Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors

• Published in: Gene therapy Vol. 12; no. 13; pp. 1042 - 1048
• Main Authors: EVERTS, M, KIM-PARK, S.-A, PREUSS, M. A, PASSINEAU, M. J, GLASGOW, J. N, PEREBOEV, A. V, MAHASRESHTI, P. J, GRIZZLE, W. E, REYNOLDS, P. N, CURIEL, D. T
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.07.2005
• Subjects: Adenoviridae - genetics; Adenovirus; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Antigen (tumor-associated); Antigens; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; Carcinoembryonic antigen; Carcinoembryonic Antigen - genetics; Expression vectors; Extracellular Matrix Proteins; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Targeting - methods; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health. Pharmaceutical industry; Immunohistochemistry - methods; Industrial applications and implications. Economical aspects; Liver; Liver - metabolism; Localization; Luciferases - genetics; Medical sciences; Mice; Mice, Transgenic; Myosin Heavy Chains; Nonmuscle Myosin Type IIB; Promoter Regions, Genetic; Proteins - genetics; Pulmonary Circulation - physiology; Receptors, Virus - genetics; Reporter gene; Transcription; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transgenic animals; Transgenic mice; Tumor markers; Tumors; Vascular Endothelial Growth Factor Receptor-1; Virus; tumor-associated antigens; Adenoviridae; Tumor associated antigen; Targeting; Induction; adenovirus; cancer; Malignant tumor; Gene therapy; Vector; Vascularization
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302491

Targeted therapies directed to tumor-associated antigens are being investigated for the treatment of cancer. However, there are few suitable animal models for testing the ability to target these tumor markers. Therefore, we have exploited mice transgenic for the human coxsackie and adenovirus receptor (hCAR) to establish a new model for transient expression of human tumor-associated antigens in the pulmonary vasculature. Systemic administration of Ad in hCAR mice resulted in an increase in transgene expression in the lungs compared to wild-type mice, as determined using a luciferase reporter gene. To reduce transgene expression in the liver, the predominant organ of ectopic Ad localization and transgene expression following systemic administration, we utilized the endothelial-specific flt-1 promoter, which resulted in a further increased lung-to-liver ratio of luciferase expression. Administration of an adenoviral vector encoding the tumor-associated antigen carcinoembryonic antigen (CEA) under transcriptional control of the flt-1 promoter resulted in selective expression of this antigen in the pulmonary vasculature of hCAR mice. Feasibility of targeting to expressed CEA was subsequently demonstrated using adenoviral vectors preincubated with a bifunctional adapter molecule recognizing this tumor-associated antigen, thus demonstrating utility of this transient transgenic animal model.