Selective depletion of anti-dsDNA long-lived plasma cells with antibody-peptide fusion protein for treatment of SLE 3602

Description Systemic lupus erythematosus (SLE) is driven by secretion of autoantibodies, particularly those specific for double stranded-DNA (dsDNA), by short- or long-lived plasma cells (PCs). Most current SLE treatments are generally immunosuppressive and indirectly decrease short-lived PCs, but new therapies are needed to selectively eliminate pathogenic long-lived PCs while preserving immunity and avoiding side effects. Prior research fusing the model antigen ovalbumin (OVA) with an antibody specific for the PC-specific protein CD138 showed selective depletion of anti-OVA long-lived PCs. We hypothesize that a similar fusion protein between anti-CD138 antibody and a dsDNA peptide mimic can selectively deplete long-lived dsDNA-specific PCs. Upon testing two previously reported peptide mimics, ALW and DWEYS, for their ability 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 with ELISA. We are currently testing in vitro models for antibody- and DWEYS-fused anti-CD138 antibody-mediated depletion prior to in vivo experiments. 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 therapies.