Abstract
The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients.
Highlights
Oncolytic viruses (OVs) are a clinically proven anticancer immunotherapy that can cause tumor debulking by selective killing of tumor cells [1]
Vaccine strains of the measles virus (MeV) have been shown to be promising anti-cancer agents because of the frequent overexpression of the host-cell receptor CD46 in human malignancies
Heterologous combinations of wild-type canine distemper virus (CDV) glycoproteins result in enhanced cell membrane fusion
Summary
Oncolytic viruses (OVs) are a clinically proven anticancer immunotherapy that can cause tumor debulking by selective killing of tumor cells (known as oncolysis) [1]. The vaccine lineage of the measles virus (MeV) is one of the most extensively investigated OVs that targets tumor cells by selectively binding to the membrane cofactor protein CD46 (MCP/CD46), frequently overexpressed in malignant tumors (https://www.proteinatlas.org/ ENSG00000117335-CD46/pathology). While the cellular receptors for pathogenic MeV are SLAMF1 (CD150) on immune cells and nectin-4 (PVRL4) on epithelial cells [2], vaccine or laboratory-adapted strains of MeV have acquired the ability to use CD46 as a receptor. As well as others, has shown a strong correlation between CD46 expression and the oncolytic potency of vaccine-lineage MeV [5,6], further underscoring the usefulness of this cell-surface protein as a target for OVs. vaccine-lineage MeV is currently being evaluated in clinical trials as a CD46-targeted therapeutic agent for cancer treatment
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