Viral vectors for cancer therapy
Inventors
Krishnan, Suma • PARRY, Trevor • PREVITE, Dana Michelle • DUERMEYER, Mary Jane
Assignees
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Publication Number
US-11918660-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding an immunomodulatory polypeptide (e.g., a pro-inflammatory cytokine such as a human IL-2 or IL-12 polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for the treatment of cancer, such as lung cancer); and articles of manufacture or kits thereof.
Core Innovation
The invention provides pharmaceutical compositions comprising a herpes simplex virus type 1 (HSV-1) comprising a recombinant HSV-1 genome. The recombinant HSV-1 genome comprises a polynucleotide encoding an IL-2 polypeptide and a polynucleotide encoding an IL-12 polypeptide, with a first promoter operably linked to the IL-2 polynucleotide and a second promoter operably linked to the IL-12 polynucleotide.
The IL-12 polypeptide comprises an IL-12 subunit alpha polypeptide and an IL-12 subunit beta polypeptide connected by a linker polypeptide. The disclosed approach relates recombinant HSV genomes carrying immunomodulatory transgenes inserted into HSV loci, including ICP4, ICP22, and UL41, and includes embodiments that are replication competent, replication defective, non-oncolytic virus, and attenuated virus.
In some embodiments, inactivating mutations in HSV gene coding sequences reduce cytotoxicity and reduce target cell proliferation by decreasing or eliminating expression of HSV genes. The document also includes embodiments directed to delivery to human respiratory/airway epithelial cells and maintains expression of immunomodulatory polypeptides such as IL-12 and IL-2.
Claims Coverage
The document includes two independent claim types covering pharmaceutical compositions. Across the independent claims, there are three core inventive features: HSV-1 recombinant genomes encoding IL-2 and IL-12 from separate operably linked promoters, IL-12 formed from alpha and beta subunits connected by a linker polypeptide, and a population of HSV-1 viruses with a replication competence constraint.
HSV-1 recombinant genome encoding IL-2 and IL-12 with separate promoters
A pharmaceutical composition comprising an HSV-1 comprising a recombinant HSV-1 genome, where the recombinant HSV-1 genome comprises a polynucleotide encoding an IL-2 polypeptide and a polynucleotide encoding an IL-12 polypeptide, wherein a first promoter is operably linked to the polynucleotide encoding the IL-2 polypeptide and a second promoter is operably linked to the polynucleotide encoding the IL-12 polypeptide.
IL-12 alpha and beta subunits connected by a linker polypeptide
A pharmaceutical composition wherein the IL-12 polypeptide comprises an IL-12 subunit alpha polypeptide and an IL-12 subunit beta polypeptide connected by a linker polypeptide.
Population of HSV-1 viruses carrying IL-2 and IL-12 recombinant genomes
A pharmaceutical composition comprising a population of HSV-1 viruses, wherein the population comprises recombinant HSV-1 genomes comprising a polynucleotide encoding an IL-2 polypeptide and a polynucleotide encoding an IL-12 polypeptide.
Replication competence constraint for the HSV-1 population
A pharmaceutical composition wherein the population of HSV-1 viruses consists entirely of either replication-defective or replication-competent viruses.
Overall, the claims cover pharmaceutical compositions using recombinant HSV-1 genomes that encode IL-2 and IL-12, with IL-12 formed from alpha and beta subunits linked by a linker polypeptide and expressed from respective promoters. A second independent claim extends this to a population of HSV-1 viruses and constrains replication competence at the population level.
Stated Advantages
Reduces cytotoxicity.
Reduces target cell proliferation.
Improved tolerability by decreasing viral gene expression and reducing toxicity.
Documented Applications
Cancer gene therapy using recombinant herpes virus constructs and pharmaceutical compositions.
Treatment in tumor treatment contexts using modified HSV-1 with reduced or eliminated HSV gene expression to decrease cytotoxicity and impact on target-cell proliferation.
Delivery to human respiratory/airway epithelial cells in the respiratory tract.
In vivo evaluation using an osteosarcoma lung metastasis model.
Combination immunomodulatory delivery including IL-12/IL-2 detection readouts and combinatorial IL-12/GM-CSF.
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