Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors
M Everts1, S-A Kim-Park, M A Preuss
1Division of Human Gene Therapy, Department of Medicine, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294-2172, USA.
Abstract:
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.
Insights
Researchers developed a new transgenic mouse model for transiently expressing human tumor antigens in lung vasculature. This model enables testing targeted cancer therapies by demonstrating selective antigen expression and targeting feasibility.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Targeted cancer therapies require effective animal models for evaluating tumor-associated antigen targeting.
- Existing models are limited for studying transient expression of human tumor antigens in specific vasculature.
Purpose of the Study:
- To establish a novel transgenic mouse model for transient expression of human tumor-associated antigens in the pulmonary vasculature.
- To demonstrate the feasibility of targeting these antigens within the established model.
Main Methods:
- Utilized mice transgenic for the human coxsackie and adenovirus receptor (hCAR) for enhanced adenoviral vector (Ad) transduction.
- Employed the endothelial-specific flt-1 promoter to direct transgene expression to the pulmonary vasculature, improving lung-to-liver expression ratios.
- Administered adenoviral vectors encoding carcinoembryonic antigen (CEA) and tested targeting with bifunctional adapter molecules.
Main Results:
- Systemic Ad administration in hCAR mice showed increased lung transgene expression compared to wild-type mice.
- The flt-1 promoter significantly enhanced the lung-to-liver ratio of transgene expression.
- Selective expression of CEA in pulmonary vasculature was achieved, and targeting feasibility was demonstrated.
Conclusions:
- The developed hCAR transgenic mouse model provides a valuable platform for studying transient expression of tumor-associated antigens in pulmonary vasculature.
- This model facilitates the preclinical evaluation of targeted therapies against tumor markers in a relevant vascular bed.
- The study demonstrates the utility of this transient transgenic model for advancing cancer research and therapeutic development.
