Replacement of adenovirus type 5 fiber shaft heparan sulfate proteoglycan-binding domain with RGD for improved tumor infectivity and targeting.
Tumor targeting on systemic adenovirus administration is key to improve the prospects of adenovirus-mediated gene therapy and virus therapy of cancer. Despite many genetic and ligand conjugation approaches this objective remains elusive. Ablation of human adenovirus type 5 (Ad5) binding to its natural receptors in airway epithelial cells, that is, the coxsackievirus and adenovirus receptor (CAR) and integrins, does not impact on the preeminent liver tropism of adenovirus in the bloodstream. This is explained by a distinct entry pathway mediated by blood factors and heparan sulfates. Mutation of the KKTK heparin sulfate-binding domain of the fiber shaft to GATK results in liver transduction detargeting, but it is not compatible with otherwise useful HI-loop tumor-targeting ligand insertions such as the insertion of Arg-Gly-Asp (RGD). To circumvent this problem we have mutated the KKTK domain to RGDK, and analyzed the liver-detargeting and tumor-targeting transduction properties of this replacement mutant. Similar to RGD at the HI-loop, RGD at this new shaft location efficiently enhances the infectivity of adenovirus and improves the tumor-to-liver transduction ratio in vivo.
Bayo-Puxan
Neus
N
Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)-Institut Català d'Oncologia, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Gimenez-Alejandre
Marta
M
Lavilla-Alonso
Sergio
S
Gros
Alena
A
Cascallo
Manel
M
Hemminki
Akseli
A
Alemany
Ramon
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005822:Genetic Vectors / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000628:therapy* / Q000821:virology*; D009842:Oligopeptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic / Q000235:genetics; D014018:Tissue Distribution; D014161:Transduction, Genetic
D019812:Heparan Sulfate Proteoglycans; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D008156:Luciferases