Selective depletion of anti-dsDNA long-lived plasma cells in SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease driven by secretion of autoantibodies including those specific for double stranded-DNA (dsDNA) by short- or long-lived plasma cells (PCs). Most SLE treatments are generally immunosuppressive and indirectly decrease short-lived PCs. New therapies are needed to selectively eliminate SLE-causing long-lived PCs while preserving immunity and avoiding side effects. Prior research fusing the model antigen ovalbumin (OVA) with an antibody specific for a PC-specific protein, CD138, showed selective depletion of anti-OVA long-lived PCs. We hypothesize that a similar fusion protein comprising anti-CD138 antibody and a dsDNA peptide mimic can selectively deplete long-lived dsDNA-specific PCs. We tested the ability of two previously reported peptide mimics, ALW and DWEYS, to competitively inhibit detection of anti-dsDNA autoantibodies from NZB/NZW mice. We found DWEYS but not ALW inhibited detection. We also validated a method to indirectly measure anti-dsDNA PCs by measuring levels of secreted antibody by ELISA. We then confirmed efficient in vivo CD138 depletion. The next step is to fuse DWEYS with anti-CD138 antibody and test for selective depletion in vitro and in vivo. Successful selective depletion of  anti-dsDNA PCs using a DWEYS/anti-CD138 fusion protein may support its future development as an improved treatment for SLE patients not benefited by current treatments.