Background/Purpose: Systemic lupus erythematosus (SLE) is characterized by expanded antibody secreting cells (ASCs) and the production of a variety of autoantibodies. Depletion of B cells by the anti-CD20 monoclonal antibody, Rituximab, has been widely used in autoimmune disease therapy. However, ASCs express low levels of CD20 and are poorly targeted. In this study, we examined the ability of TAK-079, a monoclonal against CD38 which is expressed at high levels by ASCs, to inhibit antibody production.

Methods: TAK-079 was provided by Takeda California, in collaboration with XOMA Corporation. Mononuclear cells were isolated from bone marrow aspirates or blood from healthy control (HC) and SLE patients. B cell subset frequencies were measured by flow cytometry following ex vivo depletion with TAK-079. To determine the frequency of ASCs, ELISpot was used to enumerate total IgG-producing and autoantigen specific cells. In some cultures NK cells were added to purified B cells to effect target cell killing.

Results: The addition of TAK-079 in vitro depleted 80% of plasma cell populations, which were characterized by the expression of CD27, CD38, and CD138 using flow cytometry. More importantly, with intracellular staining, cells positive for plasma cell markers BLIMP1 and IRF4, were also significantly reduced. Furthermore, TAK-079 depleted both short-lived plasma cells (CD19+ plasma cells), and long-lived plasma cells (CD19- plasma cells) from bone marrow. ASCs measured directly by ELISpot were also reduced in both HC and SLE patient samples. In HC samples, with TAK-079 treatment there was 70% reduction in the number of IgG producing cells from both blood samples and bone marrow samples. Similar depletion was seen in SLE patient samples. Additionally, the number of cells producing autoantigen specific antibodies was also dramatically reduced, including: VH4-34 9G4+ antibodies (70% reduction), anti-Ro antibody (70% reduction), and anti-dsDNA antibody (80% reduction). We elucidated the mechanism of plasma cell depletion and found that antibody-dependent cell-mediated cytotoxicity (ADCC) is an essential mechanism of plasma cell lysis in vitro by TAK-079. Purified B cells alone were unaffected by TAK-079 mAb, whereas addition of NK cells elicited TAK-079 dependent depletion of ASCs.

Conclusion: Our results highlight the potential of TAK-079 monoclonal antibody for treating SLE via plasma cell depletion. By targeting CD38, a molecule highly expressed on all plasma cells, TAK-079 effectively depleted both short lived and long-lived ASCs. Furthermore SLE ASCs producing antibodies against self-antigens were also efficiently depleted through NK cell and TAK-079 mediated ADCC in vitro.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-anti-cd38-monoclonal-antibody-tak-079-depletes-antibody-secreting-cells-from-normal-and-sle-patients/