Evaluation of adenovirus vectors containing serotype 35 fibers for tumor targeting.
There is growing evidence from in vitro studies that subgroup B adenoviruses (Ad) can overcome the limitations in safety and tumor transduction efficiency seen with commonly used subgroup C serotype 5-based vectors. In this study, we confirm that the expression level of the B-group Ad receptor, CD46, correlates with the grade of malignancy of cervical cancer in situ. We also demonstrate the in vivo properties of Ad5-based vectors that contain the B-group Ad serotype 35 fiber (Ad5/35) in transgenic mice that express CD46 in a pattern and at a level similar to humans. Upon intravenous and intraperitoneal injection, an Ad5/35 vector did not efficiently transduce normal tissue, but was able to target metastatic or intraperitoneal tumors that express CD46 at levels comparable to human tumors. When an oncolytic Ad5/35-based vector was employed, in both tumor models antitumor effects were observed. Furthermore, injection of Ad5/35 vectors into CD46 transgenic mice caused less innate toxicity than Ad5 vectors. Our data demonstrate that Ad vectors that target CD46 offer advantages over Ad5-based vectors for treatment of cancer.
Ni
S
S
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Gaggar
A
A
Di Paolo
N
N
Li
Z Y
ZY
Liu
Y
Y
Strauss
R
R
Sova
P
P
Morihara
J
J
Feng
Q
Q
Kiviat
N
N
Touré
P
P
Sow
P S
PS
Lieber
A
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D018925:Chemokines / Q000097:blood; D018899:CpG Islands; D016207:Cytokines / Q000097:blood; D019175:DNA Methylation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000628:therapy*; D051603:Recoverin / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D002583:Uterine Cervical Neoplasms / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D051916:Membrane Cofactor Protein; C496731:RCVRN protein, human; D051603:Recoverin