Pharmacodynamic changes in gene expression observed in two phase 3 trials of BAFF blockade with tabalumab in SLE

Purpose. RNA profiling was performed on 1,760 SLE patients from ILLUMINATE 1 & 2 which studied the anti-BAFF, IgG4 monoclonal antibody, tabalumab, for efficacy in SLE. This study characterized baseline and pharmacodynamic (PD)-induced changes in gene expression from these two cohorts of SLE patients. Methods. Blood was collected at baseline, week (W) 16 and W52. RNA was analyzed using Affymetrix HTA 2.0 microarrays. Serum IgG anti-dsDNA antibodies (abs), C3, C4 and IgG, IgA & IgM were measured and B cells enumerated. Statistical analyses to identify PD-induced gene changes in cohorts receiving 120 mg tabalumab Q2W and Q4W using a mixed effects model. Results. Significant PD changes were observed in Q2W and Q4W arms vs placebo for serum anti-dsDNA abs, C3 & C4, IgG, IgM & IgA, and B cells (p<0.001). Expression changes in 410 genes were identified in tabalumab-treated patients including plasma cell markers, B cell markers, TNF superfamily members, Fc & Fc-like receptors and complement. Baseline elevation of interferon responsive genes (IRG) was associated with elevated anti-dsDNA abs and decreased levels of C3 & C4. B cell number correlated with expression of B cell-associated gene PD changes in B cell and plasma cell genes were observed in both the treatment doses and associated with changes in anti-dsDNA abs, serum Ig and complement levels. Conclusions. Pharmacodynamic changes associated with tabalumab treatment included serum anti-dsDNA abs, C3 & C4, IgG, IgA & IgM, and B cells. Significant changes were observed in 410 genes consistent with BAFF blockade.