TCRm-PDL1 bi-specific molecule for the treatment of autoimmune diseases

Autoimmune diseases arise due to brakeage of regulatory mechanisms and aberrant pro-inflammatory immune response against self. Though highly effective, current available treatments globally suppress immunity, leaving patients exposed to variety of risks. Consequently, there is a great need for treatments that suppress autoreactive cells, without impairing immune system integrity.

Autoreactive CD4+ T cells activation plays a key event in autoimmunity development and is mediated by the encounter of CD4+ T cells with self-peptide presenting APCs in the context of MHC class II molecules, expressing both co-stimulatory and co-inhibitory molecules. Interaction between autoreactive T cell and co-inhibitory molecules, such as PD-L1, can induce T cell anergy.

Variety of MHC class II molecules are associated with autoimmunity, such as HLA-DR2 in Multiple Sclerosis (MS). Specific blockade of self-peptide/MHC complexes, directed by a high affinity TCRm that mimics TCR:peptide/MHC interaction, can block autoreactive T cell activation and reduce inflammation during an autoimmune disease.

Our study focus on a novel molecule that induces antigen-specific T cell suppression via PD-L1 and is targeted toward the inflamed area in MS. To that end, we constructed a fusion chimeric molecule that is targeted toward (1) MOG/HLA-DR2 epitope, which is expressed on APCs during MS and (2) PD-1 protein, which is expressed on T cells and can induce T cell suppression if targeted by PD-L1. Our results suggests that TCRm-PDL1 bi-specific molecule can specifically target MOG/DR2 expressing APCs and induce autoreactive T cell inhibition in-vitro. We are currently working assessing bi-specific molecule in-vivo activity.