Developing an antibody targeting CϵmX of mIgE for the treatment of IgE-mediated diseases (HYP4P.305)

Abstract

CϵmX (also referred to as M1’) is a discrete domain of 52 a.a. residues, located between the CH4 domain and the C-terminal membrane anchor peptide of the ϵ heavy chain of membrane-bound IgE (mIgE) on human B lymphocytes. Antibodies that target CϵmX are potentially useful in controlling IgE production for treating allergic and other IgE-mediated diseases. Herein we report that an anti-CϵmX mAb, 4B12, was shown to be effective in reducing allergen-specific IgE and IL-5 production upon the challenge of the allergen in an asthma model employing CϵmX gene knocked-in mice that express mIgE containing human CϵmX domain on B cells. 4B12 could also alleviate airway hyper-responsiveness (AHR), allergen-induced eosinophil infiltration, and lung inflammation in those mice. Furthermore, we demonstrated that a humanized 4B12 mAb (referred to as FB825) could inhibit the production of human IgE in mice that had been reconstituted with human peripheral blood mononuclear cells. Based on the abilities of 4B12 to bind to mIgE and to lyse mIgE-expressing B cells by apoptosis, ADCC, and other cytolytic mechanisms and on the above results on animal models, a phase-I human clinical trial of FB825 to investigate its IgE-related biological effects is being performed.