Figure 6.

BIIB091 blocks B‐cell activation and differentiation into antibody‐secreting and germinal center B cells in vivo. (a) Hierarchically clustered heatmap of splenic B‐cell gene expression profiles in response to in vivo anti‐IgD stimulation of B cells in mice dosed with either vehicle (Veh.) or BIIB091 at indicated doses. IgD signatures were defined as the genes differentially expressed with FDR < 0.01 and absolute log2 fold change > 1.5 in vehicle‐treated IgD‐stimulated versus vehicle‐treated unstimulated B cells. (b) Scatter plots of IgD signature cumulative z‐scores for the upregulated (right) and downregulated (left) IgD signatures versus CD69 protein z‐scores measured in anti‐IgD‐stimulated (+IgD) or unstimulated (−IgD) B cells isolated from individual mice treated with vehicle or BIIB091 at indicated doses. n = 3 or 4/group. (c) Top differentially regulated canonical pathways identified by IPA in anti‐IgD‐treated B cells isolated from mice dosed with BIIB091 at 30 mpk versus vehicle. Positive (orange) and negative (blue) z‐scores indicate the predicted degree of activation or inhibition for that pathway, respectively. (d) Inhibition of NP‐specific IgM relative titres in mice injected intraperitoneally with 30 μg of NP‐Ficoll and dosed for 10 days with vehicle or BIIB091 at indicated doses. Control groups received either vehicle or no treatment (–). Significance established by 1‐way ANOVA (comparison with vehicle group) followed by Dunnett's multiple comparison test. n = 12/treatment group. (e, f) Representative pseudocolor dot plots (e) and quantification (f) of BIIB091 inhibition of splenic germinal center B‐cell formation identified as CD3⁻CD19⁺B220⁺CD38^lowGL7⁺CD95⁺ in mice 8 days after immunisation with sheep red blood cells. Number of animals per group from n = 8 to n = 20. Significance established by 1‐way ANOVA (comparison with vehicle group) followed by Dunnett's multiple comparison test. mpk, mg kg⁻¹; Veh, vehicle; ns, not significant; *P < 0.05; ***P < 0.001.