Vectors conditionally expressing therapeutic proteins, host cells comprising the vectors, and uses thereof
Inventors
Roeth, Jeremiah F. • Reed, Charles C. • Cuthbertson, Brandon • Chada, Sunil • FOGLER, WILLIAM E.
Assignees
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Publication Number
US-10584351-B2
Publication Date
2020-03-10
Expiration Date
Abstract
This invention relates to the field of therapeutics. Most specifically, the invention provides methods of generating conditionally expressing vectors for one or more immuunomodulators under the control of a gene expression modulation system in the presence of activating ligand and uses for therapeutic purposes in animals. These vector may be provided to treat a variety of disorders, e.g., neoplastic disorders, through direct injection or through in vitro engineered cells, such as dendritic cells.
Core Innovation
The invention relates to treating a glioblastoma in a mammal by intratumorally administering a viral vector comprising a polynucleotide encoding an ecdysone receptor-based gene switch. The gene switch comprises first and second transcription factor coding sequences that interact to form a ligand-dependent transcription factor complex, including a VP-16 transactivation domain and a retinoic acid-X-receptor (RXR) polypeptide, and a GAL-4 DNA binding domain and a Choristoneura fumiferna ecdysone receptor ligand binding domain.
The viral vector additionally includes a polynucleotide encoding a polypeptide having a function of IL-12 that is operably linked to a promoter activated by the ligand-dependent transcription factor complex. The function of IL-12 is production of IFN-gamma, so ligand activation drives expression of an IL-12 functional polypeptide in the context of glioblastoma treatment.
The method further includes administering a diacylhydrazine ligand that activates the ligand-dependent transcription factor complex. The ligand is administered within a defined time period from 24 hours before administration of the vector to 24 hours following administration of the vector, and is administered daily for a period of 7 to 28 days following the first administration.
Claims Coverage
The patent text provided includes three independent claims directed to methods for treating glioblastoma in a mammal using intratumoral delivery of an ecdysone receptor-based ligand-dependent gene switch encoding IL-12 and diacylhydrazine ligand administration to activate the switch. Across the independent claims, the main inventive features are the ligand-dependent transcription factor complex components, IL-12 function linked to a ligand-activated promoter, and the timing and dose regimen for the vector and diacylhydrazine ligand.
Ecdysone receptor-based ligand-dependent gene switch driving IL-12/IFN-gamma expression
Intratumorally administering to the glioblastoma in the mammal a viral vector comprising a polynucleotide encoding an ecdysone receptor-based gene switch, wherein the polynucleotide comprises first and second transcription factor coding sequences that interact to form a ligand-dependent transcription factor complex comprising VP-16 transactivation domain and an RXR polypeptide, and a GAL-4 DNA binding domain and a Choristoneura fumiferna ecdysone receptor ligand binding domain, and a polynucleotide encoding a polypeptide having a function of IL-12 operably linked to a promoter activated by the ligand-dependent transcription factor complex, wherein the function of IL-12 is production of IFN-gamma.
Intratumoral viral vector administration with diacylhydrazine ligand activation around vector delivery
Administering to the mammal a diacylhydrazine ligand that activates the ligand-dependent transcription factor complex, wherein the ligand is first administered in a time period from 24 hours before administration of the vector to 24 hours following administration of the vector, and wherein the ligand is administered daily for a period of 7 to 28 days following the first administration.
Dose-specific diacylhydrazine ligand and vector combination for glioblastoma treatment
Intratumorally administering to the glioblastoma in the mammal a viral vector comprising a polynucleotide encoding an ecdysone receptor-based gene switch with VP-16/RXR and GAL-4/Choristoneura fumiferna ecdysone receptor ligand binding domain components and an IL-12 polypeptide operably linked to a promoter activated by the ligand-dependent transcription factor complex for production of IFN-gamma, and administering a diacylhydrazine ligand to activate the complex within the defined pre/post window and daily for 7 to 28 days.
Across the independent claims, glioblastoma treatment is achieved by intratumoral administration of a viral vector encoding an ecdysone receptor-based, ligand-dependent transcription factor complex that drives expression of an IL-12 functional polypeptide for production of IFN-gamma under control of a ligand-activated promoter, together with diacylhydrazine ligand administration within a 24-hour before to 24-hour after vector delivery window and daily dosing for 7 to 28 days. The claims differentiate key quantitative aspects through specified diacylhydrazine ligand amounts and, in one claim, a broader vector particle dose range.
Stated Advantages
Provides a method for treating glioblastoma in a mammal using an ecdysone receptor-based gene switch activated by a diacylhydrazine ligand.
Uses a gene switch to drive IL-12 expression, where IL-12 function is production of IFN-gamma.
Documented Applications
Treating a glioblastoma in a mammal by intratumoral administration of a viral vector encoding an ecdysone receptor-based gene switch and administration of a diacylhydrazine ligand.
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