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Abstract Number: 2923

T-Cell Receptor Signaling Inhibition By CC-90005, a Selective Protein Kinase C Theta Antagonist, Reduces Antigen Mediated T-Cell Activation and Arthritis Pathology in the Mouse CIA Model

Garth Ringheim1, Jolanta Kosek1, Lori Capone2, Eun Mi Hur1 and Peter H. Schafer3, 1Inflammation and Immunology Translational Development, Celgene Corporation, Summit, NJ, 2Celgene Corporation, Summit, NJ, 3Department of Translational Development, Celgene Corporation, Summit, NJ

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Arthritis, kinase and mouse model, T cells

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Session Information

Date: Tuesday, November 15, 2016

Title: T Cell Biology and Targets in Autoimmune Disease - Poster Session II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:  PKC-θ is a member of the Ca2+-independent novel PKC subfamily, most abundantly expressed in T-cells, and mediates early antigen recognition signal transduction and cell activation associated with T-cell receptor (TCR) stimulation. Inhibition of PKC-θ by CC-90005, a highly selective and orally active small molecule inhibitor of PKC-θ may provide new therapeutic treatment options for T-cell mediated rheumatic disease indications.

Methods:  Human purified T cell cultures or whole blood samples were pre-treated with CC-90005 (0.1-10 µM) followed by anti-CD3 and anti-CD28 TCR stimulation to assess the impact of PKC-θ inhibition on TCR signal transduction, expression of cell surface activation markers, proliferation, and cytokine production. A collagen-induced arthritis (CIA) model in DBA mice was used to assess the therapeutic potential of CC-90005 in treating rheumatoid disease indications. Drug was given once or twice daily in a prophylactic dosing paradigm starting 1 day before collagen sensitization. Paw swelling was measured and scored throughout a 42 day treatment schedule. Cytokine gene expression, protein levels and circulating C-terminal telopeptide collagen breakdown products (CTX-I, CTX-II) were measured on day 42.

Results:  TCR stimulation in the presence of CC-90005 resulted in the significant inhibition of T-cell activation in a concentration range of 0.3 to 10 μM in purified human T-cell and whole blood cultures. Consistent with PKC-θ being an early step in the activation of T-cells, inhibition by CC-90005 reduced TCR mediated T-cell activation at the level of target engagement (phosphorylated PKC-θ), signal transduction (phosphorylated ERK1/2 and NFkB; IkBα degradation), and cellular function (surface receptor activation marker expression, proliferation, and cytokine production). In the mouse CIA model of arthritis, reduction of clinical scores was observed at 30 and 100 mg/kg BID accompanied by reduced cytokine expression (IL-1β, IL-17 and IL-22) in the ankle joints and a dose related trend towards reduced serum levels of CTX-I and CTX-II.

Conclusion:  CC-90005, a specific inhibitor of PKC-θ, significantly inhibits TCR signal transduction pathways resulting in the inhibition of functional T-cell responses including cell surface activation marker expression, proliferation, and cytokine production. Moreover, inhibition of these T-cell functions showed efficacy in a mouse CIA model of arthritis, suggesting that selective inhibition of PKC-θ is sufficient to provide therapeutic benefit in rheumatologic diseases.


Disclosure: G. Ringheim, Celgene, 3,Celgene, 1; J. Kosek, Celgene, 1,Celgene, 3; L. Capone, Celgene, 1,Celgene, 3; E. M. Hur, Celgene, 1,Celgene, 3; P. H. Schafer, Celgene, 1,Celgene, 3.

To cite this abstract in AMA style:

Ringheim G, Kosek J, Capone L, Hur EM, Schafer PH. T-Cell Receptor Signaling Inhibition By CC-90005, a Selective Protein Kinase C Theta Antagonist, Reduces Antigen Mediated T-Cell Activation and Arthritis Pathology in the Mouse CIA Model [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/t-cell-receptor-signaling-inhibition-by-cc-90005-a-selective-protein-kinase-c-theta-antagonist-reduces-antigen-mediated-t-cell-activation-and-arthritis-pathology-in-the-mouse-cia-model/. Accessed .
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