Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted Activation.
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Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted Activation. / Samel, Dierk; Muller, Dafne; Gerspach, Jeannette; Assohou-Luty, Constance; Sass, Gabriele; Tiegs, Gisa; Pfizenmaier, Klaus; Wajant, Harald.
In: J BIOL CHEM, Vol. 278, No. 34, 34, 2003, p. 32077-32082.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted Activation.
AU - Samel, Dierk
AU - Muller, Dafne
AU - Gerspach, Jeannette
AU - Assohou-Luty, Constance
AU - Sass, Gabriele
AU - Tiegs, Gisa
AU - Pfizenmaier, Klaus
AU - Wajant, Harald
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Cell Line
KW - Apoptosis
KW - Fas Ligand Protein
KW - Antigens, Surface/metabolism
KW - Membrane Glycoproteins/metabolism
KW - Recombinant Fusion Proteins/metabolism
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Cell Line
KW - Apoptosis
KW - Fas Ligand Protein
KW - Antigens, Surface/metabolism
KW - Membrane Glycoproteins/metabolism
KW - Recombinant Fusion Proteins/metabolism
M3 - SCORING: Journal article
VL - 278
SP - 32077
EP - 32082
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 34
M1 - 34
ER -
