Engineered oncolytic herpesviruses
OwnerMichael FLOYD, Peter GRZESIK +6inventors
InventorsMichael FLOYD, Peter GRZESIK, Edward M. KENNEDY, Terry FARKALY, Lorena LERNER, Sonia FEAU, Craig A. STRATHDEE, Christophe QUÉVA
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Abstract
The present disclosure relates to recombinant oncolytic viral vectors for the treatment and prevention of cancers such as glioblastoma. The oncolytic viral vectors comprise one or more of the following features: miRNA target sequence(s) for viral replication restriction; transgene(s) encoding one or more payload molecules; a retargeting domain; mutation(s) in both UL30 and UL23 genes; and a protein with a syncytial mutation and a counterpart protein without the syncytial mutation.
Claims238
A recombinant herpesvirus, wherein the viral genome of the recombinant herpesvirus:
- (a) comprises one or more transgenes, optionally wherein the open reading frame(s) (ORFs) of the transgene(s) have a G/C content of at least 60%, at least 61%, at least 62%, at least 63%, or at least 64%;
- (b) comprises one or more miRNA target sequences;
- (c) comprises a polynucleotide encoding a retargeting domain;
- (d) comprises a UL30 viral gene encoding a DNA polymerase catalytic subunit (DPCS) and a UL23 viral gene encoding a thymidine kinase (TK), wherein the DPCS comprises a mutation, and wherein the TK comprises a mutation;
- (e) encodes a first gB and/or a second gB, wherein the first gB comprises a syncytial mutation, and wherein the second gB comprises no syncytial mutation;
- (f) encodes a first gK and/or a second gK, wherein the first gK comprises a syncytial mutation, and wherein the second gK comprises no syncytial mutation;
- (g) encodes a first gH and/or a second gH, wherein the first gH comprises a syncytial mutation, and wherein the second gH comprises no syncytial mutation;
- (h) encodes a first UL20 and/or a second UL20, wherein the first UL20 comprises a syncytial mutation, and wherein the second UL20 comprises no syncytial mutation;
- and/or
- (i) encodes a first UL24 and/or a second UL24, wherein the first UL24 comprises a syncytial mutation, and wherein the second UL24 comprises no syncytial mutation.
A cell, comprising a first nucleic acid encoding a recombinant herpesvirus and a second nucleic acid, wherein:
- (i) the viral genome of the herpesvirus encodes a first gB, wherein the first gB comprises a syncytial mutation, the second nucleic acid encodes a second gB, wherein the second gB comprises no syncytial mutation;
- or, the viral genome of the herpesvirus encodes a second gB, wherein the second gB comprises no syncytial mutation, the second nucleic acid encodes a first gB, wherein the first gB comprises a syncytial mutation;
- (ii) the viral genome of the herpesvirus encodes a first gK, wherein the first gK comprises a syncytial mutation, the second nucleic acid encodes a second gK, wherein the second gK comprises no syncytial mutation;
- or the viral genome of the herpesvirus encodes a second gK, wherein the second gK comprises no syncytial mutation, the second nucleic acid encodes a first gK, wherein the first gK comprises a syncytial mutation;
- (iii) the viral genome of the herpesvirus encodes a first gH, wherein the first gH comprises a syncytial mutation, the second nucleic acid encodes a second gH, wherein the second gH comprises no syncytial mutation;
- or the viral genome of the herpesvirus encodes a second gH, wherein the second gH comprises no syncytial mutation, the second nucleic acid encodes a first gH, wherein the first gH comprises a syncytial mutation;
- (iv) the viral genome of the herpesvirus encodes a first UL20, wherein the first UL20 comprises a syncytial mutation, the second nucleic acid encodes a second UL20, wherein the second UL20 comprises no syncytial mutation;
- or the viral genome of the herpesvirus encodes a second UL20, wherein the second UL20 comprises no syncytial mutation, the second nucleic acid encodes a first UL20, wherein the first UL20 comprises a syncytial mutation;
- and/or
- (v) the viral genome of the herpesvirus encodes a first UL24, wherein the first UL24 comprises a syncytial mutation, the second nucleic acid encodes a second UL24, wherein the second UL24 comprises no syncytial mutation;
- or the viral genome of the herpesvirus encodes a second UL24, wherein the second UL24 comprises no syncytial mutation, the second nucleic acid encodes a first UL24, wherein the first UL24 comprises a syncytial mutation.
A recombinant herpesvirus, wherein the viral genome of the herpesvirus encodes a gK comprising a syncytial mutation corresponding to 1307N of SEQ ID NO:
- 920.
A recombinant virus comprising one or more transgenes encoding one or more payload proteins selected from HPGD, ADA2, HYAL1, CHP, CCL21, IL-12, a CD47 antagonist, a TGFβ antagonist, a PD1 antagonist, a TREM2 antagonist, a biomolecule comprising chlorotoxin (CTX), or any combinations thereof.
A recombinant virus comprising:
- (a) one or more miRNA target sequences for miR-122-5p;
- (b) one or more miRNA target sequences for miR-145-5p;
- (c) one or more miRNA target sequences for miR-124-3p, miR-128T, miR-137-3p, or any combination thereof;
- (d) one or more miRNA target sequences for miR-34b-5p, miR-34c-5p, or any combination thereof;
- and
- (e) one or more miRNA target sequences for miR-129-2-3p, miR-132-3p, or any combination thereof.
A recombinant virus, wherein the viral genome of the recombinant virus encodes a protein comprising a syncytial mutation and a counterpart protein without the syncytial mutation.
A cell, comprising a first nucleic acid encoding a recombinant virus and a second nucleic acid,
- wherein the viral genome of the recombinant virus encodes a protein comprising a syncytial mutation,
- wherein the second nucleic acid encodes a a counterpart protein without the syncytial mutation.
Dependencies are inferred from the claim text.