Recombinant herpes simplex virus having modified glycoprotein gH for retargeting and use thereof
Inventors
KWON, Heechung • Baek, Hyunjung
Assignees
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Publication Number
US-12246048-B2
Publication Date
2025-03-11
Expiration Date
Abstract
Proposed are a recombinant herpes simplex virus having a modified glycoprotein gH for retargeting and the use thereof. Particularly, the recombinant herpes simplex virus is capable of infecting a target cell having a target molecule to which a cell-targeting domain specifically recognizes and binds due to the presence of the cell-targeting domain in the glycoprotein gH thereof, and is thus useful for anticancer therapy or gene therapy.
Core Innovation
The invention relates to a recombinant herpes simplex virus configured such that a cell-targeting domain that specifically recognizes and binds to a target molecule of a target cell is inserted and fused into a glycoprotein gH. The insertion position is between the region of amino acids 29 and 30 in the amino acid sequence of the gH glycoprotein comprising SEQ ID NO: 1.
The recombinant HSV-1 enables retargeting of infection toward receptor-positive cancer cells through the cell-targeting domain binding to cancer-associated antigens. Examples described include HER2, EpCAM, or CEA, and the resulting infection and induced cell death are reported to be selective relative to antigen-negative controls.
The document also describes an entry strategy in which infection is restricted via HSV glycoprotein gD substitutions, including R222N and F223I, to limit infection through HVEM rather than nectin-1. In addition, the document describes a cancer-treating pharmaceutical composition containing the recombinant virus and notes that a transgene or expression cassette may be inserted without inhibiting propagation.
Claims Coverage
The independent claim coverage includes 1 independent claim. The inventive features revolve around insertion and fusion of a cell-targeting domain into a defined position of HSV glycoprotein gH, with dependent claim refinements addressing gD substitutions for entry restriction, optional payload expression without inhibiting propagation, and use as a cancer-treating pharmaceutical composition.
gH positional fusion of a cell-targeting domain for target-specific recognition
A recombinant herpes simplex virus configured such that a cell-targeting domain specifically recognizes and binds to a target molecule of a target cell is inserted and fused into a glycoprotein gH, wherein the cell-targeting domain is inserted and fused into a position between the region of amino acids 29 and 30 in the amino acid sequence of the gH glycoprotein comprising SEQ ID NO: 1.
gD substitutions for HVEM-restricted entry
The recombinant herpes simplex virus includes substitutions of arginine at position 222 and phenylalanine at position 223 in gD (SEQ ID NO: 10) with asparagine and isoleucine, respectively.
Insertion of an expression cassette without inhibiting herpes simplex virus propagation
An expression cassette expressing at least one selected from cytokine, chemokine, immune checkpoint antagonist, co-stimulatory factor, TGFβ antagonist, heparanase, VEGFR-2 antagonist, and prodrug-activating enzyme is inserted into the viral genome without inhibiting propagation of the herpes simplex virus.
Cancer-treating pharmaceutical composition including the recombinant herpes simplex virus
A cancer-treating pharmaceutical composition comprising the recombinant herpes simplex virus of claim 1 as an active ingredient.
Overall, the claim set centers on inserting and fusing a cell-targeting domain into a defined position between amino acids 29 and 30 of gH (SEQ ID NO: 1), with dependent claim refinements addressing gD substitutions for entry restriction, optional immunomodulatory or prodrug-related payload expression without inhibiting propagation, and formulation as a cancer-treating pharmaceutical composition.
Stated Advantages
Improves or selectively enables infection and induced cell death in receptor-positive cancer cells while showing minimal infection and cytotoxicity in antigen-negative controls.
Limits infection via HVEM rather than nectin-1 through the described gD substitution strategy.
Enables insertion of an expression cassette while not inhibiting propagation of the herpes simplex virus.
Documented Applications
Cancer treatment pharmaceutical composition containing the recombinant herpes simplex virus as an active ingredient.
Selective infection and induced cell death in HER2-, EpCAM-, and CEA-positive cancer cell lines, with minimal effects in antigen-negative controls.
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