WO2021034157A1 - 암세포 표적화 영역과 hvem의 세포외 도메인의 융합 단백질을 발현할 수 있는 발현 카세트를 가지는 재조합 헤르페스 심플렉스 바이러스 및 그 용도 - Google Patents
암세포 표적화 영역과 hvem의 세포외 도메인의 융합 단백질을 발현할 수 있는 발현 카세트를 가지는 재조합 헤르페스 심플렉스 바이러스 및 그 용도 Download PDFInfo
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
- C12N2710/16641—Use of virus, viral particle or viral elements as a vector
- C12N2710/16643—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a recombinant herpes simplex virus having an expression cassette capable of expressing a fusion protein of a cancer cell targeting region and an extracellular domain of HVEM, and its use.
- anti-cancer viruses are viruses that have the characteristics of lysing cancer cells by selectively proliferating in cancer cells by manipulating the genes of living viruses, and their proliferation in normal cells is limited. Viruses released by dissolving cancer cells can produce a sustained and synergistic therapeutic effect by continuously infecting surrounding cancer cells.
- the anticancer virus can increase the anticancer effect by stimulating the human body's immune response by releasing tumor antigens with immunogenicity in the process of dissolving cancer cells, and this anticancer effect is artificially manipulated to express cytokines, chemokines, etc. May be improved.
- HSV Herpes Simplex Virus
- vaccinia virus of which HSV contains linear double-stranded DNA of 152kb.
- a polyhedral virus enveloped icosahedral virion
- HSV-1 type As a polyhedral virus (enveloped icosahedral virion), it is divided into HSV-1 type and HSV-2 type.
- HSV has many non-essential genes and has a large genome, so it is easy to manipulate or transport foreign genes, have a short replication cycle, and have high infection efficiency, and is a sugar involved in cell adhesion and infection. It has the advantage of being able to improve targeting to cancer cells because it is easy to manipulate proteins.
- T-VEC (Talimogene Laherparepvec, product name: Imlijik), approved by the US FDA in October 2015, is an anti-cancer virus treatment for malignant melanoma using HSV-1.
- T-VEC is an attenuated HSV-1 type that expresses GM-CSF (granulocyte-macrophage colony stimulating factor), which has ICP34.5 and ICP47 genes deleted to weaken pathogenicity and promotes human immune response. It is a virus.
- GM-CSF granulocyte-macrophage colony stimulating factor
- HSV is a virus with an envelope, and the entry of HSV into cells is achieved by a complex interaction of the glycoproteins gD, gB, gH/gL and gC present in the envelope.
- gD is the cell receptor HVEM (herpesvirus entry mediator, HveA), nectin-1 (HveC).
- HSV enters the cell (Hiroaki Uchida et al., Generation of Herpesvirus Entry Mediator (HVEM)- restricted Herpes Simplex Virus Type 1 Mutant Viruses: Resistance of HVEM-expressing Cells and Identification of Mutations That Rescue nectin-1 Recognition.J Virol. 2009 Apr;83(7):2951-61).
- HVEM Herpesvirus Entry Mediator
- HVEM belongs to the tumor necrosis factor receptor protein family (TNFR family), mainly T, B lymphocytes, macropages, DC cells, sensory neurons, and mucosal epithelial cells. (mucosal epithelial cells), but (Shui JW, Kronenberg M. 2013. Gut Microbes 4(2):146-151), B, T lymphoma, melanoma, colorectal cancer, hepatocellular carcinoma, It is known to be highly expressed in various tumor tissues such as breast cancer, ovarian serous adenocarcinoma, clear renal cell carcinoma, and glioblastoma (Pasero C et al., Curr Opin Pharmacol. 2012.
- TNFR family tumor necrosis factor receptor protein family
- HVEM contains four cystein-rich domains (CRDs) characteristic of the TNFR family. Two of these CRDs are reported to induce cell entry of HSV-1 and HSV-2 by binding to the gD of HSV (Sarah A Connolly et al., Structure-based Analysis of the Herpes Simplex Virus Glycoprotein D Binding. Site Present on Herpesvirus Entry Mediator HveA (HVEM).J Virol. 2002 Nov;76(21):10894-904. ).
- the present inventors previously produced a fusion protein (CEAscFv-HveA) of the scFv (single-chain variable fragment) for CEA (carcinoembryonal antigen) and the extracellular domain of HVEM, one of the HSV cell surface receptors, and the fusion protein was HSV.
- CEAscFv-HveA a fusion protein of the scFv (single-chain variable fragment) for CEA (carcinoembryonal antigen) and the extracellular domain of HVEM, one of the HSV cell surface receptors, and the fusion protein was HSV.
- the present invention is to insert the gene encoding the adapter fusion protein (CEAscFv-HveA) into the genome of HSV so that it can be expressed so that the fusion protein is expressed in HSV-infected cells, the fusion protein is HSV, CEA
- the fusion protein (HER2scFv-HveA) of the extracellular domain of HVEM and ScFv for HER2 (Human epidermal growth factor receptor 2) instead of scFv for CEA was also confirmed to target and induce infection. It was completed by confirming that the cell line expressing HER2 was targeted and induced to infect.
- an object of the present invention is to provide a recombinant HSV having an expression cassette of the fusion protein capable of expressing an adapter, which is a fusion protein of a cancer cell targeting region and an extracellular domain of HVEM.
- Another object of the present invention is to provide a pharmaceutical composition for anticancer treatment comprising the recombinant HSV as an active ingredient.
- Another object of the present invention is to provide a method for preventing or treating cancer in which the pharmaceutical composition is administered in an effective amount to a subject such as a patient.
- the present invention can express an adapter that is a fusion protein between a cancer cell targeting region (a cancer targeting region is used interchangeably with a cancer targeting domain in the present specification, or expressed as a ligand depending on the context of the present specification) and the extracellular domain of HVEM. And recombinant Herpes Simplex Virus (HSV).
- HSV Herpes Simplex Virus
- the recombinant HSV of the present invention infects a target cell, which is a cancer cell, and enters the target cell, the HSV is proliferated and an adapter, which is a fusion protein, is expressed in the cell and released to the outside of the cell together with the HSV virion proliferated by cell lysis. If the adapter has a leader sequence, it is released even before virion is released by cell lysis. The adapter released to the outside of this cell acts to induce infection or increase infection efficiency to surrounding cancer cells expressing the HSV virion and the target molecule recognized by the cancer cell targeting region of the adapter.
- an adapter which is a fusion protein
- recombinant HSV when compared to wild-type HSV virus, is an HSV that has been genetically engineered so that certain functions are lost or altered due to the introduction of artificial mutations (i.e., some nucleic acid sequences are deleted, substituted or inserted) or to express the intended protein of interest.
- recombinant HSV is in the HSV genome, without inhibiting the proliferation of HSV, and an adapter expression cassette (that is, a promoter sequence and a polyadenylation signal in which the adapter gene allows its expression)
- an adapter expression cassette that is, a promoter sequence and a polyadenylation signal in which the adapter gene allows its expression
- the recombinant HSV refers to HSV capable of expressing an adapter in infected cancer cells.
- the recombinant HSV of the present invention in particular, in addition to being engineered to express such an adapter, does not enter the cell through nectin-1 as an entry receptor, and additionally enters the cell only through the HVEM receptor. Can be manipulated.
- the HSV glycoprotein gD sequence was engineered in the following examples to allow HSV to enter the cell only through the HVEM receptor. Specifically, arginine (R) at position 222 of gD and phenylalanime (F) at position 223 are substituted with asparagine (N) and isoleucine (I), respectively, so that the function of gD is changed.
- HVEM Herpesvirus Entry Mediator
- non-essential genes include the UL3 gene (see, eg, Genbank Accession No. AFE62830.1), the UL4 gene (see, eg, Genbank Accession No. AFE62831.1), and the UL14 gene (eg, Genbank Accession No. AFE62841.1).
- UL16 gene see, eg, Genbank Accession No. AFE62843.1
- UL21 gene see, eg, Genbank Accession No.
