Senior Scientist I Evommune, Inc. Palo Alto, California, United States
Abstract Text: T cell mediated inflammatory diseases (TMDs) constitute a diverse group of illnesses in which an uncontrolled immune response damages self-tissue. Patients diagnosed with TMDs such as atopic dermatitis, psoriasis, and inflammatory bowel disease generally respond well to broad immunosuppressants. However, these therapeutics often come with significant side effects, highlighting the need for more targeted approaches. The Protein Kinase C – theta isoform (PKCt), which is expressed nearly exclusively in T cells, represents an attractive T cell restricted target for pharmaceutical intervention. Here we report results from both in vitro and in vivo studies of novel small molecule inhibitors (SMIs) which are highly specific for PKCt. Using primary human PBMCs in in vitro models of T cell activation, our SMIs potently inhibited T cell activation, without affecting cellular viability. Similarly, in in vitro models of whole primary human skin biopsies, tissue resident T cells also failed to activate after PKCt inhibition. Furthermore, in vivo studies in mice demonstrated dose-dependent inhibition of inflammation after oral administration of SMIs highly specific for PKCt, including an oxazolone-induced model of atopic dermatitis and a SCID mouse T-cell transfer colitis model. These data suggest that a highly specific SMI for PKCt could have utility in the treatment of T-cell mediated inflammatory diseases.
