Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor.
Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46-dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase-type plasminogen activator receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR-retargeted MVs expressing enhanced green fluorescent protein (eGFP) were rescued and characterized. Viral expression of chimeric MV-H was shown by reverse transcription-PCR and Western blot. In vitro viral replication was comparable to MV-GFP control. The receptor and species specificity of MV-uPAs was shown in human and murine cells with different levels of uPAR expression. Removal of the NH(2)-terminal fragment ligand from MV-uPA by factor X(a) treatment ablated the MV-uPA functional activity. Cytotoxicity was shown in uPAR-expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. I.v. administration of MV-h-uPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-m-uPA transduced murine mammary tumors (4T1) in vivo after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as shown by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in a uPAR-dependent manner.
Jing
Yuqi
Y
Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Tong
Caili
C
Zhang
Jin
J
Nakamura
Takafumi
T
Iankov
Ianko
I
Russell
Stephen J
SJ
Merchan
Jaime R
JR
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms; D006224:Cricetinae; D003412:Cricetulus; D017353:Gene Deletion; D000882:Haplorhini; D006801:Humans; D008113:Liver Neoplasms; D008459:Measles virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000502:physiology; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics
D012334:RNA, Neoplasm; D055293:Receptors, Urokinase Plasminogen Activator; D014764:Viral Proteins