- AFE62848.1 UL24 gene (see, eg, Genbank Accession No. AFE62851.1), UL31 gene (see eg, Genbank Accession No. AFE62851.1) , Genbank Accession No. AFE62859.1), UL32 gene (see, eg, Genbank Accession No. AFE62860.1), US3 gene (see, eg, Genbank Accession No. AFE62891.1), UL51 gene (eg, Genbank Accession No. AFE62880.1), UL55 gene (see, eg, Genbank Accession No. AFE62884.1), UL56 gene (see, eg, Genbank Accession No. AFE62885.1), US2 gene (eg, Genbank Accession No.
- AFE62890.1 US12 gene (e.g., Genbank Accession No. AFE62901.1; i.e., see ICP47 gene), LAT gene (see, e.g., Genbank Accession No. JQ673480.1), gB gene (e.g., Genbank Accession No. 52996 family of GU734771.1) 55710), gL gene (see, e.g., Genbank Accession No. AFE62828.1), gH gene (see, e.g., Genbank Accession No. AFE62849.1), gD gene (e.g., Genbank Accession N o. See AFE62894.1) 1) and the like.
- Genbank Accession No. AFE62901.1 i.e., see ICP47 gene
- LAT gene see, e.g., Genbank Accession No. JQ673480.1
- gB gene e.g., Genbank Accession No. 52996 family of GU7347
- the recombinant HSV of the present invention is a recombinant HSV-1 virus, a recombinant HSV-2 virus, or an HSV-1/HSV-2 chimeric virus (i.e., the genome is both a DNA derived from HSV-1 and a DNA derived from HSV-2. It may be a recombinant HSV virus including), preferably a recombinant HSV-1 virus, more preferably a recombinant HSV-1 derived from the HSV-1 KOS strain.
- HSV-1 KOS strain can be purchased from ATCC (Cat No VR-1493TM), and the genome sequence of the strain has been fully sequenced, and GenBank Accession No. JQ673480.1 (Stuart J Macdonald et al. Genome Sequence of Herpes Simplex Virus 1 Strain KOS. J Virol. 2012 Jun;86(11):6371-2).
- the genome of the HSV-1 virus is composed of 152 kb double-stranded linear DNA that encodes a total of 84 genes, and it is composed of two fragments connected to each other, a long fragment (L region) and a short fragment (S region).
- the long fragment (L region) occupies about 82% of the genome
- the short fragment (S region) occupies about 18% of the genome
- the long and short fragments occupy two intermediate inverted repeat sequences (IRLs), which are junction regions.
- TRL terminal inverted repeat segment
- 56 UL1-UL56 genes and 10 genes (UL8.5, 9.5, 10.5, 12.5, 15.5, 20.5) in the L region (UL) , 26.5, 27.5, 43.5, 49.5) exist
- 12 US1-US12 genes and 2 genes (US1.5, 8.5) exist in the S region (US)
- 4 genes in the two IRLs which are junction regions. (ICP4, ICP34.5, ICP0 and LAT) are included.
- the adapter expression cassette is configured by being operably linked to a promoter sequence for enabling its expression of the adapter gene and a polyadenylation signal sequence, which is a transcription termination signal sequence.
- operably linked means that the expressed adapter gene is linked to enable transcription and/or translation. For example, if a promoter affects the transcription of an adapter gene linked to it, the promoter is operably linked to the adapter gene.
- a promoter is located in the upper (5' side) based on the transcription initiation point of a gene, and includes a binding site for a DNA-dependent RNA polymerase, a transcription initiation point, and a transcription factor binding site. It refers to a nucleic acid sequence that has a function of controlling transcription.
- These promoters are derived from eukaryotes, in the TATA box above the transcription initiation point (usually present in the -20 to -30 position of the transcription initiation point (+1)), and the CAAT box (usually in the -75 position compared to the transcription initiation site). Presence), enhancer, transcription factor binding site, etc.
- a promoter is a constitutive promoter (a promoter that constantly induces the expression of a gene), an inducible promoter (a promoter that induces the expression of a target gene in response to a specific external stimulus), tissue Specific promoters (promoters that induce expression of genes in characteristic tissues or cells), non-tissue promoters (promoters that induce expression of genes in all tissues or cells), endogenous promoters (promoters derived from cells infected with viruses), Exogenous promoters (promoters derived from cells other than cells infected with the virus) can be used. Many of these promoters are known in the art, and appropriate ones among known ones can be selected and used.
- CMV cytomegalovirus
- RSV rous sarcoma virus
- HSV herpes simplex virus
- TK thymidine kinase
- adenovirus late promoter vaccinia virus 75K promoter
- SV40 promoter metallo Cancer cell specific promoters
- thionine (metallothionein) promoter CD45 promoter (hematopoietic stem cell specific promoter)
- CD14 promoter monocyte specific promoter
- Survivin Midkine, TERT, CXCR4, etc. specific promoter
- a cancer cell-specific promoter it is possible to increase the safety of the recombinant HSV of the present invention by inducing the expression of the adapter only in cancer cells, thereby inhibiting expression of the adapter in normal cells.
- the adapter expression cassette includes a transcription termination signal sequence in addition to a promoter, and the transcription termination signal sequence is a sequence that acts as a poly(A) addition signal, and is intended to increase the completeness and efficiency of transcription.
- the transcription termination signal sequence is a sequence that acts as a poly(A) addition signal, and is intended to increase the completeness and efficiency of transcription.
- Many transcription termination signal sequences are known in the art, and suitable ones such as the SV40 transcription termination signal sequence and the transcription termination signal sequence of HSV TK (Herpes simplex virus thymidine kinase) can be selected and used.
- the adapter expression cassette is inserted so as to be able to be expressed in the HSV genome without inhibiting the proliferation of HSV, such insertion is inserted without deletion of the HSV genome, or a part or all of the non-essential genes in the HSV genome are deleted, and the deleted position Can be inserted into
- the adapter expression cassette is inserted without deletion of the HSV genome, it can be inserted between each gene.
- Preferred positions as the insertion site are, for example, between the UL3 and UL4 genes, between the UL26 and UL27 genes, between the UL37 and UL38 genes, and between UL48 and UL49. Between genes, between UL53 and UL54 genes, between US1 and US2 genes, and the like.
- the deleted non-essential gene may be any non-essential gene as exemplified above.
- the cancer cell targeting region of the adapter is a part that specifically recognizes and binds a target molecule of a target cell, which is a cancer cell, and the target molecule recognized by the cancer cell targeting region is an arbitrary antigen present on the surface of the cancer cell. Or any receptor.
- Such an antigen or receptor preferably refers to an antigen or receptor that is expressed only in cancer cells or overexpressed in cancer cells compared to normal cells.
- EGFRvIII epidermal growth factor receptor variant III
- EGFR epidermal growth factor receptor
- Overexpressed metastin receptor ErbB receptor tyrosine kinases overexpressed in breast cancer, breast cancer, bladder cancer, Gallbladder cancers, cholangiocarcinomas, gastroesophageal cancer (esophagogastric) HER2 (Human epidermal growth factor receptor 2) overexpressed in junction cancers), tyrosine kinase-18-receptor (c-Kit) overexpressed in nutmeg renal carcinoma, HGF receptor c-Met overexpressed in esophageal adenocarcinoma, etc.
- CEA carcinoembryonic antigen
- GD2 epidermal cell adhesion molecule
- GPC3 Glypican 3 overexpressed in hepatocellular carcinoma, overexpressed in prostate cancer, etc.
- PSMA Prostate Specific Membrane Antigen
- TAG-72 tumor-associated glycoprotein 72
- GD3 disialoganglioside
- HLA overexpressed in blood cancer, solid cancer, etc.
- -DR human leukocyte antigen-DR
- MUC1 Mucin 1
- NY-ESO-1 New York esophageal squamous cell carcinoma 1
- LMP1 Latent membrane protein 1 overexpressed in nasopharyngeal neoplasms
- lung cancer non-Hodgkin's lymphoma
- colon cancer colon cancer
- pancreatic cancer pancreatic cancer
- TRAILR2 tumor-necrosis factor-related apoptosis-inducing ligand receptor
- VEGFR2 vascular endothelial growth factor receptor 2
- HGFR hepatocyte growth factor receptor
- the target molecule in the present invention is preferably HER2 or CEA.
