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A cathepsin-cleavage site between the adenovirus capsid protein IX and a tumor-targeting ligand improves targeted transduction.
MedLine Citation:
PMID:  22011643     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Human adenoviruses have a great potential as anticancer agents. One strategy to improve their tumor-cell specificity and anti-tumor efficacy is to include tumor-specific targeting ligands in the viral capsid. This can be achieved by fusion of polypeptide-targeting ligands with the minor capsid protein IX. Previous research suggested that protein IX-mediated targeting is limited by inefficient release of protein IX-fused ligands from their cognate receptors in the endosome. This thwarts endosomal escape of the virus particles. Here we describe that the targeted transduction of tumor cells is augmented by a cathepsin-cleavage site between the protein IX anchor and the HER2/neu-binding ZH Affibody molecule as ligand. The cathepsin-cleavage site did not interfere with virus production and incorporation of the Affibody molecules in the virus capsid. Virus particles harboring the cleavable protein IX-ligand fusion in their capsid transduced the HER2/neu-positive SKOV-3 ovarian carcinoma cells with increased efficiency in monolayer cultures, three-dimensional spheroid cultures and in SKOV-3 tumors grown on the chorioallantoic membrane of embryonated chicken eggs. These data show that inclusion of a cathepsin-cleavage sequence between protein IX and a high-affinity targeting ligand enhances targeted transduction. This modification further augments the applicability of protein IX as an anchor for coupling tumor-targeting ligands.Gene Therapy advance online publication, 20 October 2011; doi:10.1038/gt.2011.162.
Authors:
J de Vrij; I J C Dautzenberg; S K van den Hengel; M K Magnusson; T G Uil; S J Cramer; J Vellinga; C S Verissimo; L Lindholm; D Koppers-Lalic; R C Hoeben
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-10-20
Journal Detail:
Title:  Gene therapy     Volume:  -     ISSN:  1476-5462     ISO Abbreviation:  -     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421525     Medline TA:  Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
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