(P148) FIRST-IN-CLASS CLINICAL STAGE DEOXYCYTIDINE KINASE INHIBITOR TRE-515 BLOCKS INFLAMMATORY BOWEL DISEASE SYMPTOMS IN AN ADOPTIVE CD4 T CELL TRANSFER MOUSE MODEL
Associate Professor University of California, Los Angeles Los Angeles, California, United States
Inflammatory bowel disease (IBD) is a challenging disease in need of new treatment options. Current IBD therapies are mostly injectables, broadly immunosuppressive, and rarely obtain long-term disease remission – presenting a significant challenge. Activated and proliferating CD4 T cells are key drivers of IBD with defined roles for TH1, TH2, and TH17 CD4 T cells. Proliferating CD4 T cells require an uninterrupted supply of deoxyribonucleotides (dNTPs) for DNA synthesis. Two complementary pathways can synthesize dNTPs. The de novo pathway converts glucose and amino acids to dNTPs while the faster salvage pathway with rate-limiting enzyme deoxycytidine kinase (dCK) consumes and phosphorylates deoxyribonucleosides from the extracellular space into dNTPs. TRE-515 is an orally taken first-in-human small molecule dCK inhibitor in Phase 1 clinical trials for solid tumors where it has been shown to be well tolerated with on-target antitumor activity. TRE-515 only impacts aberrantly activated immune cells that cause disease, suggesting that it is not strongly immunosuppressive. TRE-515 pharmacodynamics can be monitored by measuring blood levels of the dCK substrate deoxycytidine. We hypothesized that dCK activity is elevated in and required for disease in the adoptive CD4 T cell transfer (ACT) preclinical IBD model, and studied dCK activity and TRE-515 in this model. Mesenteric lymph nodes dCK activity, as measured by PET with the [18F]FAC radiotracer, correlated with IBD disease activity and was significantly elevated at 8 weeks post-cell transfer in the ACT model during severe disease. Treating the ACT mice with TRE-515 starting at disease onset (3 weeks post-cell transfer) led to a significant decrease in the colon weight-to-length ratio, a measure of disease activity, as well as improved histological measures of disease including inflammation, gland loss, and edema. TRE-515-treated mice had lower levels of activated and effector memory CD4+ T cells in the mesenteric lymph nodes. TRE-515 treatments showed significant disease improvement compared to vehicle as well as non-inferiority to the standard-of-care comparator anti-IL-12/IL-23 in all disease scores. To validate our results, we conducted independent testing in another lab. Here, TRE-515 treatment of ACT mice limited weight loss and increased the percent of naïve CD4 T cells in the mesenteric lymph nodes. Our results in a preclinical model suggest that TRE-515 may have efficacy in treating IBD.