- the target cells targeted by the recombinant HSV of the present invention by the adapter are any cancer cells having a target molecule capable of targeting the cancer cell targeting region of the adapter in the present invention.
- cancer cells esophageal cancer, stomach cancer, colon cancer, rectal cancer, oral cancer, pharyngeal cancer, laryngeal cancer, lung cancer, colon cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, testicular cancer, melanoma, bladder cancer, kidney cancer, liver cancer, pancreatic cancer , Bone cancer, connective tissue cancer, skin cancer, brain cancer, thyroid cancer, leukemia, Hodgkin's disease, lymphoma, multiple myeloma, blood cancer, etc.
- the cell targeting region of the adapter may be an antibody derivative or an antibody analog in addition to a complete antibody having a specific binding ability with a target molecule.
- the antibody derivative refers to a fragment of a complete antibody or a modified antibody comprising at least one antibody variable region having a specific binding ability with a target molecule.
- Such antibody derivatives include antibody fragments such as Fab, scFv, Fv, VhH, VH, VL, and multivalent or multispecific modified antibodies such as Fab2, Fab3, minibody, diabody, tribody, tetrabody, bis-scFv, etc. Can be mentioned.
- Antibody analog refers to an artificial peptide or polypeptide having a specific binding ability with a target molecule like an antibody, but different from an antibody in structure and generally having a lower molecular weight than an antibody.
- antibody analogs include ABD, adhiron, affibody, affilin, affimer, alphabody, anticalin, armadillo repeat protein, centi Lean (centyrin), darpin (DARPin), pinomer (fynomer), Kunitz region, pronectin (pronectin), repebody (repebody), and the like.
- the cell targeting region of the adapter is preferably scFv (Single-chain variable fragment).
- scFv refers to a single-chain antibody linked via a short linker peptide of the variable region of the heavy chain (VH) and the variable region of the light chain (VL) of an immunoglobulin.
- VH variable region of the heavy chain
- VL variable region of the light chain
- the C-terminus of VH is connected to the N-terminus of VL, or the C-terminus of VL is connected to the N-terminus of VH.
- the linker peptide is a linker of any length and sequence as long as the heavy and light chains are spatially adjacent to each other to have specific binding ability with the target molecule without interfering with the intrinsic three-dimensional structure of the heavy and light chains. It may be a peptide.
- the linker is preferably made of one or more amino acids among amino acids such as Ser, Gly, Ala, Thr, etc., when considering flexibility, solubility, and resistance to proteolysis, and the length is 1 to It may be 30 amino acids, preferably 3 to 25 amino acids, more preferably 8 to 20 amino acids.
- scFv is the target molecule as HER2 or CEA as the target molecule
- scFv for HER2 is that VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2 are connected in the order of VH and linker peptide VL via a linker peptide.
- scFv for CEA is VL of SEQ ID NO: 3 and VH of SEQ ID NO: 4 via a linker peptide
- the peptide linker is preferably connected in the order of VH (ie, the C-terminus of VL is connected to the N-terminus of VH via a linker peptide).
- the scFv linker peptide for HER2 preferably has an amino acid sequence of SEQ ID NO: 5
- the scFv linker peptide for CEA preferably has an amino acid sequence of SEQ ID NO: 6.
- HVEM extracellular domain of HVEM is used in the examples below, in addition to HveA82 of SEQ ID NO: 7 (HveA82 sequence including the leader sequence is disclosed in SEQ ID NO: 8), Korean Patent No. 10-0937774 and the United States HveA87 of SEQ ID NO: 9 disclosed by Registration Patent No. 8318662 (this document is considered a part of the present specification) (HveA87 sequence including the leader sequence is disclosed in SEQ ID NO: 10), HveA102 of SEQ ID NO: 11 (leader The HveA102 sequence included up to the sequence may be disclosed in SEQ ID NO: 12) or HveA107 of SEQ ID NO: 13 (the HveA107 sequence included up to the leader sequence is disclosed in SEQ ID NO: 14). HveA87, HveA102, and HveA107 further contain 5, 20, and 25 amino acids than HveA82, respectively, and it has been confirmed that all of them can be used as HSV receptors of adapters in Korean Patent No. 10-0937774.
- a linker sequence may be posted between the cancer cell targeting region and the extracellular domain of HVEM, and this linker sequence may be a linker of any length and sequence as long as it does not inhibit the function of each domain of these adapters.
- the linker may be made of one or more amino acids of 4 amino acids Ser, Gly, Ala, and Thr, and the length is 1 to 30 amino acids, preferably 3 to 25 amino acids, and more preferably 8 to 20 amino acids. It can be dog amino acids.
- the adapter of the present invention may have a configuration in the order of NH 2 -cancer cell targeting domain-HVEM extracellular domain-COOH or the reverse order.
- the composition may be in the order of NH 2 -cancer cell targeting region-linker peptide-HVEM extracellular domain-COOH or the reverse order.
- the adapter of the present invention is at its N-terminus, specifically, if the configuration of the adapter is in the order of NH 2 -cancer cell targeting region-linker peptide-HVEM extracellular domain-COOH, then the N-terminus of the cancer cell targeting domain (VH or In the N-terminus of VL), a leader sequence may be further included at the N-terminus of the HVEM extracellular domain when the adapter is in the order of NH 2 -HVEM extracellular domain-linker peptide-cancer cell targeting domain-COOH.
- This leader sequence is a sequence that acts to induce the outflow of the adapter out of the cell by the expression of the adapter in the target cell, and the adapter induces the HSV virus to infect the adjacent target cells only after the target cell is dissolved and the HSV virus is released. It may be omitted because it does.
- scFv for the target molecule when used as the cell targeting region in the present invention, when a linker peptide is mediated between VH and VL, between VH and VL, between VH or VL and the linker peptide, between scFv and HVEM, scFv and When a linker peptide is mediated between HVEMs, an amino acid corresponding to an arbitrary restriction enzyme action site may be posted between the scFv and the linker, between the linker and HVEM, to facilitate cloning.
- EF base sequence: GAATTC
- GS (base sequence: GGATCC) in which BamHI acts) as shown in the following examples may be published.
- a recombinant HSV gene may be inserted into the HSV genome so as to express factors for inducing or enhancing an immune response against cancer cells alone or in any combination.
- factors include cytokines, chemokines, antagonists against immune checkpoints (such as antibodies, antibody derivatives or antibody analogs, especially scFv), co-stimulatory factors capable of inducing activation of immune cells (T cells or NK cells).
- an antagonist capable of inhibiting the function of TGF ⁇ that suppresses the immune response against cancer cells e.g., antibodies, antibody derivatives or antibody analogs, particularly scFv
- heparan sulfate proteoglycan constituting the solid cancer tumor microenvironment Heparanase, which can degrade heparan sulfate proteoglycan, and antagonists that can inhibit the function of VEGFR-2 (VEGF receptor-2), an angiogenic factor receptor (such as antibodies, antibody derivatives or antibody analogs, especially scFv).
- VEGFR-2 VEGF receptor-2
- an angiogenic factor receptor such as antibodies, antibody derivatives or antibody analogs, especially scFv.
- Cytokines are, for example, interleukins such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-18, and IL-24, interferons such as IFN ⁇ , IFN ⁇ , IFN ⁇ , and TNF ⁇ .
- Colony stimulating factors such as tumor necrosis factor, GM-CSF, G-CSF, and the like may be used to be expressed in recombinant HSV alone or in any combination of two or more.
- Chemokines are, for example, CCL2 (CC Motif Chemokine Ligand 2), CCL5 (RANTES), CCL7, CCL9, CCL10, CCL12, CCL15, CCL19, CCL21, CCL20, XCL-1 ((XC Motif Chemokine Ligand 1)), or the like alone or In combination, it can be used to be expressed in recombinant HSV.
