Tu126 - Development of a Novel Beta Cell Targeted Immune Suppressive PD-1 Bispecific Agonist to Treat Type 1 Diabetes

Abstract Text: Type 1 Diabetes (T1D) is an autoimmune disease driven by autoreactive T cells that destroy pancreatic islet -cells. The success of immunosuppressive therapies to preserve pancreatic islets has so far been limited, either due to safety concerns or poor efficacy. Recently, immunomodulatory therapies have emerged, e.g Teplizumab, showing efficacy in delaying onset of T1D. However, developing a tissue-targeted therapeutic approach would be safer.

We have developed a novel, targeted immune-suppressive PD-1 bispecific agonist called ImmTAAI (Immune Modulating Monoclonal-TCR Against Autoimmune Disease) that specifically binds -cells and suppress autoreactive T cells. The molecule is composed of an affinity-enhanced T cell receptor (TCR) specific for the peptide-HLA-A*02 complex of pre-pro-insulin PPI15-24 fused to a PD-1-agonist.
PPI PD-1 agonist ImmTAAI co-localized with ENTPD3-labeled -cells in “ex vivo” pancreas tissue slices of non-diabetic and diabetic donors. Treatment of pancreatic slices from a T1D diabetic donor at onset, resulted in an increase of T cell mobility within the islets suggesting PD-1 ImmTAAI-mediated reduction of -cell-T cell interaction.

In in vitro experiments, -cell bound ImmTAAIs suppressed TCR signaling, increased T cell motility, inhibited cytokine secretion, protected -cell from autoreactive CD8+ T cell and NK cell killing. The molecule does not compete with PD-L1 avoiding impact on natural immune tolerance. Finally, the molecule did not interfere with mixed lymphocyte reaction confirming its sparing systemic immunity.

In conclusion, these features indicate that the tissue-targeted PPI PD-1 agonist ImmTAAI may be an attractive and novel approach to treat T1D, offering improved efficacy and safety over systemically acting therapeutics.