Background and aims Pathogenic auto-antibodies produced by plasma cells are key drivers of many auto-immune diseases such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Sjogren’s Syndrome (SS). In addition, solid organ transplant rejection is also mediated by antibodies produced against the donor organ. Plasma cells are highly metabolically active antibody factories and thus sensitive to depletion by proteasome inhibitors. Ixazomib, an oral proteasome inhibitor, was recently approved in the US and Canada for use in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received at least 1 prior therapy. The Keyhole limpet hemocyanin (KLH) model of T cell-dependent antigen response was used to determine if ixazomib depletes plasma cells resulting in a reduction of antibodies.
Methods Briefly, rats were immunised with KLH and TiterMax adjuvant then treated with ixazomib twice weekly until study termination.
Results Treatment with ixazomib significantly inhibited anti-KLH antibodies by 34% (p<0.05) versus vehicle. Additionally, KLH plasma cells quantified by ELISpot were decreased 78% (p<0.01) in the spleen and 53% (p<0.01) in the bone marrow compared to control. To gain some understanding of the selectivity of plasma cell depletion total White Blood Cells, Red Blood Cells (RBC) Platelets, Neutrophils, and total Lymphocytes were quantified with small a reduction only seen in RBCs and platelets.
Conclusions Ixazomib depleted plasma cells resulting in reduced antibodies suggesting further preclinical studies are warranted in diseases with pathogenic antibodies such as SLE, RA, SS and solid organ transplant rejection.
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