MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum.
Animals
Antibodies, Neutralizing
/ immunology
Distemper Virus, Canine
/ genetics
Female
Hemagglutinins, Viral
/ genetics
Humans
Immune Sera
/ immunology
Measles virus
/ genetics
Membrane Cofactor Protein
/ immunology
Mice
Mice, SCID
Multiple Myeloma
/ genetics
Oncolytic Virotherapy
/ methods
Ovarian Neoplasms
/ genetics
Protein Binding
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
12
06
2020
accepted:
05
01
2021
revised:
16
02
2021
pubmed:
4
2
2021
medline:
24
6
2021
entrez:
3
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33534834
doi: 10.1371/journal.ppat.1009283
pii: PPATHOGENS-D-20-01271
pmc: PMC7886131
doi:
Substances chimiques
Antibodies, Neutralizing
0
CD46 protein, human
0
Hemagglutinins, Viral
0
Immune Sera
0
Membrane Cofactor Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009283Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: The work described here is subjected to a patent application by the Mayo Clinic entitled “Engineering the Hemaglutinin and Fusion Proteins of Canine Distemper Virus” that has been out-licensed. MAM-A and SJR are named inventors. SJR is a founder and equity holder of Vyriad. MAM-A reports honorarium fees from Biomere. The other authors have nothing to declare.
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