Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted Activation.
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.
Samel
Dierk
D
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
Muller
Dafne
D
Gerspach
Jeannette
J
Assohou-Luty
Constance
C
Sass
Gabriele
G
Tiegs
Gisa
G
Pfizenmaier
Klaus
K
Wajant
Harald
H
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*
D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins