Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus
Open accessAbstract
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.
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CC-90009 targets GSPT1 and GSPT2, which are essential regulators of translation termination.
“CC-90009 differs from the other thalidomide analogues in that it targets the substrates G1 to S phase transition protein 1 homologue (GSPT1) and GSPT2, which are also known as eukaryotic peptide chain release factor GTP-binding subunits ERF3A and ERF3B, respectively, reflecting their roles as essential regulators of translation termination113,121.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [121]
Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often a C2H2 zinc finger domain, that binds to a composite thalidomide analogue-CRBN surface.
“Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often in the form of a Cys2-His2 (C2H2) zinc finger domain, that binds to a composite thalidomide analogue–CRBN surface17,117,121,167.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [121]
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- Authors
- Schafer, P. H., Ye, Y., Wu, L., Kosek, J., Ringheim, G., Yang, Z., Liu, L., Thomas, M., Palmisano, M., & Chopra, R.
- Affiliations
- Celgene (United States) (US)
- Institute of Cancer Research (GB)
- Corresponding author
- Schafer, Peter H
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 77
- Issue
- 10
- Pages
- 1516-1523
- ISSN
- 0003-4967 (ISSN-L)
- PMC
- PMC6161670
- OpenAlex
- W2891364583
- Cited by
- 78
- References
- 24
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 14 · 2021: 14 · 2020: 10 · 2019: 8 · 2018: 2
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Celgene
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- iberdomide, Ikaros, Aiolos, IKZF1, IKZF3, systemic lupus erythematosus, immunomodulation, autoantibody production, anti-dsDNA antibodies, antiphospholipid antibodies, B cells, T cells, monocytes, interleukin-2, IL-1β, pharmacodynamics, healthy volunteers
- MeSH terms
- Autoantibodies, Double-Blind Method, Flow Cytometry, Heterocyclic Compounds, 4 or More Rings, Humans, Leukocytes, Mononuclear, Lupus Erythematosus, Systemic, Morpholines, Peptide Hydrolases, Phthalimides, Piperidones, RNA, Messenger, Blotting, Western, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Immunomodulation, Healthy Volunteers
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