Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

Abstract

Background: In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. Methods: This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. Results: RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC 50 of 2.5 -0.7 nM and PGD 2 production from mast cells with an IC 50 of 8.3 -1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC 50 (RN983) ¼ 59 lg/kg) than the bagonist salbutamol (IC 50 (salbutamol) ¼ 15 lg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC 50 (RN983) ¼ <3 lg/kg) than the inhaled corticosteroid budesonide (IC 50 (budesonide) ¼ 27 lg/kg) in the mouse model of the LAR. Conclusions: Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and b-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

Transcriptomic Signatures and Functional Network Analysis of Chronic Rhinosinusitis With Nasal Polyps

“…Previous studies on the genome-wide gene expression profile of CRSwNP showed increased ALOX5AP gene expression levels in the nasal polyps of patients with aspirin-intolerant asthma (Sekigawa et al, 2009 ) and decreased methylation levels of ALOX5AP in a genome-wide methylation profile of nasal polyps (Cheong et al, 2011 ). BTK, a member of the Tec family of tyrosine kinases, has been indicated to play crucial roles in B cell development and signal transduction downstream of the high-affinity receptor for IgE (FcεR) on mast cells and basophils in an ovalbumin-induced mouse model of asthma (Phillips et al, 2016 ). However, there have been no studies on BTK in chronic nasal diseases.…”

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

“…According to previous studies, immune dysfunction and abnormal expression of inflammation factors are closely associated with capillary bronchial asthma, bronchitis and other infant asthmatic diseases (28)(29)(30). Notably, Li et al (31) have demonstrated that the PKA-dependent NF-κB signaling pathway is a novel target for drug action in asthma therapy.…”

Pulmonary Manifestations of Predominantly Antibody Deficiencies

“…It has been shown to prevent influenza-induced acute lung injury through reduction of pro-inflammatory mediators [52]. Btk inhibitor RN983 showed much more anti-inflammatory potency than corticosteroid budesonide in mouse lung in form of inhalation [53]. This makes it effective in the treatment of allergic asthma.…”