A targeted, high affinity TCR based therapy for the treatment of Type I Diabetes

Despite strong rationale, efforts to generate immunosuppressive therapies that protect pancreatic islets and ameliorate Type I Diabetes (T1D) have not been successful due to either safety concerns or lack of persistent efficacy. To overcome these issues and address the significant unmet need in T1D, we are using our high affinity TCR technology to design a novel targeted therapy that can selectively deliver immunosuppressive effectors (e.g interleukin-2) to pancreatic islets. Such a bi-specific ImmTAAI^TM (Immune Mobilising Monoclonal-TCR Against AutoImmune Disease) molecule will be targeted to the inflamed pancreas of T1D patients, to inhibit the functionality of infiltrating autoreactive T cells and suppress pancreatic b-cell destruction. As a basis for such a targeted therapy, we increased the affinity of a wild-type T cell receptor (TCR), restricted to the HLA-A*02:01 Preproinsulin (PPI) peptide ALWGPDPAAA _(15-24), from micromolar to picomolar levels. We then demonstrated the specificity of this TCR by staining human iPSC-derived b-cells and donor tissue with a biotinylated version of the protein. To further assess specificity, we fused the TCR to a scFv anti-CD3 fragment and tested this construct in the presence of PBMCs against a human iPSC-derived b-cell PPI positive and several negative cell lines. Using in vitro IFN-g ELISpot assay, we demonstrate high specificity of this engineered TCR towards human b-cells and minimal cross-reactivity against antigen negative cells. Furthermore, the high affinity TCR fused to the immunomodulatory molecule Interleukin-2 (IL-2) induces T regulatory cell activation when targeted to human b-cells. By targeting IL-2 molecule to pancreatic islets, we endeavour to enhance T regulatory suppression function at the site of inflammation while avoiding undesired systemic effects. Ultimately, we are aiming to generate novel ImmTAAI^TM therapeutics that can safely and effectively preserve b-cell function in diabetic patients and lead to amelioration of disease.