1. Academic Validation
  2. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor

Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor

  • Blood. 2007 Feb 1;109(3):1156-64. doi: 10.1182/blood-2006-04-019398.
Yumiko Wada 1 Rongzhen Lu Dan Zhou John Chu Teresa Przewloka Shijie Zhang Long Li Yaming Wu June Qin Vishwasenani Balasubramanyam James Barsoum Mitsunori Ono
Affiliations

Affiliation

  • 1 Synta Pharmaceuticals Corp, Lexington, MA 02421, USA. ywada@syntapharma.com
Abstract

The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17-producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T-cell transfer severe combined immunodeficiency (SCID) mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in interferon-gamma (IFN-gamma) production was observed in ex vivo culture of lamina propria cells harvested from Animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA-5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis.

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