011 Targeted inhibition of complement C3 deposition at the basement membrane zone in pemphigoid disease

Autoantibodies against structural proteins of the basement membrane zone (BMZ) cause dermal-epidermal adhesion loss in pemphigoid diseases. Biopsies usually show IgG and C3 at BMZ, indicating complement (C) activation that facilitates attraction inflammatory cells blister formation. We generated 23 anti BP180 antibody (ab) clones from two bullous (BP) patients by phage display. All ab were validated ELISA immunofluorescence (IF). Unexpectedly, our monovalent scFv abs displaced patient immobilized antigen vitro. When injected into human skin organ culture, scFvs non pathogenic, because for pathogenicity bivalent with cross linking C fixing properties are required. As a proof concept we exploited this designing allow targeted inhibition BMZ: An was fused C1s inhibiting domain tested classical pathway an ex vivo assay. Our recombinant molecule bound to normal sections preincubated BP sera efficiently inhibited fixation C5a anaphylatoxin liberation. Another fusion protein designed alternative not effective model, illustrating dependence on BP. Because is expressed BMZ skin, mucous membranes, retina, innovative approach may be translated various dependent diseases affecting these tissues, e.g., pemphigoid, epidermolysis bullosa acquisita, or age related macular degeneration. Alternatively, compound exchanged other pharmaceutically active drugs, allowing delivery broad range membranes.