Targeted Measles Virus Vector Displaying Echistatin Infects Endothelial Cells via αvβ3 and Leads to Tumor Regression

Abstract

Targeting tumor-associated vascular endothelium by replicationcompetent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin AvB3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin AvB3 on the COOH terminus of the viral attachment (H) protein and rescued the replicationcompetent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 10 6 plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin AvB3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors. (Cancer Res 2005; 65(12): 5292-300)

Characteristics of Oncolytic Vesicular Stomatitis Virus Displaying Tumor-Targeting Ligands

“…To our knowledge, no other successful attempt to display a ligand on a replication-competent VSV has been reported. Since our laboratory has had some success targeting other virus types for the purpose of oncolytic virotherapy (32,43,44), we decided to explore the feasibility of targeting VSV by displaying tumor-targeting ligands on its G protein.…”

“…We also used echistatin, a 49-amino-acid snake venom disintegrin peptide that has very high affinity toward ␣V␤3, ␣5␤1, and ␣IIb␤3 integrins (31) to explore the possibilities of rescuing replication-competent VSV. Previously, echistatin was displayed on oncolytic measles viruses that were subsequently shown to target tumor vasculature (32).…”

Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas

“…Finally, the migratory function of BOECV/ MV-Edm within the tumor must have subsided, most likely because MV-Edm finally overcame the resistance of BOECs to early cell death. Elucidating the mechanisms of intratumoral virus spread and of MV-Edm-induced cell death, and modulating them, such as by arming MVEdm with additional tumor cytotoxic effectors, 11,25,26 will address the challenge of increasing the efficacy of BOEC/ MV-Edm for therapy of gliomas and other tumors.…”

Tumor vascular targeting therapy with viral vectors

“…They developed an Echistatin-targeted measles virus vector (MV-ERV), which binds the ␣ v ␤ 3 integrin receptor with a high affinity , was displayed on the COOH terminal of the viral attachment H protein. 81 …”