- CCL2 CC Motif Chemokine Ligand 2
- CCL5 RANTES
- CCL7, CCL9 CCL10
- CCL12 CCL15
- CCL19 CCL19
- CCL21 CCL21
- CCL20 XCL-1 ((XC Motif Chemokine Ligand 1)
- Antibodies to immune checkpoints are PD-1 (programmed cell death-1), PD-L1 (programmed cell deathligand 1), PD-L2 (programmed cell death-ligand 2), CD27 (cluster of differentiation 27), and CD28 (cluster of differentiation 28), CD70 (cluster of differentiation 70), CD80 (cluster of differentiation 80), CD86 (cluster of differentiation 86), CD137 (cluster of differentiation 137), CD276 (cluster of differentiation 276), KIRs (killer-cell immunoglobulin-like receptors), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced TNFR-related protein (GITR), glucocorticoid-induced TNFR-related protein ligand (GITRL), cytolytic T lymphocyte associated antign-4 (CTLA-4) Antagonists against the back can be used alone or in combination to be expressed in recombinant HSV.
- PD-1 programmed cell death-1
- PD-L1 programmed cell death
- Co-stimulatory factors are CD2, CD7, LIGHT, NKG2C, CD27, CD28, 4-1BB, OX40, CD30, CD40, LFA-1 (lymphocyte function-associated antigen-1), ICOS (inducible T cell co-stimulatory factor), and CD3 ⁇ .
- CD3 ⁇ , CD3 ⁇ and the like may be used alone or in combination to be expressed in recombinant HSV.
- recombinant HSV can be engineered to express prodrug-activating enzymes that convert prodrugs into drugs that are toxic to cancer cells.
- prodrug activating enzymes include cytosine deaminase (Cytosine deaminase) that converts 5-FC (5-fluorocytosine), a prodrug into 5-fluorouracil (5-FU), and cyclophosphamide (CPA), a prodrug.
- Rat cytochrome P450 (CYP2B1), which converts into a drug that is a phosphoramide mustard (PM), and carboxylesterase that converts the prodrug irinotecan (SN-38150) into a drug that is SN-38 ( carboxylesterase), a bacterial nitroreductase that converts BC1954, a prodrug into 4-hydroxylamine151, a DNA crosslinking agent, 6-methylpurine-2'-deoxyriboside, a prodrug PNP (purine nucleoside phosphorylase) isolated from Escherichia coli that converts (6-methypurine-2'-deoxyriboside) into 6-methylpurine, and the like.
- CYP2B1 which converts into a drug that is a phosphoramide mustard (PM), and carboxylesterase that converts the prodrug irinotecan (SN-38150) into a drug that is SN-38 ( carboxylesterase), a bacterial
- recombinant HSV may be engineered to express TRAIL (TNF-Related Apoptosis Inducing Ligand).
- TRAIL TNF-Related Apoptosis Inducing Ligand
- TRAIL is known to induce cancer cell death by binding to its receptor, which is overexpressed in cancer cells (Kaoru Tamura et al. Multimechanistic Tumor Targeted Oncolytic Virus Overcomes Resistance in Brain Tumors. Mol Ther. 2013 Jan;21(1):68- 77).
- factors or prodrug activating enzymes for inducing or enhancing an immune response are, as in the above-described adapter, the expression cassette of the gene (that is, the gene is Constructs operably linked with the neylation signal sequence) are inserted into the HSV genome without inhibiting the proliferation of HSV, such insertions without deletion of the HSV genome, or in which some or all of the non-essential genes in the HSV genome are deleted and deleted. Can be inserted in position. At this time, if it is inserted without deletion of the HSV genome, it can be inserted between each gene.
- the expression cassette of the gene that is, the gene is Constructs operably linked with the neylation signal sequence
- Preferred insertion positions are, for example, between the UL3 and UL4 genes, between the UL26 and UL27 genes, between the UL37 and UL38 genes, between the UL48 and UL49 genes, and between the UL53 and UL54 genes. Between, between US1 and US2, and the like.
- a non-essential gene is deleted and inserted at the deleted position or inserted into the gene without deletion of the non-essential gene, such a non-essential gene may be selected from any of the non-essential genes described above.
- the present invention relates to an anti-cancer pharmaceutical composition
- an anti-cancer pharmaceutical composition comprising the above-described recombinant HSV as an active ingredient.
- the pharmaceutical composition of the present invention has anti-cancer use against carcinomas expressing a target molecule targeted by the targeting region of the adapter expressed by recombinant HSV.
- carcinoma is as previously described in relation to the target molecule.
- the composition of the present invention has anticancer use against carcinomas having tumor cells expressing CEA or HER2.
- the tumor cells expressing CEA include colon cancer cells, gastric cancer cells, lung cancer cells, breast cancer cells, rectal cancer cells, colon cancer cells, liver cancer cells, and the like.
- tumor cells expressing HER2 are breast cancer cells, ovarian cancer cells.
- the anti-cancer includes the death of cancer cells, the decrease in the viability of the cancer cells, the inhibition or delay of the pathological symptoms of cancer due to the inhibition of the proliferation of cancer cells, the inhibition or delay of the onset of such pathological symptoms, the inhibition of cancer metastasis, and the inhibition of cancer recurrence. It means that.
- the pharmaceutical composition of the present invention may further include a recombinant adapter molecule in addition to the above-described recombinant HSV, which is an active ingredient.
- the recombinant adapter molecule refers to a fusion protein having a cancer cell targeting region, which is the same as the fusion protein of a cancer cell targeting region and an extracellular domain of HVEM, which is expressed by the recombinant HSV described above, by a recombinant method.
- having the same cancer cell targeting region as the adapter expressing recombinant HSV means that when the cancer cell targeting region of the adapter expressing HSV uses HER2 as the target molecule, the cancer cell targeting region of the adapter molecule also uses HER2 as the target molecule. do.
- the method of producing the intended protein of interest by the recombinant method is to prepare an expression vector capable of expressing the target protein, and then E. coli, yeast, animal cells (CHO cells, NSO cells, BHK cells, Sp2 cells, HEK-293 cells). ), etc., transforming into a host cell, culturing, and separating the target protein, and the method for producing the target protein by such a recombinant method is very well known in the art (Sambrook et al, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, (2001)), in particular, Korean Patent No. 10-0937774 and US Patent No.
- 8318662 may be referred to for the preparation of a recombinant adapter molecule used in the present invention.
- a recombinant adapter molecule is additionally included in the pharmaceutical composition of the present invention, and when the recombinant HSV and the recombinant adapter molecule, which are active ingredients of the present invention, are administered to a patient together, there is an effect of increasing the initial infection efficiency of the recombinant HSV.
- the pharmaceutical composition of the present invention may be used in combination or mixed with a licensed anticancer agent.
- anticancer agents include metabolic antagonists, alkylating agents, topoisomerase antagonists, microtubule antagonists, plant-derived alkaloids, and any anticancer agents that exhibit cytotoxicity to cancer cells, any cytokine medicines, any antibody medicines, any immune checkpoint inhibitor medicines.
- Any cell therapy (car-T cell therarpy, car-NK cell therapy) pharmaceuticals, and the like.
- Taxol Nitrogen Mustard, Imatinib, Oxaliplatin, Gefitinib, Bortezomib, Sunitinib, Carboplatin, Cisplatin, Rituximab, Erlotinib, Sorafenib, IL-2 Drug, INF- ⁇ Drug, INF - ⁇ pharmaceuticals, trastuzumab, blinatumumab, ipilimumab, pepbrolizumab, nivolizumab, atezolizumab, duvalumab, bevacizumab, cetuximab, tisagenrexel ( Tisagenlecleucel, Kimria), axicaptagen silorucel (Tisagenlecleucel Axicabtagene Ciloleucel, Yescata) may be exemplified, and other anticancer agents known in the art in addition to these exemplified anticancer agents are mixed with the pharmaceutical composition of the present invention
- the pharmaceutical composition of the present invention may be prepared in an oral or parenteral dosage form by a conventional method known in the art according to the route of administration, including a pharmaceutically acceptable carrier or excipient.
