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Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker
Kah-Whye Peng1, Kathleen A Donovan, Urs Schneider
1Molecular Medicine Program, Mayo Foundation, Rochester, MN 55905, USA. peng.kah@mayo.edu
Abstract:
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 2 critical steps toward generating such a retargeted virus: (1) a new specificity domain against the plasma cell marker CD38 was constructed in the form of a single-chain antibody (scFv) and (2) 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-alpha 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-alpha CD38. In contrast, CHO cells expressing CD38 became susceptible to infection by MV-alpha CD38 but not MV-Edm. Removal of the displayed scFv rendered MV-alpha CD38 noninfectious on CHO-CD38 cells. Tumorigenicity of CHO-CD38 cells in immunocompromised mice was significantly attenuated by MV-alpha CD38, resulting in enhanced survival of these mice compared with the control group.
Insights
Researchers engineered measles virus (MV) to target multiple myeloma cells by adding a CD38-specific antibody. This retargeted virus effectively infected cancer cells while sparing normal cells, showing promise for cancer therapy.
Area of Science:
- Virology
- Oncology
- Immunology
Background:
- Multiple myeloma is a disseminated plasma cell malignancy requiring systemic therapy.
- Current measles virus (MV-Edm) has oncolytic activity but lacks specificity for myeloma cells.
- Targeting viral entry to myeloma cells is crucial to minimize damage to healthy tissues.
Purpose of the Study:
- To retarget measles virus (MV) for specific infection of multiple myeloma cells.
- To engineer a measles virus variant with specificity for the CD38 plasma cell marker.
Main Methods:
- Constructed a single-chain antibody (scFv) targeting CD38.
- Displayed the anti-CD38 scFv on the measles virus hemagglutinin (H) glycoprotein via a cleavable linker.
- Assessed viral replication, infectivity on CD38-expressing cells, and oncolytic efficacy in vivo.
Main Results:
- The modified measles virus (MV-alpha CD38) efficiently incorporated the scFv and replicated comparably to the wild-type virus.
- MV-alpha CD38 specifically infected CD38-expressing cells, while wild-type MV did not infect these cells.
- In vivo studies showed significant attenuation of CD38-expressing tumor cell growth and enhanced survival in mice treated with MV-alpha CD38.
Conclusions:
- Retargeting measles virus with an anti-CD38 scFv successfully redirected viral entry to myeloma-specific targets.
- This engineered virus demonstrates potent oncolytic activity against CD38-positive cancer cells with minimal off-target effects.
- The study provides a promising strategy for developing targeted oncolytic viral therapies for multiple myeloma.