016 PC111, a novel, First In Class, human anti-FasL antibody for the treatment of Pemphigus: a translational study

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, slow onset of action frequent clinical relapses; therefore, innovative non-immunosuppressive therapies needed provide rapid, safer long-lasting responses. Patients’ autoantibodies (PVIgG) fundamental for initiating the pathologic mechanisms pemphigus. We have recently demonstrated that soluble Fas Ligand (sFasL), massively up-regulated released from keratinocytes upon PVIgG binding, essential blister formation. In fact, FasL/Fas binging activates caspases, which degrade desmogleins thus inducing acantholysis. Furthermore, animals specifically lack sFasL protected PVIgG-induced Against this background, we developed PC111, an anti-FasL human IgG4 monoclonal antibody high affinity FasL (KD<500 pM) potent inhibitory activity in acantholysis assays (IC50 < 0.05 μg/ml). While use corresponding mouse against murine blocked formation passive transfer active pemphigus models, now confirm protective effects PC111 two different ex-vivo models. Firstly, subcutaneous injection reduced up 50% dose dependent manner anti-desmoglein 1 3 scFv-induced model. Secondly, very effect blocking These initial results indicate promising candidate treatment To further test efficacy new model, by swapping gene one, be used as platform in-vivo PoC studies.