Reduction of serum IgE by depletion of the IgE B cell lineage - a novel approach for the treatment of allergic diseases (140.7)

Abstract Anti-IgE antibody targeting of serum IgE is an efficacious treatment for asthma and other allergic diseases. Currently, therapeutic anti-IgE antibodies neutralize free serum IgE, but do not affect IgE production. We have developed monoclonal antibodies that disrupt IgE production by binding to the M1' domain of human membrane IgE, a 52 amino acid extracellular segment on human IgE-switched B cells and plasmablasts that is not present in serum IgE. Using genetically modified mice that contain the human M1' domain knocked into the mouse IgE locus, we demonstrate that our anti-M1' antibodies reduce serum IgE and IgE plasma cells, but not other immunoglobulin isotypes, in vivo. Anti-M1' antibodies are effective when delivered prophylactically and therapeutically in mouse immunization, asthma, and Nippostrongylus infection models. Moreover, the anti-M1' antibodies are active on primary human cells in vivo, reducing serum IgE and IgE plasma cells in a human PBMC-SCID mouse model. In vitro and in vivo studies indicate that anti-M1' antibodies trigger apoptosis of IgE B cells and may therefore abolish IgE memory. Anti-M1' targeting of IgE B cells is a promising new therapy for the treatment of asthma and allergy.