Potent systemic anticancer activity of adenovirally expressed EGFR-selective TRAIL fusion protein.

Abstract

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.

• Authors: Edwin Bremer, Gooitzen M van Dam, Marco de Bruyn, Manon van Riezen, Marike Dijkstra, Gera Kamps, Wijnand Helfrich, Hidde Haisma
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 16 Issue 12 Pg. 1919-26 (Dec 2008) ISSN: 1525-0024 [Electronic] United States
• PMID: 18813279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Fusion Proteins
• TNF-Related Apoptosis-Inducing Ligand
• ErbB Receptors

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis
• Cells, Cultured
• ErbB Receptors (genetics, metabolism)
• Genetic Therapy
• Humans
• Liver (metabolism)
• Mice
• Mice, Nude
• Neoplasms (genetics, metabolism, pathology)
• Recombinant Fusion Proteins (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Xenograft Model Antitumor Assays