Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice

Abstract

IgE-mediated hypersensitivity is central to the pathogenesis of asthma and other allergic diseases. Although neutralization of serum IgE with IgE-specific antibodies is in general an efficacious treatment for allergic asthma, one limitation of this approach is its lack of effect on IgE production. Here, we have developed a strategy to disrupt IgE production by generating monoclonal antibodies that target a segment of membrane IgE on human IgE-switched B cells that is not present in serum IgE. This segment is known as the M1′ domain, and using genetically modified mice that contain the human M1′ domain inserted into the mouse IgE locus, we demonstrated that M1′-specific antibodies reduced serum IgE and IgE-producing plasma cells in vivo, without affecting other immunoglobulin isotypes. M1′-specific antibodies were effective when delivered prophylactically and therapeutically in mouse models of immunization, allergic asthma, and Nippostrongylus brasiliensis infection, likely by inducing apoptosis of IgE-producing B cells. In addition, we generated a humanized M1′-specific antibody that was active on primary human cells in vivo, as determined by its reduction of serum IgE levels and IgE plasma cell numbers in a human PBMC-SCID mouse model. Thus, targeting of human IgE-producing B cells with apoptosis-inducing M1′-specific antibodies may be a novel treatment for asthma and allergy.

Application of Microneedles to Skin Induces Activation of Epidermal Langerhans Cells and Dermal Dendritic Cells in Mice

“…In recent years, investigation of vaccine development has broadened to include various diseases such as infectious disease, cancer, neural disease, and allergic disease. [52][53][54] Our findings in the present study provide an incentive to explore the potency of physical techniques for transdermal drug delivery, such as microneedles.…”

Interleukine-33 and Soluble St2 and Their Correlation With Asthma Severity and as Future Therapeutic Targets.

“…IL-33 protein was predominantly expressed by ASMC and epithelial and endothelial cells in asthmatic lungs but was absent in control samples. Thus, IL-33 is expressed by ASMC in asthmatic lungs and shows promise as a potential inflammatory marker for asthma [16] . Soluble ST 2 .…”

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

“…CemX is thought to play a role in determining the outcome of cell signaling, following B cell receptor engagement 16 ; however, its function has not been fully elucidated. Unlike omalizumab that binds to both membrane-bound IgE (mIgE) and free IgE, an anti-CemX antibody targets only mIgE and therefore can target mIgEexpressing B lymphoblasts and memory B cells to downregulate IgE production 17,18 without being neutralized by free IgE. Thus, a therapeutic anti-CemX antibody could potentially be administered less frequently at smaller doses than omalizumab.…”