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Publication Number
US-9884080-B2
Publication Date
2018-02-06
Expiration Date
Abstract
The present invention relates to a poxvirus comprising a defective F4L and/or I4L gene, to composition comprising such poxvirus and to the methods and use of such compositions and poxviruses for therapeutic purposes, and more particularly for the treatment of cancer.
Core Innovation
The disclosure describes poxvirus oncolytic vectors engineered to improve safety while retaining oncolytic activity. The recombinant poxvirus consists essentially of a defective I4L gene and/or a defective F4L gene, and a defective J2R gene, and does not comprise a defective vaccinia growth factor gene. The poxvirus is not NYVAC and is oncolytic.
The disclosure addresses oncolytic poxviruses in general and identifies safety and toxicity issues associated with high-dose vaccinia. It further defines relevant viral genes including I4L/R1, F4L/R2, and J2R/TK, and relates defective gene configurations to reduced pathogenicity and virulence.
The disclosure also includes combinations with nucleic acids of interest, including suicide/prodrug-sensitizing systems, and specifically discusses an antitumor strategy using 5-fluorocytosine with an associated suicide gene system (FCU1) in conjunction with the engineered oncolytic poxviruses. Documented findings include replication specificity and tumor-preferential biodistribution, and improved tumor control when paired with the prodrug system.
Claims Coverage
The independent claims cover methods for treating tumors and for reducing cancer by administering an oncolytic recombinant poxvirus defined by a specific combination of defective genes, exclusion of defective vaccinia growth factor gene content, and a proviso excluding NYVAC, for a period of time required to elicit the desired effect. Across the claims, the main inventive features include the defective I4L and/or defective F4L gene(s), defective J2R gene, exclusion of a defective vaccinia growth factor gene, and the requirement that the poxvirus is oncolytic and not NYVAC. Dependent claim refinements include systemic administration and timing/sequencing of prodrug administration relative to poxvirus administration.
Defective I4L and/or defective F4L and defective J2R gene configuration
A recombinant poxvirus consisting essentially of a defective I4L gene and/or a defective F4L gene; and a defective J2R gene.
Exclusion of defective vaccinia growth factor gene content
The recombinant poxvirus does not comprise a defective vaccinia growth factor gene.
Oncolytic poxvirus not NYVAC proviso
With the proviso that said poxvirus is not NYVAC and that said poxvirus is oncolytic.
Treatment period to elicit the desired effect
Administering the recombinant poxvirus to a host organism or cell for such period of time as required to elicit the desired effect.
Systemic route of administration
Administering the poxvirus via the systemic route.
Prodrug administration with pharmaceutically acceptable quantity
Administering a pharmaceutically acceptable quantity of a prodrug to a host organism or cell.
Prodrug administered at least 3 days after poxvirus
Administering a pharmaceutically acceptable quantity of a prodrug to a host organism or cell at least 3 days after administering a poxvirus.
Prodrug administered at least 7 days after poxvirus
Administering a pharmaceutically acceptable quantity of a prodrug to a host organism or cell at least 7 days after administering a poxvirus.
The claim set defines oncolytic recombinant poxviruses by essential defective gene elements, excludes defective vaccinia growth factor gene content, and requires that the poxvirus is oncolytic and not NYVAC. The independent claims cover tumor treatment or cancer reduction for a time required to elicit the desired effect, while dependent claims further refine administration route and prodrug timing relative to poxvirus dosing.
Stated Advantages
Improved safety while retaining oncolytic activity.
Reduced pathogenicity/virulence relative to higher-risk configurations, as supported by reduced toxicity measures described in the document.
Tumor-preferential biodistribution and replication specificity favoring tumor cells over non-target cellular contexts.
Improved antitumor efficacy and tumor control when combined with a prodrug/prodrug-sensitizing system.
Documented Applications
Treating tumors in a host organism or cell.
Reducing cancer in a host organism or cell.
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