Session Type: Abstract Submissions (ACR)
Epratuzumab is a humanized monoclonal antibody (mAb) that targets the B cell-specific protein CD22 and is currently in Phase 3 clinical trials in patients (pts) with systemic lupus erythematosus (SLE). The mechanism of action of epratuzumab appears to involve immunomodulation of B cells, for example by inducing loss of B Cell Receptor (BCR)-related proteins from the cell surface, and inhibiting signaling through the BCR. The present analysis aimed to understand the effect of epratuzumab on B cells in SLE pts enrolled in the Phase 2b EMBLEM™ study (NCT00624351), and its open label extension (OLE), SL0008 (NCT00660881), in which epratuzumab produced clinically relevant, sustained improvements in disease activity in pts with moderate-to-severe SLE.1–3
In EMBLEM™, pts were treated with placebo or 1 of 5 cumulative doses (cd) of epratuzumab (200mg–3600mg cd over the 12-week [wk] study). In the OLE, all pts received 2400mg cd epratuzumab (1200mg at Wks 0 and 2 of repeating 12-wk cycles). Blood samples withdrawn at various time points were analyzed by flow cytometry using a panel of antibodies against cell surface markers (CD19, CD22, CD27, IgD, CD95) in order to identify B cell subsets; CD22 expression was monitored using S-HCL-1, a non-competing anti-CD22 mAb.
In EMBLEM™ there was a small (10–15%) median decrease in the numbers of CD22+ naïve B cells and a quantitatively similar increase in CD22+ memory B cells in pts treated with epratuzumab but not placebo, which did not appear to be dose-dependent. During OLE, total B cell numbers continued to decline, reaching a median decrease of 50–60% after 9–12 months epratuzumab treatment before stabilizing with no further decrease. There was a rapid decrease (~80%) of CD22 expression on naïve, memory and transitional B cell subsets demonstrated at the first time point assessed (1 week) in the epratuzumab treatment groups (no changes were observed in the placebo group), which was maintained throughout the OLE. In vitro data demonstrated that this loss occurred primarily through epratuzumab-induced internalization of cell surface CD22. Moreover, the in vitro data demonstrated a bell-shaped concentration response, suggestive of bivalency. Finally, there was a gradual decline in the numbers of CD27-/IgD- B cells expressing CD95 throughout the OLE, from 41% at EMBLEM™ baseline to 27% at OLE Year 2.
Epratuzumab treatment of pts with SLE induced a protracted but defined reduction in the number of peripheral blood B cells over time, reaching a median reduction of 50–60% after 9–12 months treatment. CD22 expression was rapidly lost on all B cell subsets, and the loss maintained throughout the OLE. There was a gradual decline with epratuzumab treatment in the number of CD27-/IgD- B cells expressing CD95, a subset of activated memory B cells previously shown to be elevated in SLE and increased during lupus flare.4
1. Wallace D.J. Ann Rheum Dis 2014;73(1):183-190
2. Clowse M. Arthritis Rheum 2013;65(Suppl10):1738
3. Kalunian K. Arthritis Rheum 2013;65(Suppl10):1739
4. Jacobi A. Arthritis Rheum 2008;58:1762
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacodynamic-effects-of-the-cd22-targeted-monoclonal-antibody-epratuzumab-on-b-cells-in-patients-with-systemic-lupus-erythematosus/