Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors.
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.
Everts
M
M
Division of Human Gene Therapy, Department of Medicine, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294-2172, USA.
Kim-Park
S-A
SA
Preuss
M A
MA
Passineau
M J
MJ
Glasgow
J N
JN
Pereboev
A V
AV
Mahasreshti
P J
PJ
Grizzle
W E
WE
Reynolds
P N
PN
Curiel
D T
DT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D011652:Pulmonary Circulation / Q000502:physiology*; D011991:Receptors, Virus / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1
D002272:Carcinoembryonic Antigen; D016326:Extracellular Matrix Proteins; D011506:Proteins; D011991:Receptors, Virus; C085301:adenovirus receptor; D008156:Luciferases; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains