ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 820

CC-220: A Clinical Stage Immunomodulatory, Antifibrotic Drug For Systemic Sclerosis

Jörg HW Distler1, Yongqing Wang2, Pawel Zerr3, Katrin Palumbo4, Gerald Horan5, Peter Schafer5 and Bashar Kahaleh6, 1Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Medicine, University of Toledo, Toledo, OH, 3Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 4Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 5Department of Translational Development, Celgene Corporation, Summit, NJ, 6Medicine/Rheumatology, University of Toledo, Toledo, OH

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s-Pathogenesis, Animal Models and Genetics I: Therapeutic Interventions in Preclinical Animal Models of Scleroderma

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic Sclerosis (SSc) is an autoimmune fibrotic disease in which B cells may play a crucial role in pathogenesis. CC-220 is an immunomodulatory drug with antifibrotic activity in early clinical development.  CC-220 binds with high affinity to cereblon, part of the DCX (DDB1-CUL4–X-Box) ubiquitin ligase complex, and regulates ubiquitination of target proteins including key regulators of hematopoietic cell differentiation and activation. CC-220-treatment suppresses B cell proliferation, differentiation, Ig secretion, and cytokine production. In addition to its B cell suppressive properties, CC-220 has demonstrated antifibrotic activity both in vitro and in vivo. This combination of B cell suppressive and antifibrotic properties makes CC-220 an intriguing potential therapeutic for SSc. To better characterize its activity, we evaluated CC-220 in primary cells from SSc patients and in mouse models of scleroderma.

Methods: Primary dermal fibroblasts were isolated from both normal volunteers and SSc patients and cultured for 24 hours in presence of CC-220 or vehicle control.  Gene expression was evaluated by quantitative RT-PCR.   Dermal thickening was induced in mice by intradermal injection of bleomycin every other day for 3 weeks. CC-220 was orally administered at 30 mg/kg daily and skin samples were processed for histology, hydroxyproline analysis and quantitative RT-PCR. Tight skin-1 (Tsk) mice were similarly treated for 5 weeks. 

Results: CC-220 had little to no effect on basal or TGFβ-stimulated expression of profibrotic genes in normal fibroblasts.  However, in fibroblasts derived from SSc patients, CC-220 treatment induced a robust, dose-dependent normalization of the expression of key fibrotic mediators including COL1a1, α-SMA, PAI-1, FN and MMP1.  We next wondered if this broad therapeutic effect, specific to the SSc fibroblasts, might be mediated by epigenetic mechanisms, so we measured expression of the DNA methyltransferase, Dnmt1.  Dnmt1 is elevated in SSc fibroblasts, and CC-220 induced a dose-dependent decrease in expression, suggesting that CC-220 may mediate its antifibrotic activity, at least in part, via regulation of epigenetic modifiers. 

To evaluate its antifibrotic potential in vivo,CC-220 was tested in a bleomycin-induced skin fibrosis model and in Tsk mice, a genetic model of scleroderma skin disease.  In the bleomycin model, CC-220 treatment significantly prevented dermal thickening and inhibited expression of profibrotic genes in the skin, including COL1a1 and TGFβ1.  In Tsk mice, CC-220 treatment resulted in highly significant decreases in dermal thickness and in skin collagen content as measured by hydroxyproline.  Gene expression of COL1a1 and CTGF are elevated in the skin of Tsk mice and were significantly decreased by CC-220 treatment. 

Conclusion: CC-220 potently regulates key profibrotic factors and has demonstrated antifibrotic efficacy in vitro and in vivo.  The combined antifibrotic efficacy and B cell suppressive activity make it a promising candidate for treatment of SSc

Disclosure:

J. H. Distler,

Celgene,

2;

Y. Wang,
None;

P. Zerr,
None;

K. Palumbo,
None;

G. Horan,

Celgene,

3;

P. Schafer,

Celgene,

3;

B. Kahaleh,

Celgene,

2.

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