Pemphigus is a rare and debilitating autoimmune blistering disease due to keratinocyte cell-cell detachment (acantholysis). Treatments focus on immune suppression but are often associated with severe side effects, gradual onset of action and clinical relapse; therefore, new and more targeted and non-immunosuppressive therapies are needed to provide rapid, safer and long-lasting responses. Patients’ autoantibodies (PVIgG) are fundamental for initiating the pathomechanisms of pemphigus. Yet, we have recently demonstrated that soluble Fas Ligand (sFasL), that is massively up-regulated and released from keratinocytes upon PVIgG binding, is essential for blister formation. FasL activates caspases, which degrade desmogleins inducing acantholysis. Furthermore, animals that specifically lack sFasL are protected from PVIgG-induced acantholysis. Against this background, we have developed PC111, a new anti-sFasL human IgG4 monoclonal antibody with high affinity to FasL (KD=150 pM) and potent inhibitory activity in human keratinocyte acantholysis assays (IC50 < 0.05 µg/ml). While use of a corresponding mouse antibody against murine FasL blocked blister formation in passive transfer and active pemphigus mouse models, we now confirm protective effects of PC111 in two different ex vivo pemphigus models. Firstly, we induced PV by injecting a bi-specific anti-desmoglein (dsg) 1 and 3 single-chain antibody variable fragment (scFv) in healthy human skin biopsies. A subcutaneous injection of PC111 reduced blister formation up to 50% in a dose dependent manner. Secondly, we induced PV by s.c. injection of purified PVIgG in healthy human skin. Again we demonstrated a very potent inhibitory effect of PC111 in blocking blister formation up to 72hrs. These initial results indicate that PC111 is a promising clinical candidate for the treatment of pemphigus; in vivo confirmation and IND enabling studies are planned.

ESDR028 - PC111, a monoclonal anti-Fas Ligand antibody, blocks blister formation in human pemphigus

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING