Recombinant herpes simplex virus for multiple targeting and use thereof
Inventors
KWON, Heechung • Baek, Hyunjung
Assignees
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Publication Number
US-12629399-B2
Publication Date
2026-05-19
Expiration Date
Abstract
Proposed are a recombinant herpes simplex virus for multiple targeting and the use thereof. Particularly, a recombinant HSV capable of multiple targeting through multiple expression of an adapter, which is a fused protein of a cancer-cell-targeting domain and an extracellular domain of HVEM, a recombinant HSV capable of multiple targeting by having a modified glycoprotein so as to enable retargeting, in addition to being capable of expressing the adapter that is the fused protein of the cancer-cell-targeting domain and the extracellular domain of HVEM, and the use of the virus for anti-inflammatory therapy are disclosed.
Core Innovation
The invention relates to a recombinant herpes simplex virus for multiple targeting. The virus comprises at least two expression cassettes, each capable of expressing an adapter, and the adapter is a fused protein comprising a targeting domain that binds to a cancer cell target molecule and an extracellular domain of Herpesvirus Entry Mediator HveA (HVEM) that binds to a glycoprotein gD.
Each of the at least two expression cassettes is inserted into a genome of a herpes simplex virus without inhibiting propagation of the herpes simplex virus. A leader sequence is attached to the N-terminus of the cancer cell target domain or the extracellular domain of HVEM, and the expression cassettes are inserted between UL3 and UL4 genes, between UL26 and UL27 genes, between UL48 and UL49 genes, between UL53 and UL54 genes, or between US1 and US2 genes in the genome of the virus.
The recombinant herpes simplex virus also includes another targeting domain that binds to a cancer cell target molecule and is inserted and fused into a position between amino acids 29 and 30 in glycoprotein gH, wherein the glycoprotein gH has a sequence consisting of SEQ ID NO: 3. The cancer cell target molecule is an antigen or a receptor on a surface of a cancer cell that is expressed only in a cancer cell or is overexpressed in a cancer cell compared to a normal cell.
In addition, the invention provides a recombinant herpes simplex virus further engineered to include an expression cassette that expresses an immune- or tumor-targeting agent selected from cytokines, chemokines, immune-checkpoint antagonists, co-stimulatory factors, TGFβ antagonists, heparanase, VEGFR-2 antagonists, or prodrug-activating enzymes, and this additional expression cassette is inserted into the viral genome without inhibiting herpes simplex virus propagation.
Claims Coverage
The provided material identifies one inventive backbone directed to a recombinant herpes simplex virus for multiple targeting. The claim coverage includes four inventive features: adapter expression cassettes with an HVEM extracellular domain that binds gD, insertion of those cassettes at specified HSV loci without inhibiting propagation, a second targeting domain inserted into glycoprotein gH at a defined position, and an additional expression cassette for an immune- or tumor-targeting agent.
Multiple targeting adapter with HVEM extracellular domain binding gD
A recombinant herpes simplex virus for multiple targeting comprising at least two expression cassettes wherein each expression cassette expresses an adapter, the adapter being a fused protein comprising a targeting domain that binds to a cancer cell target molecule and an extracellular domain of Herpesvirus Entry Mediator HveA (HVEM) that binds to a glycoprotein gD.
Non-inhibitory insertion of adapter expression cassettes into defined HSV loci
The at least two expression cassettes are inserted into a genome of a herpes simplex virus without inhibiting propagation of the herpes simplex virus, wherein a leader sequence is attached to the N-terminus of the cancer cell target domain or the extracellular domain of HVEM, and the expression cassettes are inserted between UL3 and UL4 genes, between UL26 and UL27 genes, between UL48 and UL49 genes, between UL53 and UL54 genes, or between US1 and US2 genes in the genome.
Second targeting domain fused into glycoprotein gH between amino acids 29 and 30
Another targeting domain that binds to a cancer cell target molecule, wherein the another targeting domain is inserted and fused into a position between amino acids 29 and 30 in glycoprotein gH, and wherein the glycoprotein gH has a sequence consisting of SEQ ID NO: 3.
Additional expression cassette for immune- or tumor-targeting agent
A further engineered recombinant herpes simplex virus including an expression cassette that expresses an immune- or tumor-targeting agent selected from cytokines, chemokines, immune-checkpoint antagonists, co-stimulatory factors, TGFβ antagonists, heparanase, VEGFR-2 antagonists, or prodrug-activating enzymes, inserted into the viral genome without inhibiting herpes simplex virus propagation.
Overall, the claim coverage centers on engineering HSV with multiple targeting by combining at least two adapter-expressing cassettes that fuse a cancer-targeting domain to HVEM (HveA) for gD binding, insertion of those cassettes into specified HSV gene loci without inhibiting viral propagation, a targeting domain fused into glycoprotein gH at a defined position with SEQ ID NO: 3, and an additional immune- or tumor-targeting expression cassette.
Stated Advantages
Higher infection efficiency and killing compared to single-targeting.
Increased plaque/proliferation/amplification and increased infection/cytotoxicity in HER2+ or EpCAM+ cells.
Tumor growth inhibition in a xenograft model with intratumoral dosing.
Documented Applications
Application to carcinoma and tumor suppression in a xenograft model using intratumoral dosing.
Use of recombinant HSV constructs directed to HER2 and/or EpCAM cancer cell target molecules, including dual-targeting constructs with adapter and gH-ligand viruses.
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