Developing an antibody targeting CεmX of mIgE for the treatment of allergic and other IgE-mediated diseases (VAC6P.954)

Abstract

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. Based on its abilities to bind to mIgE with high affinity and to lyse mIgE-expressing B lymphocytes by apoptosis, ADCC, and other cytolytic mechanisms, humanized 4B12 monoclonal antibody (h4B12 mAb) is now under preclinical development. In an allergic asthma animal model employing genetically modified mice that express mIgE containing human CεmX domain, we have demonstrated that mAb 4B12 was effective in reducing antigen-specific IgE, but not immunoglobulins of other isotypes. 4B12 could also markedly alleviate airway hyperresponsiveness (AHR) to inhaled methacholine in those mice. Furthermore, we have demonstrated that h4B12 could inhibit the production of human IgE in mice that had been reconstituted with human PBMCs. We have now developed a transfected CHO cell line capable of producing h4B12 at a high yield in preparation for human clinical trials.