title: Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted Activation.
abstract: We describe the construction of a FasL fusion protein devoid of systemic toxicity, inducing apoptosis only on cell-surface antigen-positive cells. The fusion protein consists carboxyl-terminally of the extracellular domain of FasL and amino-terminally of a fibroblast activation protein (FAP)-specific single chain antibody fragment (sc40-FasL). The latter allows immobilization-dependent conversion of the inactive soluble FasL fusion protein into an entity with membrane FasL-like activity. Thus, sc40-FasL efficiently induced apoptosis only in FAP-expressing cells. In accordance with a strict target-selective activity of sc40-FasL, the intravenous application of this reagent in mice revealed no signs of systemic toxicity and prevented growth of xenotransplanted FAP-positive (but not FAP-negative) tumor cells. The principle described here for the first time, in which cell-surface antigen-mediated activation of Fas permits local activation of Fas in vivo, opens novel avenues for the use of Fas signaling in cancer therapy.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Samel
authors.forename: Dafne
authors.initials: D
authors.lastname: Muller
authors.forename: Jeannette
authors.initials: J
authors.lastname: Gerspach
authors.forename: Constance
authors.initials: C
authors.lastname: Assohou-Luty
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins