Genetically engineered attenuated measles virus specifically infects and kills primary multiple myeloma cells.
The applicability of cytoreductive treatment of malignant diseases using recombinant viruses strongly depends on specific recognition of surface receptors to target exclusively neoplastic cells. A recently generated monoclonal antibody (mAb), Wue-1, specifically detects CD138(+) multiple myeloma (MM) cells. In this study, a haemagglutinin (H) protein that was receptor-blinded (i.e. did not bind to CD46 and CD150) was genetically re-engineered by fusing it to a single-chain antibody fragment (scFv) derived from the Wue-1 mAb open reading frame (scFv-Wue), resulting in the recombinant retargeted measles virus (MV)-Wue. MV-Wue efficiently targeted and fully replicated in primary MM cells, reaching titres similar to those seen with non-retargeted viruses. In agreement with its altered receptor specificity, infection of target cells was no longer dependent on CD150 or CD46, but was restricted to cells that had been labelled with Wue-1 mAb. Importantly, infection with MV-Wue rapidly induced apoptosis in CD138(+) malignant plasma cell targets. MV-Wue is the first fully retargeted MV using the restricted interaction between Wue-1 mAb and primary MM cells specifically to infect, replicate in and deplete malignant plasma cells.
Hummel
Horst-Dieter
HD
Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97078 Würzburg, Germany.
Kuntz
Gabriele
G
Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97078 Würzburg, Germany.
Russell
Stephen J
SJ
Molecular Medicine Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Nakamura
Takafumi
T
Molecular Medicine Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Greiner
Axel
A
Institut für Pathologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
Einsele
Hermann
H
Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97078 Würzburg, Germany.
Topp
Max S
MS
Medizinische Klinik und Poliklinik II, Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97078 Würzburg, Germany.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001854:Bone Marrow Cells; D002522:Chlorocebus aethiops; D005818:Genetic Engineering / Q000379:methods*; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008459:Measles virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D009101:Multiple Myeloma; D010950:Plasma Cells / Q000166:cytology / Q000821:virology*; D053668:Syndecan-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014709:Vero Cells
D000911:Antibodies, Monoclonal; D006389:Hemagglutinins, Viral; D007128:Immunoglobulin Fragments; C508241:SDC1 protein, human; D053668:Syndecan-1