Targeted Delivery of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand To Keratinocytes with A Pemphigus Monoclonal Antibody

We determined the feasibility of using an anti-desmoglein (Dsg) monoclonal antibody, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) to produce Px44TRAIL. We chose TRAIL as a biologic model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44TRAIL caused apoptosis of Jurkat cells and inhibited interferon-γ production by activated CD4+ T cells. Enzyme-linked immunoassay with Px44TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture or human xenografts detected TRAIL on keratinocytes. Px44TRAIL caused apoptosis of hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44TRAIL maintained its stability and biological activity at 37o for at least 48 hr. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative

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Dsg, Desmoglein; GFP, Green fluorescent protein; TRAIL, tumor necrosis factor -related apoptosis-inducing ligand; HNSCC, head and neck squamous cell carcinoma; scFvs, single chain variable fragment antibodies; HA, hemaggultinin

Journal of Investigative Dermatology

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