Inhibition of ITK by Novel SLP76pTYR Targeted Only ITK Signaling and Enhanced Tregs
Facilitates graft-versus-leukemia effect (GVL) while minimizing graft-versus-host disease (GVHD).
Graft versus host disease (GVHD) remains the second leading cause of death following allogeneic hematopoietic stem cell transplant (allo-HCT). In allo-HCT, mature donor T cells in the donor inoculum play a central role in mediating graft-versus-leukemia (GVL) responses against residual leukemia cells that persist after conditioning regimens and also in facilitating donor immune reconstitution. However, the same donor cell population that mediates the GVL effect also causes significant GVHD. Despite decades of research and improvements in post-transplant immunosuppressive therapies, GVHD remains a significant cause of morbidity and mortality in allo-HCT recipients. Current treatments to suppress GVHD following allo-HCT involve general immunosuppressive agents, such as cyclosporine A, that block donor T Cell Receptor (TCR)-mediated signaling and hence, general T cell activation. However, these agents can simultaneously inhibit GVL effects, increasing the chance of relapse and higher mortality.
This SUNY Upstate Medical University technology is a novel inhibitor that explicitly targets the SLP76-ITK interaction and signaling by preventing the SH2 domain of ITK from docking onto SLP76 at tyrosine 145. This peptide specifically disrupts ITK SH2 docking to pY145 of SLP76, a specific scaffold of interest, without inhibiting its activity or affecting its ability to be involved in other pathways. Disrupting this specific interaction is critical for eliminating GVHD while eliciting the desirable GVL effects during allo-HCT. To ensure this peptide enters cells easily and that its cellular localization can be monitored, it incorporates a C-terminal TAT-peptide and an N-terminal fluorescent FITC dye respectively named SLP76145pTYR peptide. Targeting the SLP76:ITK interaction and its downstream factors significantly suppresses GVHD pathogenesis while maintaining GVL effects in an allo-HSCT.
- Minimal GVHD but maintains GVL activity.
- Significantly reduces production of inflammatory cytokines and migration to GVHD target organs.
- Cancer autoimmunity therapy
- Organ transplants
- Many other potential medical treatments
PCT application filed on 4/9/2021: PCT/US2021/026724
- TRL 4 –in vivo experiments completed
This technology is available for licensing.
This technology could be of significant value to pharmaceutical companies and others involved in the development and application of medical treatments.