Treatment of pemphigus and other neglected skin conditions with PC111, a human anti-Fas Ligand monoclonal antibody: a potential disease modifier

Background: Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease with high morbidity and mortality, treated mainly with long-term immunosuppressants. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is an acute, life-threatening drug reaction with severe skin and mucosal involvement. No approved therapies currently exist for SJS/TEN. Aim: To demonstrate that the soluble form of Fas ligand (sFasL) is a relevant therapeutic target in both PV and SJS/TEN, and to provide evidence that PC111, a fully human monoclonal antibody against sFasL, is effective in both conditions. Evidence review: In PV, autoantibodies (PVIgG) target desmogleins, leading to blistering via signaling cascades. sFasL, released upon PVIgG binding, contributes to this process by promoting desmoglein degradation and acantholysis. In SJS/TEN, elevated sFasL induces keratinocyte apoptosis, contributing to epidermal detachment. Findings: PC111 blocks acantholysis and blister formation in PV through a local, rapid mechanism, downstream of the immune system, thus differentiating from the currently used immunosuppressive treatments. In SJS/TEN, PC111 prevents keratinocyte apoptosis induced by patient serum and improves ocular symptoms in a mouse model. Its fast action suggests potential for early intervention to halt disease progression. Conclusions: PC111 may act as a disease-modifying agent, promoting long-term remission in PV and preventing progression in early-stage SJS/TEN.