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Published on: January 22, 2019
Barzolvolimab blocks SCF-enhanced IgE activation without inducing apoptosis in KIT-D816V mast cells
Mengjie Hu1, Jiajun He2, Yanyan Luo1
1Charité - University Medical Center Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Allergology, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
Background:
KIT D816V drives constitutive mast cell (MC) signaling and is central to the pathogenesis of clonal mast cell activation disorders including systemic mastocytosis. These conditions may present with severe anaphylaxis despite low KIT D816V mutation burden. Since neoplastic mast cells may co-express mutant and wild-type (WT) KIT, the functional relevance of ligand-dependent signaling and activation remains incompletely understood. Barzolvolimab has demonstrated efficacy in WT MC-driven diseases, but its effects on KIT-mutated MCs remain unclear.
Objective:
To assess the effects of barzolvolimab on KIT D816V-mutated MCs.
Methods:
We established and characterized primary-like human MC models, including isogenic hiPSC-derived WT and heterozygous KIT D816V MCs, PSC-derived MCs and HMC-1.2 cell line. Barzolvolimab effects on apoptosis, KIT signaling, and IgE-mediated activation were investigated using flow cytometry, Western blotting, and functional degranulation assays.
Results:
Barzolvolimab induced dose-dependent apoptosis and inhibited SCF-induced KIT signaling in WT MCs, but had no effect on mutant MC viability or signaling. Notably, barzolvolimab effectively suppressed SCF-enhanced IgE-mediated MC activation across all primary-like models, including KIT D816V MCs, as evidenced by reduced β-hexosaminidase release and CD63 expression. This inhibitory effect occurred at low nanomolar concentrations and was independent of cytotoxicity.
Conclusions:
Our findings demonstrate a functional dissociation between KIT-dependent survival and activation pathways in mutated MCs. While barzolvolimab does not reduce the viability of KIT-mutated MCs, it effectively suppresses SCF-dependent amplification of IgE-mediated activation, supporting its potential as a therapeutic option for symptomatic patients harboring KIT mutations, particularly for the control of mediator-related symptoms.
