Background/Purpose: Systemic Lupus Erythematosus (SLE) is characterized by chronic inflammation that can affect various organs.  Hyperactive B cells appear to be key drivers in SLE disease. Although some monoclonal antibody (MAb) therapies targeting B cells have shown positive therapeutic effect, these therapies do not effectively deplete plasma cells or autoantibodies. MEDI-551 is an antibody-dependent cellular cytotoxicity (ADCC)-enhanced, humanized, anti-CD19 MAb. Previous studies demonstrated that MEDI-551 can effectively deplete a broad range of tissue B cells in naïve mice. In immunized mice, MEDI-551 led to depletion of tissue plasma cells and a reduction of serum titers of responding antibodies.  In this study, we examined the ability of MEDI-551 to deplete B cells in the SLE1-huCD19 TG mice and the impact on the autoimmune phenotype.

Methods: SLE1-huCD19 TG mice were given either a single IV dose of MEDI-551 or repeated doses biweekly for up to twelve weeks.  The number of B cells in the blood, spleen and bone marrow (BM) were detected by flow cytometry staining.  In the spleen and bone marrow, the number of antibody secreting cells (ASC) specific for total IgG and IgM as well as anti-dsDNA IgG and IgM were determined by ELIspot.  Serum autoantibody and total immunoglobulin levels were determined by ELISA. 

Results: Aged SLE1-huCD19 TG mice display classical autoimmune symptoms, including antibodies against self antigens and hyper-activation of B and T cells. A single dose of 10mg/kg MEDI-551 led to depletion of 90% of B cells in spleen, BM, and blood at day 7 post injection.  Spleen germinal center B cells and plasma cells (PC) were largely sensitive to MEDI-551, and their numbers were reduced by 72%. BM PC, with numbers 80% less than spleen PC, were not significantly affected. In a follow-up longitudinal study, the SLE1-huCD19 TG mice were given biweekly dosing of MEDI-551 or PBS for up to twelve weeks.  Repeated dosing of MEDI-551 resulted in significant (>90%) and sustained B cell depletion throughout the duration of the experiment. At week 12, spleen ASC were reduced by ≥90%; whereas, only dsDNA IgM BM ASC were reduced (70%).  This reduction in spleen PC was correlated with a 40-80% reduction in autoantibodies specific for dsDNA, histone, and ANA. Total serum immunoglobulins were reduced ~50% compared to control by 12 weeks.

Conclusion: In the autoimmune SLE1-huCD19 TG model, MEDI-551 is able to eliminate naïve as well as activated germinal center B cells and PC in spleen, but spared a majority of BM PC.  MEDI-551 dosing resulted in a robust reduction of autoantibodies, whereas total Ig was moderately reduced. Thus, MEDI-551’s novel ability to remove a broad range of B cells and eliminate most disease-driving autoantibodies in an SLE model warrants continued research.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/medi-551-depletes-a-majority-of-murine-b-cells-and-reduces-serum-titers-of-autoantibodies-in-the-sle1-hucd19-tg-mice/