- Such pharmaceutically acceptable carriers or excipients have no specific toxicity to the human body and do not inhibit the activity or properties of the drug, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, algae.
- Nate gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water (e.g., saline and sterile water), syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc , Magnesium stearate, mineral oil, Ringer's solution, buffer, maltodextrin solution, glycerol, ethanol, dextran, albumin, or any combination thereof.
- water e.g., saline and sterile water
- syrup methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate
- talc Magnesium stearate, mineral oil, Ringer's solution, buffer, maltodextrin solution, glycerol, ethanol, dextran, albumin, or any combination thereof.
- suitable carriers or excipients include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like.
- suitable carriers or excipients include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like.
- the above ingredients may be used alone or in combination, and other conventional pharmaceutical additives such as antioxidants, buffers, and bacteriostatic agents may be added and used as needed.
- the pharmaceutical composition of the present invention when formulated as an oral dosage form, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and parenteral dosage forms, especially when formulated as injections, can be formulated as unit dosage ampoules or It can be prepared in multiple dosage forms.
- the pharmaceutical composition of the present invention can be prepared in the form of solutions, suspensions, tablets, pills, capsules, sustained-release preparations, and the like.
- the pharmaceutical composition of the present invention is formulated in the form of a unit dosage form suitable for administration in the body of a patient according to a conventional method in the pharmaceutical field, and an oral route of administration or an administration method commonly used in the art, Or skin, intralesional, intravenous, intramuscular, intraarterial, intramedullary, meningeal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, vaginal, It can be administered by a parenteral route such as a rectal route.
- the dosage (effective amount) of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration mode, patient's age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate, and response sensitivity. It can be prescribed, and those skilled in the art can appropriately determine the dosage in consideration of these factors.
- the pharmaceutical composition of the present invention is prepared as an injection in a unit dosage form, and when prepared as an injection in a unit dosage form, the amount of recombinant HSV virus contained per unit dose of the pharmaceutical composition of the present invention is 10 2 -10 It may be in the range of 14 pfu, especially in the range of 10 4 -10 11 pfu.
- the present invention relates to a method for treating or preventing cancer (i.e., a method for treating or preventing tumors) comprising administering to a subject, such as a patient, a pharmaceutical composition comprising a recombinant HSV as described above in an effective amount. .
- the treatment method of the present invention can be applied to any carcinoma having such a target molecule.
- the treatment method of the present invention is preferably applied to a carcinoma expressing CEA or HER2.
- the treatment method of the present invention can be used in combination with the other cancer treatments without limitation.
- the aforementioned cytotoxic anticancer drugs, cytokine drugs, antibody drugs, immune checkpoint inhibitor drugs, cell therapy drugs (car-T cell therarpy, car-NK cell therapy) drugs, radiation therapy therapy, surgical therapy, etc. are the pharmaceuticals of the present invention. It can be used in combination before and after administration of the composition or by simultaneous administration.
- the present invention when the pharmaceutical composition of the present invention is administered during the administration period according to the recommendations of a medical expert, etc. to a patient to which the present invention is applied, the present invention can exhibit intended medical effects such as cancer treatment or preventive effect. It refers to the amount to which the pharmaceutical composition of the present invention is administered. As described above, such an effective amount can be appropriately determined by a person skilled in the art, such as a medical professional, according to the patient's age, weight, sex, and pathological condition.
- the pharmaceutical composition may be administered as an injection to a patient or the like, for example, intralesional (intralesional, intratumoral), intravenous, intramuscular, intra-arterial, etc. by a parenteral route of administration.
- a recombinant herpes simplex virus having an expression cassette capable of expressing a fusion protein of a cell targeting region and an extracellular domain of HVEM and its use can be provided.
- the fusion protein When the recombinant HSV infects the target cell and enters the target cell, the fusion protein is expressed in the cell along with the proliferation of HSV and released to the outside of the cell together with the proliferated HSV virion by cell lysis, or the adapter is used to generate a leader sequence. If so, it is released even before virion release by cell lysis.
- the fusion protein released to the outside of this cell acts to induce infection or increase infection efficiency to surrounding cancer cells expressing the HSV virion and the target molecule recognized by the cancer cell targeting region.
- 1 is a schematic diagram of the KOS-37 BAC genome structure and BAC gene removal by the Cre-Lox system.
- FIG. 2 is a schematic diagram of the genomic structure of the HVEM-restricted HSV-1, KOS-gD-R222N/F223I virus.
- FIG. 3 is a schematic diagram of the genome structure of the KOS-EmGFP-gD-R222N/F223I virus, which is an HVEM-restricted HSV-1 expressing EmGFP.
- Fig. 4 is a result showing fluorescence expression of HVEM-restricted HSV-1 expressing EmGFP and specific point infection to cells with HVEM receptors.
- Figure 5 is a schematic diagram of the genomic structure of the KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus expressing the HER2scFv-HveA adapter and KOS-HveA-HER2scFv-EmGFP-gD/R222N/F223I expressing the HveA-HER2scFv adapter
- It is a schematic diagram of the genome structure of the virus and the KOS-CEAscFv-HveA-EmGFP-gD/R222N/F223I virus expressing the CEAscFv-HveA adapter.
- FIG. 6 shows the entire sequence of the HER2scFv-HveA adapter, the HveA-HER2scFv adapter, and the CEAscFv-HveA adapter and the configuration of the corresponding sequence.
- FIG. 7 is a result showing the specific infection of the KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus expressing the HER2scFv-HveA adapter into HER2 expressing cells.
- Figure 8 is a result showing the specific cell death of HER2 expressing cells of the KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus expressing the HER2scFv-HveA adapter.
- FIG. 9 is a result of comparing the degree of apoptosis in HER2 expressing cells of wild-type virus (HSV-1 KOS) and KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus (Her2 Adapter) expressing HER2scFv-HveA adapter to be.
- HSV-1 KOS wild-type virus
- KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus Her2 Adapter
- Figure 10 is a result showing the specific infection of CEA-expressing cells of the KOS-CEAscFv-HveA-EmGFP-gD/R222N/F223I virus expressing the CEAscFv-HveA adapter.
- Figure 12 is a specific infection of KOS-HER2scFv-HveA-EmGFP-gD/R222N/F223I virus expressing HER2scFv-HveA adapter and KOS-HveA-HER2scFv-EmGFP-gD/R222N/F223I virus expressing HveA-HER2scFv adapter This is the result of comparing the degree.
- 13 is a result showing the extracellular expression of the adapter of the HER2scFv-HveA adapter-expressing virus and the result of observing the spread of the virus infection to surrounding cancer cells.
- the HSV-1 gene is composed of a large gene up to 152 kb, so to insert a foreign gene or to introduce a mutation at a specific location, KOS-37 BAC (Genbank Accession No. MF156583) (Gierasch WW et al. J. Virol Methods. 2006. 135:197-206) was used.
- HSV-1 KOS strain is a kind of HSV-1 strain mainly used in laboratories because its characteristics are well known and useful for gene function and etiology investigation (Smith KO. Proc. Soc. Exp. Biol. Med. 1964. 115:814-816).
- KOS-37 BAC produced by inserting the BAC plasmid into the KOS gene, enables cloning at the bacterial level through transformation into DH10B bacteria (Invitrogen) (Gierasch WW et al.; J. Virol Methods. 2006. 135 :197 ⁇ 206).
- KOS-37 BAC bacterial artificial chromosomes (BACs) are inserted along with LoxP sites on both sides of the HSV-1 KOS genome between UL37 and UL38. It was produced to remove the BAC gene later using the Cre-Lox system.
- the schematic diagram is shown in FIG. 1.
- HSV-1 gD amino acid sequence GenBank Accession No. ASM47818, SEQ ID NO: 15
- arginine, R arginine
- phenylalanine phenylalanime, F
- the gD-R222N/F223I HSV-1 virus substituted with (isoleucine, I) was prepared.
