Background and aims Auto-antibodies to nuclear constituents and type I Interferons (IFN) such as IFN-a play key roles in pathogenesis of Systemic Lupus Erythematosus (SLE). Ixazomib, an oral proteasome inhibitor, 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. Proteasome inhibitors like ixazomib that may deplete plasma cells and cellular sources of IFN-a are also attractive for autoimmune diseases like SLE. To investigate the potential of ixazomib the MRL/lpr model was used as it has extensively been shown to replicate many features of SLE.
Methods MRL/lpr animals received oral ixazomib twice a week for 4 weeks.
Results Ixazomib suppressed the time-dependent increase in anti-dsDNA IgG antibodies, resulting in 73% (p<0.01) inhibition of autoantibodies at the end of treatment versus vehicle. In ELISpot assays, ixazomib decreased the number of anti-dsDNA IgG antibody-secreting cells in spleen by 25% (p<0.01). In addition, FACS analysis revealed that ixazomib decreased both splenic plasma cells by 39% (p<0.001) and plasmacytoid dendritic cells (pDCs) by 38% (p<0.01), with treatment.
Conclusions These findings suggest that ixazomib may be an effective agent for treating antibody-mediated diseases such as SLE by depleting both plasma cells the source of pathogenic antibodies and pDCs the main source of type I IFN production.
An ongoing randomised, double-blind phase Ib study is investigating multiple rising doses of Ixazomib (MLN9708) for the treatment of patients with ISN/RPS class III, IV or V lupus nephritis who have not responded adequately to current therapy.
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