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Immunology

PMB702 (Candidate nominating) : Suppressing Th17, Blocking Fibrosis

In our immunology program, we have identified a novel target that is overexpressed in Th17 cells. In animal models of autoimmune and fibrotic diseases, expression of this target increases at disease sites as pathology progresses. Concurrently, there is a rise in Th17-associated proteins, including IL-17, IL-23, RORγt, and GM-CSF. Notably, knockout of this target is non-lethal; knockout animals develop and grow normally. Moreover, these animals exhibit a reduced number of CD4+T cells and decreased expression of the target protein, IL-17, IL-21, IL-23, GM-CSF, STAT3, and RORγt.
Through our research, we have identified lead compounds that inhibit this target enzyme at nanomolar concentrations and block several IBD-related pathways. Mechanistic studies demonstrate that these compounds selectively suppress Th17 cell differentiation without affecting other T cell subsets, such as Th1 cells. Given the central role of Th17 cells in driving autoimmune and fibrotic diseases, we evaluated the efficacy of our lead compounds in animal models of multiple sclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, and IBD. In all models tested, the compounds showed clear therapeutic benefit. In immune cell analysis, the lead PMB702 showed selective suppression of Th17 as expected, and also Th17.1 indicating that it blocks differentiation into more pathogenic subsets of Th17. This mechanism is similar to those of IL-23p19 antibodies. Since PMB702 also block fibrosis lie TL-1A antibodies, we plan to advance our candidate as a novel therapy for IBD, with the dual potential to control both inflammation and fibrosis. We also see strong potential for expanding its use to a broader range of autoimmune and fibrotic conditions.

Immunology Thereapy Strategy

*Modified from a figure of Arch. Immunol. Ther. Exp. (2015) 63:435
Action of PMB702
Effects of PMB702 on the CD4+T cell differentiation to Th1 and Th17
  • Inflammatory Bowel Disease (IBD)
  • Multiple Sclerosis (MS)
  • Psoriasis
  • Rheumatoid Arthritis (RA)
  • Idiopathic pulmonary fibrosis (IPF)