Targeted measles virus vector displaying echistatin infects endothelial cells via alpha(v)beta3 and leads to tumor regression.
Targeting tumor-associated vascular endothelium by replication-competent 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 alpha(v)beta3, 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 alpha(v)beta3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent 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 alpha(v)beta3. 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.
Hallak
Louay K
LK
Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
Merchan
Jaime R
JR
Storgard
Chris M
CM
Loftus
Joseph C
JC
Russell
Stephen J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells; D002417:Cattle; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D006224:Cricetinae; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008459:Measles virus / Q000235:genetics*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000098:blood supply / Q000628:therapy / Q000821:virology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000628:therapy / Q000821:virology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism
D015703:Antigens, CD; C497857:CD46 protein, human; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D010455:Peptides; D014764:Viral Proteins; C057986:echistatin