Establishment of Membrane-Bound IgA1-Specific Antibody Possessing Antibody-Dependent Cellular Cytotoxicity Activity.

Abstract

Therapeutic agents targeting B cells, such as rituximab, have been proven to be effective in several diseases. However, since this therapy targets the whole B cell population, there are still concerns about critical adverse events. Therefore, a new type of antibody that can specifically deplete a particular type of B cell may have the potential to become an efficient and safer therapy. Membrane-bound IgA1 (mIgA1) is expressed on soluble IgA1 (sIgA1) producing B cells and/or their precursor, B cells. Although most of the amino acid sequence in the N-terminal regions of the extracellular domains of mIgA1 and sIgA1 is shared, there is a membrane type-specific region, named the membrane-bound immunoglobulin isotype-specific (migis-α) region, at the membrane-proximal region of mIgA1. We hypothesized that the migis-α region would be a suitable antigen for therapeutic antibodies to target mIgA1-expressing B cells without binding to sIgA1, which may cause undesired adverse effects and poor pharmacokinetics (PK). We established two anti-migis-α monoclonal antibodies (mAbs), KM4641 and KM4644, by immunization of the synthetic peptide corresponding to an migis-α region. These mAbs both showed robust binding to mIgA1-expressing transfectant cells. As we expected, neither mAbs bound to sIgA1 and we found that the mAbs recognized different seven to eight amino acid sequences within the migis-α region. Furthermore, the rat-human chimeric type of both mAbs showed antibody-dependent cellular cytotoxicity against mIgA1-expressing transfectant cells. Taken together, this study showed that established mAbs have therapeutic potential in IgA-related diseases, such as IgA nephropathy.