58-LB: ß-Cell Targeted Immune Suppressive PD-1 Bispecific Agonists: A Novel Approach to Treat Type 1 Diabetes

Abstract

The success of immunosuppressive therapies to preserve pancreatic islets and treat Type 1 Diabetes (T1D) has, so far, been limited either due to safety concerns or lack of persistent efficacy. Restricting T cell suppression to the pancreas, thereby avoiding systemic immunosuppression, may overcome these issues and is thus an attractive option for T1D. One possible approach to inhibit the destruction of pancreatic β-cells in T1D is to activate the PD-1 receptor on autoreactive T cells only when they enter in the pancreas. The PD-1 pathway is a key immune checkpoint that limits T cell responses and helps to maintain peripheral tolerance. Blocking this pathway in cancer patients has been shown to cause diabetes-like symptoms. Therefore, stimulating PD-1 to inhibit autoreactive T cells and treat this disease is an appealing concept. To create β-cell-restricted inhibitors of autoreactive T cells, we designed targeted PD-1 agonist bispecific molecules that contain a high affinity TCR specific for a pHLA complex expressed on the surface of pancreatic β-cells. We show that these bispecific molecules bind specifically to immortalized β-cell lines and primary β-cells from disaggregated pancreatic islets. Once bound to target pHLA, these bispecifics engage PD-1 on attacking T cells and inhibit TCR signaling resulting in potent inhibition of T cell effector functions. At picomolar concentrations, these bispecifics suppress secretion of inflammatory cytokines from cytotoxic T cells and inhibit β-cell killing by autoreactive CD8+ T cells. Importantly, these PD-1 agonists are unable to inhibit T cells when free in solution and not bound to target cells. Hence, these immune modulating bispecifics have the potential to limit autoimmunity in pancreatic islets while avoiding systemic immunosuppression. These features make them an attractive and novel platform to treat T1D. Disclosure G. Bossi: Employee; Self; Immunocore Limited. V. Gonzalez: None. C. M. Lucato: None. K. Page: None. N. Smith: Employee; Self; Immunocore Limited. L. Whaley: Employee; Self; Immunocore Limited. H. Ghadbane: Employee; Self; Immunocore Ltd. D. Knight: Employee; Self; Immunocore Limited. E. Henderson: Employee; Self; Immunocore Ltd. S. Hearty: Employee; Self; Immunocore Limited. T. Mahon: None. A. P. Curnock: Employee; Self; Immunocore Ltd. P. Weber: Employee; Self; Immunocore Ltd., Stock/Shareholder; Self; Vertex Pharmaceuticals Incorporated. P. Weber: Employee; Self; Immunocore Ltd., Stock/Shareholder; Self; Vertex Pharmaceuticals Incorporated. J. Kumaran: None. L. J. Bawden: Employee; Self; Immunocore Ltd. R. Figueiredo: None. K. E. Wiseman: None. R. O’dwyer: Employee; Self; Immunocore ltd. D. Overton: None.