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. 2020 Apr;34(4):1197-1201.
doi: 10.1038/s41375-019-0620-8. Epub 2019 Nov 12.

Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN

Chad C Bjorklund  1 , Jian Kang  1 , Michael Amatangelo  1 , Ann Polonskaia  1 , Mark Katz  1 , Hsiling Chiu  1 , Suzana Couto  2 , Maria Wang  2 , Yan Ren  2 , Maria Ortiz  3 , Fadi Towfic  1 , J Erin Flynt  1 , William Pierceall  1 , Anjan Thakurta  4
Affiliations

Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN

Chad C Bjorklund et al. Leukemia. 2020 Apr.
No abstract available

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Conflict of interest statement

All authors, except MK are employees of and have equity ownership, except AP in Celgene Corporation.

Figures

Fig. 1
Fig. 1
Iberdomide activity in pomalidomide-resistant cell lines. a Relative cereblon protein (blue bars; left Y-axis) in the pomalidomide-resistant cell lines as determined by densitometry of the Western blots from Supplemental Fig. 3A, normalized to their individual actin loading control and to their parental sensitive counterparts. Represented as % change relative to parental. Overlaid is the relative % proliferation inhibition of iberdomide (iber – 0.1 μM; green bars) on those individual cell lines as determined by 3H-thymidine incorporation. b Western blot analysis showing the effects of either pomalidomide (1 μM) or iberdomide (0.1 μM) on the degradation kinetics of Aiolos in the parental sensitive KMS12BM and pomalidomide-resistant KMS12BM/PR. Actin is shown as a loading control. c PBMC co-culture experiments where isolated, CD3-stimulated PBMCs were incubated with iberdomide (0.0001–1 μM) for 72 h, and then combined with either the parental MM1.S (CFSE-stained) or pomalidomide-resistant MM1.S/PR (CFSE-stained) cells for the final 4 h. CFSE + cells were gated on and evaluated for apoptosis by flow cytometry using Annexin-V and ToPro3+ staining. Bars represent % of viable target cells compared to vehicle control (DMSO). Shown here is the representative of three independent experiments
Fig. 2
Fig. 2
Wide range of cereblon protein expression in the bone marrow of MM patients previously treated with IMiDs. a Dual stained (CD138+ = red and cereblon = brown) immunohistochemical analysis of bone marrow tissue at screening for ten patients in the ongoing clinical study (NCT02773030). b Compiled H-score boxplot analysis (see “Materials and methods”) comparing nuclear, cytoplasmic and total cereblon staining in IHC samples shown in a. c Compiled IHC H-score analysis of ten patients of either Ikaros, Aiolos or ZFP91 on screening and at cycle 2 day 15
See this image and copyright information in PMC

References

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