MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19

Abstract

Objective: To evaluate treatment with MEDI-551, a humanized anti-human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19).

Methods: Sle1.hCD19-Tg mice were given either a single intravenous dose of MEDI-551 or repeated doses of MEDI-551 biweekly for up to 12 weeks. The numbers of B cells in the blood, spleen, and bone marrow were determined by flow cytometry assay. In the spleen and bone marrow, the number of IgM- and IgG-specific antibody-secreting cells (ASCs) and the number of ASCs specific for anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunospot assay. Serum autoantibody and total immunoglobulin levels were determined by enzyme-linked immunosorbent assay, and levels of inflammatory proteins were tested using a multianalyte profiling platform.

Results: MEDI-551 treatment of Sle1.hCD19-Tg mice resulted in effective and sustained B cell depletion throughout the duration of the experiment. The frequency of IgM and IgG ASCs in the spleen was reduced by ≥90%, whereas in the bone marrow, the total ASC frequency was not changed. Levels of autoantibodies specific for dsDNA as well as antihistone and antinuclear antibodies were each reduced by 40-80%, but total serum immunoglobulin levels were largely unchanged at the end of 12 weeks of treatment.

Conclusion: These findings highlight the ability of MEDI-551 to deplete B cells and ASCs in autoimmune Sle1.hCD19-Tg mice. MEDI-551 treatment resulted in a robust reduction of autoantibodies but had minimal effect on total serum immunoglobulins. Thus, the novel ability of MEDI-551 to remove a broad range of B cells as well as to lower most disease-driving autoantibodies in an autoimmune disease mouse model warrants continued research. Several clinical studies to explore the safety and activity of MEDI-551 in autoantibody-associated autoimmune diseases are ongoing.