Oncolytic HSV vector
AssigneeUniversity of Pittsburgh—Of the Commonwealth System of Higher Education
InventorsHiroaki Uchida, Justus B. Cohen, Joseph C. Glorioso, III, Paola Grandi
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Abstract
The present invention provides a recombinant oncolytic Herpes Simplex Virus (oHSV) comprising a non-HSV ligand specific for a molecule (protein, lipid, or carbohydrate determinant) present on the surface of a cell (such as a cancer cell) and one or more copies of one or more microRNA target sequences inserted into one or more HSV gene loci, preferably one or more HSV gene(s) required for replication of HSV in normal (i.e., non-cancerous) cells. The invention further provides stocks and pharmaceutical compositions comprising the inventive oHSV and methods for killing tumor cells employing the inventive oHSV.
Claims35
A recombinant oncolytic Herpes Simplex Virus (oHSV), comprising:
- (a) a non-HSV ligand displayed on the surface of the oHSV envelope, which is specific for a molecule present on the surface of a cancer cell;
- (b) a plurality of copies of one or more microRNA target sequences inserted into one or more loci of an HSV gene required for HSV replication in normal (non-cancerous) cells;
- (c) a deletion of the internal repeat (joint) region in the HSV genome comprising one copy of the ICP0, ICP34.5, LAT, and ICP4 genes and the ICP47 promoter;
- and
- (d) a transgene that encodes a protein or polypeptide that induces patient immune response against cancer.
A recombinant oncolytic Herpes Simplex Virus (oHSV), comprising:
- (a) a non-HSV ligand specific for a protein present on the surface of a cancer cell, wherein the non-HSV ligand is an scFv specifically binding EGFR or EGFRvIII and which is inserted between residues 1 and 25 of an oHSV viral envelope glycoprotein, wherein the glycoprotein is gD;
- (b) 4 copies of the reverse complement of a microRNA (miR)-124 target sequence, each of said copies separated by spacers of eight nucleotides, inserted into the 3′ untranslated region (UTR) of ICP4 of the oHSV genome;
- (c) a deletion of the internal repeat (joint) region in the HSV genome comprising one copy of the ICP0, ICP34.5, LAT, and ICP4 genes and the ICP47 promoter;
- and
- (d) a transgene that encodes a protein or polypeptide that induces patient immune response against cancer.
A recombinant oncolytic Herpes Simplex Virus (oHSV), comprising:
- (a) a non-HSV ligand displayed on the surface of the oHSV envelope, which is specific for a molecule present on the surface of a cancer cell;
- (b) a plurality of copies of one or more microRNA target sequences inserted into one or more loci of an HSV gene required for HSV replication in normal (non-cancerous) cells, wherein at least one of the microRNA target sequences is a miR-124 target sequence;
- (c) a deletion of the internal repeat (joint) region in the HSV genome comprising one copy of the ICP0, ICP34.5, LAT, and ICP4 genes and the ICP47 promoter;
- (d) a transgene that encodes a protein or polypeptide that induces patient immune response against cancer;
- and
- (e) a second transgene encoding a matrix metalloproteinase (MMP), wherein the MMP is MMP9.
Dependencies are inferred from the claim text.