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Adenovirus Tumor Targeting and Hepatic Untargeting by a Coxsackie/Adenovirus Receptor Ectodomain Anti–Carcinoembryonic Antigen Bispecific Adapter

¹ Departments of Biological Chemistry and Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California and ² Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Harvey R. Herschman, Molecular Biology Institute, University of California at Los Angeles, 341 Boyer Hall, 611 Charles E. Young Drive East, Los Angeles, CA 90095. Phone: 310-825-8735; Fax: 310-825-1447; E-mail: hherschman{at}mednet.ucla.edu.

Adenovirus vectors have a number of advantages for gene therapy. However, because of their lack of tumor tropism and their preference for liver infection following systemic administration, they cannot be used for systemic attack on metastatic disease. Many epithelial tumors (e.g., colon, lung, and breast) express carcinoembryonic antigen (CEA). To block the natural hepatic tropism of adenovirus and to "retarget" the virus to CEA-expressing tumors, we used a bispecific adapter protein (sCAR-MFE), which fuses the ectodomain of the coxsackie/adenovirus receptor (sCAR) with a single-chain anti-CEA antibody (MFE-23). sCAR-MFE untargets adenovirus-directed luciferase transgene expression in the liver by >90% following systemic vector administration. Moreover, sCAR-MFE can "retarget" adenovirus to CEA-positive epithelial tumor cells in cell culture, in s.c. tumor grafts, and in hepatic tumor grafts. The sCAR-MFE bispecific adapter should, therefore, be a powerful agent to retarget adenovirus vectors to epithelial tumor metastases. [Cancer Res 2007;67(11):5354–61]