- HVEM HVEM
- FIG. 2 A schematic diagram of the genomic structure of HVEM-restricted HSV-1 is shown in FIG. 2.
- the gD-R222N/F223I HSV-1 virus was prepared by using a Counter selection BAC modification kit (GeneBridges, Inc.) and R222N/F223I mutations in the gD portion of KOS-37 BAC according to the manufacturer's protocol. Introduced.
- the E.coli clone containing KOS-37 BAC was transformed with a RecE capable of performing homologous recombination and a pRed/ET plasmid capable of expressing RecT (Muyrers JP et al.; Nucleic Acids Res. 1999. 27(6):1555-1557).
- gD-rpsL using a homologous region primer set forward primer gD-rpsL For: SEQ ID NO: 16, reverse primer gD-rpsL Rev: SEQ ID NO: 17
- forward primer gD-rpsL For: SEQ ID NO: 16
- reverse primer gD-rpsL Rev SEQ ID NO: 17
- the gD-rpsL-neo/kan cassette is the gD homologous region at the insertion site and the rpsL gene, a selective marker that makes it sensitive to streptomycin, and the neo/kan gene, which makes kanamycin resistance. Will be constructed .
- the rpsL gene makes it sensitive to streptomycin antibiotics
- the neo/kan gene makes E.coli having kanamycin resistance.
- L-arabinose (Sigma-Aldrich) was added to the E.coli clone containing KOS-37 BAC and pRedET to activate the function of pRed/ET to enable homologous recombination to express RecE and RecT.
- 200 ng of the produced gD-rpsL-neo/kan cassette was transformed.
- the gD-rpsL-neo/kan cassette is inserted at the gD position of the KOS-37 BAC by homologous recombination.
- coli with gD-rpsL-neo/kan inserted in KOS-37 BAC has kanamycin resistance, but streptomycin resistance is blocked due to the rpsL gene.
- E. coli selected in the kanamycin medium was determined that gD-rpsL-neo/kan was inserted, and the final gene was inserted.
- L-arabinose Sigma-Aldrich
- the selected candidate group was DNA isolated using the DNA prep method (Horsburgh BC et al., Methods enzymol. 1999. 306:337-352), and whether N and I were introduced at positions 222 and 223 in gD, respectively. Was confirmed by PCR (ploymerase chain recation) and DNA sequencing.
- the following virus was produced by extracting the completed KOS37-BAC-gD-R222N/F223I DNA using a Large construct DNA purification kit (Macherey0-Nagel), and then 2 ⁇ 10 5 Cre-Vero- HVEM cells were transfected with 1 ug of DNA using Lipofectamine 2000 reagent (Invitrogen). Cells were cultured in DMEM medium (Dulbecco's Modified Eagle's Medium (Welgene)) using 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10% FBS (fetal bovine serum, Wellgen).
- DMEM medium Dulbecco's Modified Eagle's Medium (Welgene)
- Welgene penicillin/100 ⁇ g/ml streptomycin
- FBS fetal bovine serum, Wellgen
- the Cre -Vero-HVEM cell line is a cell line that induces HVEM protein expression by inserting the HVEM gene into the Cre-Vero cell line (Gierasch et al.; J. Virol Methods. 2006. 135:197 ⁇ 206).
- the reason for use is that the BAC gene of KOS 37 BAC can be removed using the Cre recombinant enzyme (recombinase) of the cell, and the infection of the KOS-gD-R222N/F223I virus by overexpression of HVEM is effective, so it is easy to mass-produce the virus in the future.
- KOS-gD-R222N/F223I produced in Example 1 An expression cassette capable of expressing EmGFP (Emerald Green Fluorescent Protein) was inserted at the position of the virus gene UL26/UL27. This is to facilitate observation of virus production and infection degree using EmGFP as a marker.
- EmGFP cassette pCDNA6.2-GW/EmGFP-miR plasmid (Invitrogen) was used.
- FIG. 3 The genome schematic diagram of HVEM-restricted HSV-1 expressing UL26/27-EmGFP is shown in FIG. 3.
- KOS37-BAC-gD in the structure of pCMV-EmGFP-tkpA using the cytomegalovirus gene promoter and tkpA, the polyadenylation signal of HSV TK (Herpes simplex virus thymidine kinase) for EmGFP expression. -Inserted into R222N/F223I.
- the E.coli clone containing the KOS37-BAC-gD-R222N/F223I genome was transformed into a RecE capable of performing homologous recombination and a pRed/ET plasmid capable of expressing RecT (Muyrers JP et al.; Nucleic Acids Res. 1999. 27(6):1555-1557).
- a set of homologous region primers containing a position to introduce a target gene between UL26 and UL27 forward primer UL26/27-rpsL_For: SEQ ID NO: 19, reverse primer UL26/27-rpsL_Rev: SEQ ID NO: 20
- UL26/27-rpsL-neo/kan cassette cassette
- L-arabinose Sigma-Aldrich
- the UL26/27-rpsL-neo/kan cassette is inserted at the UL26/27 position of KOS37-BAC-gD-R222N/F223I.
- UL26/27-rpsL-neo/kan-inserted E. coli has kanamycin resistance, but streptomycin resistance is blocked by the rpsL gene.
- E. coli selected in the kanamycin medium was determined to have UL26/27-rpsL-neo/kan inserted, and proceeded to the final step of inserting the target gene.
- L-arabinose Sigma-Aldrich
- pRed/ET E.coli with UL26/27-rpsL-neo/kan cassette Induction
- 200 ng of UL26/27-tkpA-EmGFP-pCMV cassette were transformed.
- the UL26/27-tkpA-EmGFP-pCMV cassette uses pCDNA6.2-GW/EmGFP-miR plasmid (Invitrogen) as a template, and forward primer UL26-tkpA_For (SEQ ID NO: 21) and reverse primer UL27-pCMV_Rev (SEQ ID NO: It was produced using number 22).
- streptomycin resistance blocked by rpsL is activated when the existing UL26/27-rpsL-neo/kan cassette and the inserted UL26/27-tkpA-EmGFP-pCMV are replaced.
- candidates were selected in streptomycin medium ( Heermann R et al., Microb Cell Fact. 2008. 14:. doi: 10.1186).
- the selected candidates were separated by DNA using the DNA prep method (Horsburgh BC et al., Methods enzymol. 1999. 306:337-352).
- J1 cells are young hamster kidney cell lines that are deficient in HVEM and Nectin-1, which are the virus HSV-1 receptors (Petrovic B et al ., 2017. PLoS Pathog. 19;13(4):e1006352).
- J-Nectin and J-HVEM cell lines are cell lines that overexpress Nectin-1 and HVEM in J1 cells, respectively (Petrovic B et al ., 2017. PLoS Pathog.
- Each cell line was cultured in DMEM medium (Welgene) using 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10% fetal bovine serum (FBS).
- DMEM medium Welgene
- FBS fetal bovine serum
- the obtained KOS-EmGFP-gD-R222N/F223I virus was infected with 10 MOI (multiplicity of infection), and after 24 hours, the expression of the fluorescent protein and the degree of virus infection were observed through a fluorescence microscope ( BaeK HJ et al ., Mol Ther. 2011. 19(3):507-514).
- Fig. 4 The results are shown in Fig. 4 in the upper and lower sides of a photo taken in a fluorescence microscope mode and a photo taken in an optical microscope mode. Referring to the upper fluorescence micrograph of FIG. 4, it can be seen that the J1 cell line and the J-Nectin cell line are not infected, but only the J-HVEM cell line is infected.
- the scFv for HER2 is a structure in which the VH of SEQ ID NO: 1 and the VL of SEQ ID NO: 2 are connected via a linker peptide of SEQ ID NO: 5, and the scFv for CEA is the VL of SEQ ID NO: 3 and the VH of SEQ ID NO: 4 It is a structure linked via the linker peptide of 6, HveA is HveA82 of SEQ ID NO: 7 excluding the leader sequence for the HER2scFv-HveA adapter and CEAscFv-HveA adapter, and SEQ ID NO: 8 including the leader sequence for the HveA-HER2scFv adapter It's Hve82.
