Autoantibody-mediated autoimmune diseases, such as bullous pemphigoid (BP), pose a significant clinical burden due to their chronic nature and reliance on broad immunosuppression. BP is caused by autoantibodies targeting structural proteins of the skin, primarily BP180, leading to inflammation and blistering. Current therapies, including corticosteroids and B-cell depletion (e.g., rituximab), often induce remission but are associated with considerable side effects and delayed therapeutic response.

This project investigates a novel, targeted treatment strategy using engineered Fc-fusion proteins called Seldegs (Selective Degraders). Seldegs consist of disease-specific autoantigens (e.g., BP180) fused to modified Fc domains that bind the neonatal Fc receptor (FcRn) in a pH-independent manner. This promotes selective internalization and lysosomal degradation of pathogenic autoantibodies without affecting non-pathogenic IgG.

A BP180-specific Seldeg was successfully developed, expressed, and validated in preliminary work. The aim of this project is to evaluate its therapeutic effect in humanized mouse models expressing human FcRn. Key experiments will determine whether Seldegs can selectively reduce BP180 autoantibody levels in vivo and accelerate disease control compared to conventional therapies. This approach could enable rapid symptom relief, minimize side effects, and potentially alter disease course. Moreover, it provides mechanistic insight into IgG recycling and opens new perspectives for the early, targeted treatment of autoimmune diseases even before clinical onsett