reports a relationship with CEVA Animal Health that includes: consulting or advisory. Laurent Reber reports a relationship with argenx BV that includes: consulting or advisory and funding grants. Laurent Reber reports a relationship with Novartis that includes: consulting or advisory. Laurent Reber has patent #WO2019197607 issued to INSERM. Laurent Reber has patent #WO2022/058571 licensed to Neovacs. Laurent Reber has patent #WO2019/229153 licensed to Neovacs. Laurent Reber has patent #WO2021/219544 issued to Institut Pasteur. Laurent Reber is employed by Néovacs s.a If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.)

## Acknowledgments

We apologize to the many contributors to this field whose work was not cited because of space limitations. W.P.M.W acknowledges support from the Region Occitanie Midi-Pyrénées and the Fondation ARC pour la recherche sur le cancer. L.L.R. acknowledges support from the French ANR (Agence Nationale de la Recherche) grants 'Asthmab' ANR-20-CE15-0026 and 'AllergyVACS2' ANR-24-CE18-6970, and the European Research Council (ERC-2021-CoG 101043749).

## Data availability

No data was used for the research described in the article.

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