FRI0002 Pharmacodynamic Effects of the CD22-Targeted Monoclonal Antibody Epratuzumab on B Cells in Cynomolgus Monkeys and in Patients with Systemic Lupus Erythematosus

Background 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). Epratuzumab is not a B cell depleting mAb and its mechanism of action involves 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. 1,2 Objectives This analysis aimed to understand the effect of epratuzumab on B cell pharmacodynamics, both in Cynomolgus monkeys and in SLE pts enrolled in the Phase 2b EMBLEM™ study (NCT00624351), and its open-label extension (OLE) SL0008 (NCT00660881). Methods Cynomolgus monkeys (n=10 per group) received 0, 10, 60 or 160mg/kg epratuzumab IV for 5 cycles, where each cycle consisted of 4 once-weekly doses of epratuzumab followed by 4 treatment-free weeks. In EMBLEM™, pts were treated with placebo or 1 of 5 cumulative doses (cd) of epratuzumab (200mg–3600mg cd over the 12-week study; n=37–39 per group). In the OLE, all pts (n=203) received 2400mg cd epratuzumab. Blood samples withdrawn at various time points were analyzed by flow cytometry using a panel of antibodies against cell surface markers (CD19, CD22, CD27, IgD, CD95) in order to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. Results In Cynomolgus monkeys, treatment at all dose levels induced a partial but dose-independent decrease in B cell counts. The maximum decrease in B cell counts (∼50%) was achieved for all dose levels during the second cycle of dosing and did not increase with further cycles of dosing. The B cell decreases were maintained during the treatment-free weeks, but there was evidence for recovery after the last dose. In EMBLEM™ there was a small (10–15%) median decrease in the proportion of naive B cells and a quantitatively similar increase in memory B cell proportions 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 of epratuzumab treatment before stabilizing with no further decrease. There was a rapid decrease (∼80%) of CD22 expression on all B cell subsets, which was maintained throughout the OLE. In vitro data demonstrated a bell-shaped concentration response, suggestive of a requirement for 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. Conclusions Epratuzumab treatment of both Cynomolgus monkeys and SLE pts induced a protracted but defined reduction (∼50%) in the number of peripheral blood B cells over time, although the kinetics were somewhat faster in monkeys. In pts, 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 numbers of an activated memory B cell subset previously shown to be elevated in SLE and increased during lupus flare. 3 References Sieger N. Arth Rheum 2013;65:770. Rossi E. Blood 2013;122:3020. Jacobi A. Arth Rheum 2008;58:1762 Disclosure of Interest A. Shock Employee of: UCB Pharma, B. Kilgallen Employee of: UCB Pharma, W. Koetse Employee of: UCB Pharma, C. Stach Employee of: UCB Pharma, S. Bongardt Employee of: UCB Pharma, C. Galateanu Employee of: UCB Pharma, L. Brackenbury Employee of: KWS Biotest mandated by UCB Pharma for analyses, N. Williams Employee of: KWS Biotest mandated by UCB Pharma for analyses, A. Wolfreys Employee of: UCB Pharma