Director of Autoimmune Research Immunocore Ltd. Abingdon, England, United Kingdom
Abstract Text: Tissue-restricted immune modulation is a promising approach to overcome many issues associated with current immunosuppressants and provide improved therapies against autoimmune diseases. We recently described targeted PD-1 agonist bispecifics that consist of a high affinity TCR targeting domain fused to a PD-1 agonist moiety to inhibit autoreactive T cells. These molecules, once bound to target cells, activate the PD-1 pathway on interacting T cells and potently inhibit inflammatory cytokine production and cytotoxic activity. Importantly, in the absence of target cell binding, these targeted bispecifics are unable to inhibit T cells. To advance this targeted immune suppressive approach towards the clinic, skin-directed PD-1 agonists are now being engineered to treat T cell driven diseases such as vitiligo and atopic dermatitis. For this, two separate skin targets have been identified and characterized: a novel peptide HLA melanocyte antigen and a highly abundant, HLA-unrestricted target found on skin antigen presenting cells. PD-1 agonist bispecifics engineered against these targets inhibit TCR signaling and inflammatory cytokine release in Jurkat and primary T cells with picomolar potency. Again, the immune suppressive activity of these novel molecules is dependent on target cell binding. Overall, the immune modulating bispecifics described here have the potential to deliver potent, skin-restricted T cell inhibitors that avoid systemic immunosuppression and could benefit patients with dermatological autoimmune or inflammatory diseases.
