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This article explores the relationship between KIT expression, mast cell abundance and activity, and the Th2-high endotype in asthmatic airways. The study analyzed gene expression data sets from patients with asthma and healthy subjects, finding that patients with asthma had higher KIT expression and a greater abundance of mast cells and Th2 cells compared to controls. Additionally, the study categorized patients into KIT-high and KIT-low groups, finding that the KIT-high group exhibited a higher abundance of mast cells and basophils, increased FcεRI signaling, and correlation with the Th2-high endotype. The findings suggest that KIT or mast cells could be potential therapeutic targets in asthma. However, the study has limitations, such as the use of bronchial epithelial brushing samples and the potential influence of asthma treatments on immune cell abundance. [Extracted from the article]

Abbreviations: CIndU, chronic inducible urticaria; ColdU, cold urticaria; FcR, Fc receptor; Ig, immunoglobulin; KIT, KIT proto-oncogene, receptor tyrosine kinase; MC, mast cell; MRGPRX2, mas-related G protein-coupled receptor-X2; QoL, quality of life; SCF, stem cell factor; SD, symptomatic dermographism. Katie Bitting, Barry Hedgespeth, Lauren C. Ehrhardt-humbert, Greer K. Arthur, Alicia G. Schubert, Peter bradding, Stephen l. Tilley, Glenn Cruse We identify that MS4A6A is expressed in human mast cells and has high sequence homology to Fc RI . These changes were reversed by anti-IL-6 treatment ( I AL i -M + anti-IL-6) and phenocopy by adding rIL-6 alone. [Extracted from the article]

Background: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)‐mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX‐0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose‐dependent plasma tryptase suppression indicative of systemic mast cell ablation. Methods: This is an open‐label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12‐week follow‐up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). Results: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Background: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC‐targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX‐0159, an anti‐KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. Methods: CDX‐0159‐mediated KIT inhibition was tested in vitro using KIT‐expressing immortalized cells and primary human mast cells. CDX‐0159 safety and pharmacokinetics were evaluated in a 13‐week good laboratory practice (GLP)‐compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double‐blinded placebo‐controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX‐0159. Results: CDX‐0159 inhibits SCF‐dependent KIT activation in vitro. Fc modifications in CDX‐0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX‐0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX‐0159 led to dose‐dependent, profound suppression of plasma tryptase, a MC‐specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. Conclusion: CDX‐0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell‐driven disorders. [ABSTRACT FROM AUTHOR]