title: CXCL12 retargeting of an adenovirus vector to cancer cells using a bispecific adapter.
abstract: Ad vectors are promising delivery vehicles for cancer therapeutic interventions. However, their application is limited by promiscuous tissue tropism and hepatotoxicity. This limitation can be avoided by altering the native tropism of Ads so that they can be redirected to the target cells through alternate cellular receptors. The CXCR4 chemokine receptor belongs to a large superfamily of G-protein-coupled receptors and is known to be upregulated in a wide variety of cancers, including breast cancer and melanoma. These receptors have been associated with cancer cell survival, progression, and metastasis. In the current study, an Ad to cancer cells overexpressing CXCR4 by using a bispecific adapter, sCAR-CXCL12, was retargeted. The sCAR-CXCL12 adapter contained the soluble ectodomain form of the native Ad5 receptor (sCAR), which was fused to a mature human chemokine ligand, CXCL12, through a short peptide linker. A dramatic increase in the infectivity of cancer cells using a targeted Ad vector compared with an untargeted vector was observed. Furthermore, sCAR-CXCL12 attenuated Ad infection of liver ex vivo and in vivo and enhanced Ad vector infection of xenograft tumors implanted in immunodeficient SCID-bg mice. Thus, the sCAR-CXCL12 adapter could be used to retarget Ad vectors to chemokine receptor-positive tumors.
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA.
authors.forename: Samia M
authors.initials: SM
authors.lastname: O'Bryan
authors.affiliation: Departments of Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rivera
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Mathis
keywords: CXCL12; CXCR4; adapter; adenovirus serotype 5; cancer; chemokine receptor; gene therapy; hCAR; human coxsackievirus and adenovirus receptor; retargeting; viral vector