045 Melanocyte-targeted Bispecific PD-1 Agonists as Localized Immune Suppressants against Vitiligo

Vitiligo is an autoimmune skin disease mediated by autoreactive T cells that destroy epidermal melanocytes, causing depigmentation. Current treatments, e.g. corticosteroids or UV light therapy, have limited efficacy with inconsistent repigmentation in many patients. Some emerging therapies, e.g. JAK inhibitors, show promising activity but carry potential systemic safety risks. Tissue-restricted immune modulation is a promising approach to overcome many issues associated with systemic immunosuppressants. In vitiligo, localized suppression of autoreactive CD8 T cells may be achieved by engaging inhibitory receptors on these cells as they attack melanocytes. The PD-1 pathway is a key immune checkpoint that inhibits T cell responses and helps to maintain peripheral tolerance. Blocking this pathway in cancer patients has been shown to cause autoimmune related diseases, including vitiligo. Furthermore, a recent report described defective PD-L1 up-regulation in melanocytes from vitiligo patients, suggesting that PD-1 driven tolerance is impaired in this disease. Therefore, designing melanocyte-targeted PD-1 agonists that trigger this pathway in attacking autoreactive T cells and inhibit their activity is an attractive approach to treat vitiligo. Here we describe targeted PD-1 agonist bispecifics that consist of an affinity enhanced TCR targeting domain specific for a melanocyte pHLA complex, fused to a PD-1 agonist moiety. These novel molecules, once bound to melanocytes, activate the PD-1 pathway on interacting T cells, potently inhibit TCR mediated signalling, suppress T cell activation and inflammatory cytokine production. Importantly, in the absence of target cell binding, these molecules are unable to inhibit T cells. In conclusion, the immune modulating bispecifics described here have the potential to deliver potent melanocyte-restricted T cell inhibitors that avoid systemic immunosuppression and could improve skin repigmentation in vitiligo patients.