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Published on: January 22, 2019
Barzolvolimab blocks stem cell factor-enhanced IgE activation without inducing apoptosis in KITD816V 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:
KITD816V drives constitutive mast cell (MC) signaling and is central to the pathogenesis of clonal MC activation disorders, including systemic mastocytosis. These conditions may present with severe anaphylaxis despite low KITD816V mutation burden. Because neoplastic MCs may coexpress 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:
We assessed the effects of barzolvolimab on KITD816V-mutated MCs.
Methods:
We established and characterized primary-like human MC models, including isogenic human induced pluripotent stem cell-derived WT and heterozygous KITD816V MCs, peripheral CD34+ stem cell-derived MCs, and HMC-1.2 cell line. Barzolvolimab effects on apoptosis, KIT signaling, and IgE-mediated activation were investigated by flow cytometry, Western blot analysis, and functional degranulation assays.
Results:
Barzolvolimab induced dose-dependent apoptosis and inhibited stem cell factor-induced KIT signaling in WT MCs, but it had no effect on mutant MC viability or signaling. Notably, barzolvolimab effectively suppressed stem cell factor-enhanced IgE-mediated MC activation across all primary-like models, including KITD816V 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:
A functional dissociation between KIT-dependent survival and activation pathways occurs in mutated MCs. Barzolvolimab does not reduce the viability of KIT-mutated MCs, but it effectively suppresses stem cell factor-dependent amplification of IgE-mediated activation, thus supporting its potential as a therapeutic option for symptomatic patients harboring KIT mutations, particularly for the control of mediator-related symptoms.
