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Abstract
Objectives IKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) are susceptibility loci for systemic lupus erythematosus (SLE). The pharmacology of iberdomide (CC-220), a cereblon (CRBN) modulator targeting Ikaros and Aiolos, was studied in SLE patient cells and in a phase 1 healthy volunteer study.
Methods CRBN, IKZF1 and IKZF3 gene expression was measured in peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy volunteers. Ikaros and Aiolos protein levels were measured by Western blot and flow cytometry. Anti-dsDNA and anti-phospholipid autoantibodies were measured in SLE PBMC cultures treated for 7 days with iberdomide. Fifty-six healthy volunteers were randomised to a single dose of iberdomide (0.03–6 mg, n=6 across seven cohorts) or placebo (n=2/cohort). CD19+ B cells, CD3+ T cells and intracellular Aiolos were measured by flow cytometry. Interleukin (IL)-2 and IL-1β production was stimulated with anti-CD3 and lipopolysaccharide, respectively, in an ex vivo whole blood assay.
Results SLE patient PBMCs expressed significantly higher CRBN (1.5-fold), IKZF1 (2.1-fold) and IKZF3 (4.1-fold) mRNA levels compared with healthy volunteers. Iberdomide significantly reduced Ikaros and Aiolos protein levels in B cells, T cells and monocytes. In SLE PBMC cultures, iberdomide inhibited anti-dsDNA and anti-phospholipid autoantibody production (IC50 ≈10 nM). Single doses of iberdomide (0.3–6 mg) in healthy volunteers decreased intracellular Aiolos (minimum mean per cent of baseline: ≈12%–28% (B cells); ≈0%–33% (T cells)), decreased absolute CD19+ B cells, increased IL-2 and decreased IL-1β production ex vivo.
Conclusions These findings demonstrate pharmacodynamic activity of iberdomide and support its further clinical development for the treatment of SLE.
Trial registration number NCT01733875; Results.
- systemic lupus erythematosus
- B cells
- autoantibodies
- autoimmunity
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Footnotes
Handling editor Josef S Smolen
Contributors PHS, YY, LW, JK, GR, MT, MP and RC conceptualised and designed the study. LW and JK conducted the preclinical experiments. PHS, YY, MT, MP and RC planned and conducted the clinical trial. All authors were integral in the interpretation of the results. ZY and LL performed the programming and statistical analysis of the clinical data. PHS, YY, LW, JK and GR prepared the data and the first draft of the manuscript. All authors were involved in critical review of the data as well as drafting and revising the manuscript, and all have approved the final version of the paper to be published.
Funding This study was sponsored by Celgene, Summit, New Jersey, USA.
Competing interests The authors either are, or have been, employees and shareholders of Celgene.
Patient consent Not required.
Ethics approval Schulman Associates IRB
Provenance and peer review Not commissioned; externally peer reviewed.
Presented at This manuscript is based on work previously presented and published as a conference abstract at (a) The American College of Rheumatology Annual Scientific Meeting, San Diego, USA, 26-30 October 2013, and (b) The European League Against Rheumatism Annual European Congress of Rheumatology, Rome, Italy, 10-13 June 2015.