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THU0006 Novel Changes in B and T-Cell Phenotypes with Belimumab in An Autoantibody Mediated Disease
  1. C. Barrett1,
  2. R.B. Henderson1,
  3. N. Galwey1,
  4. S. Flint2,
  5. A. Gibson1,
  6. C. Savage1
  1. 1GlaxoSmithKline, Stevenage
  2. 2Addenbrookes Hospital, Cambridge, United Kingdom

Abstract

Background Belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus. Belimumab has also been shown to reduce anti-phospholipase A2 receptor (PLA2R) autoantibodies and proteinuria in a mechanistic study in primary membranous nephropathy (PMN)1. Here we report an interim analysis of B and T cell phenotypes in PMN subjects treated with belimumab to further elucidate the mechanism of action in autoantibody mediated disease.

Objectives To characterize changes in B and T lymphocyte phenotypes in PMN patients treated with belimumab, as a comparison with known pharmacodynamic (PD) effects in SLE2, and to assess correlation with anti-PLA2R autoantibody.

Methods 14 anti-PLA2R autoantibody positive PMN patients received 10mg/kg iv belimumab every 4 wks (or 2 wks) for up to 100 wks. 11 of these completed at least 28 wks treatment. Whole blood was collected at baseline, Wks 8, 16 and 28 for analysis of B and T-cell phenotypes by flow cytometry. Serum levels of anti-PLA2R antibodies were measured by ELISA (Euroimmun). Statistical analysis to identify PD-induced changes in lymphocyte subsets was carried out by paired t-test (2 tailed) against baseline.

Correlations between anti-PLA2R antibody and B and T-cell subsets, either at a specific time point or in the linearised trend over time, were calculated using Pearson's correlation coefficient (r).

Results There was a significant reduction (-63%, p=0.002) in absolute numbers of naive B cells (CD19+ CD27-) at Wk 8 which was sustained through to Wk 28. There was a significant increase in absolute numbers of memory B cells (CD19+ CD27+) at Wk 8 (70%, p=0.023) which increased further through to Wk 28. Plasmablasts (or SLE subset, CD19lo CD38hi CD27hi) showed a trend at Wk 8 to decrease (-64%, p=0.20) but with high variance and low cell numbers.

In addition, the expression (mean fluorescence intensity) of BAFF-R (B-cell activating factor receptor) on B-memory cells increased through Wk 28, while expression of TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor) decreased. Activated cells as identified by surface CD95 expression, decreased as a proportion of B-memory cells through Wk 28. No clear trend was seen in T-regulatory or T-activated cells.

There was a significant negative correlation between decrease in absolute numbers of naive B-cells and immunological efficacy defined as level of anti-PLA2R antibody remaining at Wk 28 (r=-0.87, p=0.0005). Correlations were also seen between antibody and changes in proportion of B-memory CD95+ cells.

Conclusions This mechanistic trial of belimumab in PMN has enabled a novel analysis of PD endpoints, confirming but also extending the PD effects previously reported in studies of SLE. Changes in B-cell subsets were associated with improvements in levels of autoantibody in PMN which in turn correlates with proteinuria. Further analysis of longer term anti-PLA2R antibody kinetics as related to early changes in B and T cell phenotypes may also be informative.

  1. Willcocks L, Barrett C, Brenchley P et al. Nephrology Dialysis Transplantation. 2015; 30 (Supplement 3): iii32–iii33.

  2. Stohl W, Hiepe F, Latinis KM et al. Arthritis & Rheumatism. 2012;64(7):2328–2337.

Acknowledgement This study was funded by GSK (study sponsor) (BEL116472, NCT01610492).

Disclosure of Interest C. Barrett Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, R. Henderson Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, N. Galwey Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, S. Flint Grant/research support from: GlaxoSmithKline, A. Gibson Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Savage Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline

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