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