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FRI0002 Pharmacodynamic Effects of the CD22-Targeted Monoclonal Antibody Epratuzumab on B Cells in Cynomolgus Monkeys and in Patients with Systemic Lupus Erythematosus
  1. A. Shock1,
  2. B. Kilgallen2,
  3. W. Koetse2,
  4. C. Stach3,
  5. S. Bongardt3,
  6. C. Galateanu4,
  7. L. Brackenbury5,
  8. N. Williams5,
  9. A. Wolfreys1
  1. 1UCB Pharma, Slough, United Kingdom
  2. 2UCB Pharma, Raleigh, United States
  3. 3UCB Pharma, Monheim, Germany
  4. 4UCB Pharma, Brussels, Belgium
  5. 5KWS Biotest, Bristol, United Kingdom

Abstract

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 Blood samples withdrawn at various time points were analyzed by flow cytometry using a panel of antibodies against cell surface markers (CD19, CD22, CD27, IgD, CD95) in order to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 naïve 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

  1. Sieger N. Arth Rheum 2013;65:770.

  2. Rossi E. Blood 2013;122:3020.

  3. 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

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