Potent systemic anticancer activity of adenovirally expressed EGFR-selective TRAIL fusion protein.
Previously, we demonstrated potent tumor cell-selective pro-apoptotic activity of scFv425:sTRAIL, a recombinant fusion protein comprised of EGFR-directed antibody fragment (scFv425) genetically fused to human soluble TNF-related apoptosis-inducing ligand (sTRAIL). Here, we report on the promising therapeutic systemic tumoricidal activity of scFv425:sTRAIL when produced by the replication-deficient adenovirus Ad-scFv425:sTRAIL. In vitro treatment of EGFR-positive tumor cells with Ad-scFv425:sTRAIL resulted in the potent induction of apoptosis of not only infected tumor cells, but importantly also of up to 60% of noninfected EGFR-positive tumor cells. A single intraocular injection of Ad-scFv425:sTRAIL in tumor-free nu/nu mice resulted in predominant liver infection and concomitant high blood plasma levels of scFv425:sTRAIL. These mice showed no sign of Ad-scFv425:sTRAIL-related liver toxicity. Identical treatment of mice with established intraperitoneal renal cell carcinoma xenografts resulted in rapid and massive tumor load reduction and subsequent long-term survival. Taken together, adenoviral-mediated in vivo production of scFv425:sTRAIL may be exploitable for systemic treatment of EGFR-positive cancer.
Bremer
Edwin
E
Groningen University Institute for Drug Exploration (GUIDE), Department of Pathology & Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, Groningen, The Netherlands.
van Dam
Gooitzen M
GM
de Bruyn
Marco
M
van Riezen
Manon
M
Dijkstra
Marike
M
Kamps
Gera
G
Helfrich
Wijnand
W
Haisma
Hidde
H
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D066246:ErbB Receptors