- the leader sequence of SEQ ID NO: 33 is contained at the N-terminus, that is, at the front of the VH of HER2scFv and the VL of CEAscFv.
- EF base sequence: GAATTC
- EcoRI action site for facilitating cloning
- GS base sequence: GGATCC
- BamHI action site has been added to facilitate cloning, which is also a sequence that can be excluded from the adapter.
- bGHpA is a bgh-PolyA (bovine growth hormone polyadenylation) signal sequence.
- amino acid sequence and gene sequence of the full length of the HER2scFv-HveA adapter used in this example are disclosed in SEQ ID NO: 23 and SEQ ID NO: 24, respectively, and the amino acid sequence and gene sequence of the full length of the HveA-HER2scFv adapter are SEQ ID NO: 25 and SEQ ID NO: 26, and the amino acid sequence and gene sequence of the CEAscFv-HveA adapter full length are disclosed in SEQ ID NO: 27 and SEQ ID NO: 28, respectively.
- Insertion of the HER2scFv-HveA adapter expression cassette, the HveA-HER2scFv adapter expression cassette, and the CEAscFv-HveA adapter expression cassette was performed using a counter selection BAC modification kit (GenBridges. Inc) as in Examples 1 and 2 above. It proceeded according to the manufacturer's protocol.
- the pRed/ET plasmid expressing RecE and RecT performing a homologous recombination function in the E.coli clone containing the KOS37-BAC-EmGFP-gD-R222N/F223I genome produced in Example 2 above was prepared. Transformed (Muyrers JP et al .; Nucleic Acids Res. 1999. 27(6):1555-1557).
- a set of homologous region primers (forward primers HSV-1_UL3/4-rpsL-neo_for: SEQ ID NO: 29, reverse primers HSV-1_UL3/4-) containing the position to be introduced into the target gene between UL3 and UL4 rpsL-neo_rev: SEQ ID NO: 30) was used to prepare a UL3/4-rpsL-neo/kan cassette.
- E. coli has kanamycin resistance, but streptomycin resistance is blocked by the rpsL gene.
- E. coli selected in the kanamycin medium was determined to have UL3/4-rpsL-neo/kan inserted, and proceeded to the final step of inserting the target gene.
- the UL3/4-pCMV-Her2scFv-HveA-bGHpA cassette and the UL3/4-pCMV-HveA-Her2scFv-bGHpA cassette and the UL3/4-pCMV-CEAscFv-HveA-bGHpA cassette are pCDNA3.1-HER2scFv-HveA plasmid, pCDNA3. 1-HveA-HER2scFv plasmid, pCDNA3.1-CEAscFv-HveA plasmid (BaeK HJ et al ., Mol Ther. 2011.
- the candidate group was selected in streptomycin medium using the principle that the -bGHpA is replaced and the blocked streptomycin resistance is activated by rpsL (Heermann R et al., Microb Cell Fact. 2008. 14:. doi: 10.1186).
- the selected candidates were separated by DNA using the DNA prep method (Horsburgh BC et al., Methods enzymol.
- Example 4 Targeting HER2 or CEA-expressing cancer cells using an adapter-expressing anti-cancer virus
- Example 4-1 Targeting of HER2-expressing cancer cells using HER2scFv-HveA adapter-expressing anti-cancer virus
- HER2scFv-HveA adapter prepared in Example 3 KOS-Her2scFv-HveA-EmGFP-gD-R222N/F223I virus expresses the HER2scFv-HveA adapter to induce virus infection into surrounding cancer cells, or apoptosis after infection In order to check whether to induce
- the cell lines used in the experiment are cell lines that do not express HER2 (J1, CHO-K1, MDA-MB-231) and cell lines that express HER2 (J-HER2, CHO-HER2, SK-OV-3).
- Chinese hamster ovary cell lines CHO-K1 and CHO-HER2 were 100 U/ml penicillin/100 ⁇ g/ in HaM's F-12K medium (Welgene).
- ml streptomycin (Welgene) and 10% fetal bovine serum (FBS) were used to culture and J1, J-HER2 (Petrovic B et al ., 2017. PLoS Pathog.
- MDA-MB-231 ATCC, HTB-26
- ovarian cancer cell line SK-OV-3 ATCC, HTB-77
- DMEM medium 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10 % FBS was used to incubate.
- HER2-specific virus infection 1 ⁇ 10 4 J cell lines are 10 MOI, 1.5 ⁇ 10 4 CHO cell lines are 1 MOI, 1 ⁇ 10 4 SK-OV-3 and MDA-MB-231 cell lines were infected with the HER2scFv-HveA adapter-expressing virus prepared in Example 3 at an MOI of 0.1. After 90 minutes, the medium was replaced with fresh medium to remove residual initial virus and HER2scFv-HveA adapter. Three days after infection, virus infection was observed in each cell line by fluorescence expression (BaeK HJ et al ., Mol Ther. 2011. 19(3):507-514).
- Fig. 7 The results are shown in Fig. 7 on the left and right of a picture taken in an optical microscope mode and a picture taken in a fluorescence microscope mode, respectively. Referring to the fluorescence micrograph on the right side of FIG. 7, it can be seen that the cell lines expressing HER2 are specifically infected with CHO-Her2, J-Her2, and SK-OV-3.
- the HSV-1 infection pathway has a mechanism of action in which gB and gC attach to cells and enter cells by gD.
- CHO-Her2, J-Her2, SK-OV-3 which are cell lines expressing HER2, are the first to infect the virus even though HVEM receptors are deficient, which infects the HER2scFv-HveA adapter-expressing virus prepared in Example 3. At this time, this is because the virus contains a trace amount of HER2scFv-HveA adapter bound to gD or expressed HER2scFv-HveA adapter during virus production through Cre-Vero-HVEM cells.
- HVEM-restricted herpes virus (gD/NI) and HER2scFv-HveA adapter-expressing virus (Her2 Adapter) were used in the HER2-expressing cell line, 1 ⁇ 10 4 .
- SK-OV-3 cells were infected with 2 MOI, and the results of measuring apoptosis through staining of cells using Alamar blue (sigma) on each of the cells on days 1, 2, 3, 4, and 5 are shown in FIG. Done. It can be seen that the apoptosis-inducing effect of the HER2scFv-HveA adapter-expressing virus (Her2 Adapter) is significantly higher than that of the general herpes virus (HSV-1 KOS).
- Example 4-2 Targeting of CEA-expressing cancer cells using CEAscFv-HveA adapter-expressing anti-cancer virus
- KOS-CEAscFv-HveA-EmGFP-gD/R222N/F223I virus prepared in Example 3 induces infection of the virus into surrounding cancer cells by expressing the CEAscFv-HveA adapter as follows: We conducted the experiment together.
- the cell lines used in the experiment were a cell line that does not express CEA (CHO-K1) and a cell line that expresses CEA (CHO-CEA, MKN45).
- Chinese hamster ovary cell lines CHO-K1, CHO-CEA cell lines were 100 U/ml penicillin/100 ⁇ g in HaM's F-12K medium (Welgene).
- CEA-specific virus infection 1.5 ⁇ 10 4 CHO-K1, CHO-CEA cells were infected with the virus at 10 MOI. After 90 minutes, the medium was replaced with fresh medium to remove residual initial virus and CEAscFv-HveA adapter. After 72 hours, the degree of virus infection in each cell line was observed with a fluorescence microscope.
- Fig. 10 The results are shown in Fig. 10 on the left and right of a picture taken in an optical microscope mode and a picture taken in a fluorescence microscope mode, respectively. Referring to the fluorescence micrograph on the right side of FIG. 10, it can be seen that the CHO-K1 cell line was hardly infected, and the CHO-CEA cell line was clearly infected.
- the gD R222N/F223I mutant virus expressing CEAscFv-HveA showed slight infection with the CHO-K1 cell line deficient in HVEM and Nectin-1, as described above, with gB and gC cell adhesion alone as described above. This is because infection of the can occur (BaeK HJ et al ., Mol Ther. 2011. 19(3):507-514).
