Advancements in GVHD Treatment: The Emergence of DWP213388 as a Dual ITK and BTK Inhibitor

The text discusses the development of a new treatment for graft-versus-host disease (GVHD), a serious complication following hematopoietic stem cell transplantation. The condition is marked by heightened T and B cell activity, and current treatments like Ibrutinib and steroids have limited effectiveness due to toxic side effects. A novel dual inhibitor, DWP213388, was created to target both T and B cells without significant off-target effects, aiming to enhance patient survival without severe side effects.

The inhibitor's activity and selectivity were tested through biochemical assays, with target occupancy in human T and B cells measured using an ELISA-based assay. Mouse spleen and thymus tissues were used to determine occupancy after oral administration of DWP213388. Cellular assays were conducted to evaluate the compound's impact on BCR or TCR activation and cytokine secretion. In vitro and in vivo mixed lymphocyte reaction (MLR) assays were performed to assess T cell proliferation.

In a mouse GVHD model, DWP213388 at a dosage of 10 mg/kg improved clinical symptoms and achieved a 100% survival rate, outperforming Ibrutinib. The compound showed substantial occupancy of BTK and ITK and suppressed various T and B cell subsets. A cytomegalovirus (CMV) study indicated that DWP213388 does not compromise the immune response, as it does not reduce the number of NK cells and CD8+ T cells or affect virus elimination.

The results suggest that DWP213388, with its potent pharmacological activity and selectivity against ITK and BTK without affecting EGFR, could be a promising next-generation therapeutic for GVHD, offering improved efficacy and safety.