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- W4309284017 abstract "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 the BMZ, indicating complement (C) activation that facilitates attraction and activation of inflammatory cells and blister formation. We generated 23 anti BP180 antibody (ab) clones from two bullous pemphigoid (BP) patients by phage display. All ab clones were validated by ELISA and immunofluorescence (IF). Unexpectedly, our monovalent scFv abs displaced patient IgG from immobilized antigen in vitro. When injected into human skin organ culture, anti BP180 scFvs were non pathogenic, because for pathogenicity bivalent abs with cross linking and C fixing properties are required. As a proof of concept we exploited this non pathogenicity by designing proteins that allow targeted C inhibition at the BMZ: An anti BP180 scFv was fused with a C1s inhibiting domain and tested for targeted inhibition of the classical C activation pathway at the BMZ, in an ex vivo assay. Our recombinant molecule bound to normal human skin sections preincubated with BP sera and efficiently inhibited C3 fixation and C5a anaphylatoxin liberation. Another fusion protein designed for targeted inhibition of the alternative pathway was not effective in our model, illustrating the dependence on the classical C activation pathway in human BP. Because BP180 is expressed at the BMZ of skin, mucous membranes, and the retina, this innovative approach may be translated to various C dependent diseases affecting these tissues, e.g., mucous membrane pemphigoid, epidermolysis bullosa acquisita, or age related macular degeneration. Alternatively, the compound domain may be exchanged for other pharmaceutically active drugs, allowing for targeted delivery to the BMZ in a broad range of other diseases of the skin and mucous membranes." @default.
- W4309284017 created "2022-11-25" @default.
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- W4309284017 date "2022-12-01" @default.
- W4309284017 modified "2023-09-25" @default.
- W4309284017 title "011 Targeted inhibition of complement C3 deposition at the basement membrane zone in pemphigoid disease" @default.
- W4309284017 doi "https://doi.org/10.1016/j.jid.2022.09.020" @default.
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