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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-07-2195.
Submitted July 31, 2002
Accepted November 7, 2002
Oncolytic measles viruses displaying a single chain antibody against CD38, a myeloma cell marker
Kah-Whye Peng*, Kathleen A Donovan, Urs Schneider, Roberto Cattaneo, John A Lust, and Stephen J Russell
Molecular Medicine Program, Mayo Foundation, Rochester, MN, USA
Division of Hematology and Internal Medicine, Mayo Foundation, Rochester, MN, USA
Department of Virology, University of Freiburg, Freiburg, Germany
* Corresponding author; email: peng.kah{at}mayo.edu.
Live attenuated measles virus (MV-Edm) has potent oncolytic activity against myeloma xenografts in mice. Therapy of multiple myeloma, a disseminated plasma cell malignancy, would require systemic administration of the virus. Thus, the virus should ideally be targeted to infect only myeloma cells to minimize collateral damage to normal tissues: viral binding to its natural receptors must be ablated and a new specificity domain that targets entry into myeloma cells be added. This study covers two critical steps towards generating such a retargeted virus: (I) a new specificity domain against the plasma cell marker CD38 was constructed in the form of a single chain antibody (scFv), (II) display of that scFv on the measles viral envelope glycoprotein successfully redirected virus entry through CD38 expressed on target cells devoid of the natural MV receptors. The anti-CD38 scFv was tethered to the C-terminus of the hemagglutinin (H) glycoprotein of MV-Edm through a Factor Xa protease cleavable linker. Immunoblot analysis demonstrated that the scFv was efficiently incorporated into recombinant viral particles. Replication of MV- CD38 was not hindered by the scFv, reaching titers comparable to MV-Edm. Chinese hamster ovary (CHO) cells were resistant to infection by MV-Edm and MV-CD38. In contrast, CHO cells expressing CD38 became susceptible to infection by MV-CD38 but not MV-Edm. Removal of the displayed scFv rendered MV-CD38 non-infectious on CHO-CD38 cells. Tumorigenicity of CHO-CD38 cells in immunocompromised mice was significantly attenuated by MV-CD38, resulting in enhanced survival of these mice compared to the control group.
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