- the KOS-EmGFP-gD-R222N/F223I virus (gD/NI, control group) produced in Example 2 was in the MKN45 cell line of 6 ⁇ 10 4 and the above implementation.
- KOS-CEAscFv-HveA-EmGFP-gD-R222N/F223I (scCEA-HveA) obtained in Example 3 were each infected with 1 MOI. After 90 minutes, the medium was replaced with fresh medium to remove residual initial virus and CEAscFv-HveA adapter. After 72 hours, the degree of virus infection in each cell line was observed with a fluorescence microscope.
- Fig. 11 The results are shown in Fig. 11 on the left and right of a picture taken in an optical microscope mode and a picture taken in a fluorescence microscope mode. Looking at the picture on the right, it can be seen that the KOS-CEAscFv-HA-EmGFP-gD-R222N/F223I virus is specifically infected with cancer cells compared to the control group KOS-EmGFP-gD-R222N/F223I virus in MKN45 cells.
- HER2scFv-HveA adapter expression KOS-Her2scFv-HveA-EmGFP-gD-R222N/F223I virus and HveA-HER2scFv adapter expression KOS-HveA-HER2scFv-EmGFP-gD-R222N/
- the experiment was carried out as follows.
- the cell lines used in the experiment were CHO-K1, a cell line that does not express HER2, and CHO-HER2, a cell line that expresses HER2.
- Chinese hamster ovary cell lines CHO-K1 and CHO-HER2 were 100 U/ml penicillin/100 ⁇ g/ in HaM's F-12K medium (Welgene). ml streptomycin (Welgene) and 10% FBS (fetal bovine serum) were used to incubate.
- the HER2scFv-HveA, HveA-HER2scFv adapter-expressing viruses prepared in Example 3 were infected with 1 MOI in 1.5 ⁇ 10 4 CHO-K1 and CHO-HER2 cell lines. . After 90 minutes, the medium was replaced with a fresh medium to remove residual initial virus and HER2scFv-HveA, HveA-HER2scFv adapters. Three days after infection, VP16, a protein essential for the transcription of the early virus genes, was stained and the infection of the adapter-expressing viruses having different structures was observed with a fluorescence microscope (BaeK HJ et al ., Mol Ther. 2011. 19(3)). :507-514).
- the gD R222N/F223I mutant virus expressing HER2scFv-HveA or HveA-HER2scFv showed slight infection to the CHO-K1 cell line deficient in HVEM and Nectin-1. This is because some infection can occur even with cell adhesion alone ((BaeK HJ et al ., Mol Ther. 2011. 19(3):507-514).
- CHO-Her2 a cell line expressing HER2, is the first virus to infect the virus even though it lacks the HVEM receptor.
- the virus is Cre-Vero- This is because HER2scFv-HveA adapter and HveA-HER2scFv adapter are bound or expressed HER2scFv-HveA is contained in a trace amount in the process of virus production through HVEM cells.
- Vero-HVEM cell line The cell line used in the experiment was the Vero-HVEM cell line (Gierasch et al.; J. Virol Methods. 2006. 135:197-206). Vero-HVEM cell line was cultured in DMEM medium (Dulbecco's Modified Eagle's Medium (Welgene) using 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10% FBS (fetal bovine serum, Wellgen)).
- DMEM medium Dulbecco's Modified Eagle's Medium (Welgene) using 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10% FBS (fetal bovine serum, Wellgen)).
- Vero-HVEM cells were infected with KOS-Her2scFv-HveA-EmGFP-gD-R222N/F223I and control KOS-EmGFP-gD-R222N/F223I virus at a MOI of 0.1. 90 minutes later, In order to remove the residual initial virus and HER2scFv-HveA adapter, the medium was replaced with a new medium containing no FBS, 48 hours later, the medium was collected, and the Western blot method was used to confirm the expression of the HER2scFv-HveA adapter in the collected medium. Was used to measure the protein expression level.
- the cell line used in the experiment is the SK-OV-3 cell line.
- SK-OV-3 cell line an ovarian cancer cell line, was prepared in DMEM medium (Dulbecco's Modified Eagle's Medium (Welgene)) with 100 U/ml penicillin/100 ⁇ g/ml streptomycin (Welgene) and 10% FBS (fetal bovine serum, Wellgen). ) was used to culture the cells.
- DMEM medium Dulbecco's Modified Eagle's Medium (Welgene)
- FBS fetal bovine serum, Wellgen
- the results are shown at the bottom of FIG. 13. Looking at the results at the bottom of FIG. 13, 24 hours after infection, one infected group was observed by the KOS-Her2scFv-HveA-EmGFP-gD-R222N/F223I virus. Then, 48 hours and 72 hours passed, the virus was observed to rapidly spread to the surrounding cancer cells of the first infected group.
- the adapter inserted through intracellular infection of the KOS-Her2scFv-HveA-EmGFP-gD-R222N/F223I virus is released outside the cell, binds to the antigen on the surface of the surrounding cancer cells, and lysis Viruses released by the virus either target an adapter to which cancer cells are already bound, or by an adapter bound to the virus, an infection spread to surrounding cancer cells expressing a target molecule was confirmed.
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Abstract
Description
Claims (20)
- 헤르페스 심플렉스 바이러스의 증식을 저해하지 않으면서 그 게놈에, 암세포 표적화 영역과 HVEM의 세포외 도메인의 융합 단백질을 발현할 수 있는 발현 카세트가 삽입되어 있는, 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 HVEM의 세포외 도메인은 서열번호 7 또는 8의 아미노산 서열로 이루어진 HveA82, 서열번호 9또는 10의 아미노산 서열로 이루어진 HveA87, 서열번호 11 또는 12의 아미노산 서열로 이루어진 HveA102 또는 서열번호 13 또는 14의 아미노산 서열로 이루어진 HveA107인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 융합단백질은 그 암세포 표적화 영역과 그 HVEM(HveA)의 세포외 도메인은 1 내지 30개 아미노산으로 이루어진 링커 펩티드에 의해 연결되어 있는 융합단백질인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제3항에 있어서,상기 링커 펩티드의 아미노산은 Ser, Gly, Ala 및 Thr 중 하나 이상의 아마노산으로 이루어진 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 암세포 표적화 영역은 표적세포인 암세포의 표적분자를 특이적으로 인식하여 결합하는 영역이고,상기 표적분자는 암세포에서만 발현되거나 정상세포에 비해 암세포에서 과발현되는 암세포 표면의 항원 또는 수용체인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제5항에 있어서,상기 항원 또는 수용체는 EGFRvⅢ, EGFR, 메타스틴 수용체(Metastin receptor), 수용체 타이로신 카이나제(Receptor tyrosine kinases), HER2(Human epidermal growth factor receptor 2), 타이로신 카이나제-18-수용체(c-Kit), HGF 수용체 c-Met, CXCR4, CCR7, 엔도테린-A 수용체, PPAR-δ(peroxisome proliferator activated receptor δ), PDGFR-α(Platelet-derived growth factor receptor α), CD133, CEA(carcinoembryonic antigen), EpCAM(Epithelial cell adhesion molecule), GD2(disialoganglioside), GPC3(Glypican 3), PSMA(Prostate Specific Membrane Antigen), TAG-72(tumor-associated glycoprotein 72), GD3(disialoganglioside), HLA-DR(human leukocyte antigen-DR), MUC1(Mucin 1), NY-ESO-1(New York esophageal squamous cell carcinoma 1), LMP1(Latent membrane protein 1), TRAILR2(tumor-necrosis factor-related apoptosis-inducing ligand receptor), VEGFR2(vascular endothelial growth factor receptor 2), HGFR(hepatocyte growth factor receptor), CD44 또는 CD166인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 암세포 표적화 영역은 표적세포인 암세포의 표적분자인 HER2를 특이적으로 인식하여 결합하는 도메인이고,그 영역은 서열번호 1의 VH와 서열번호 2의 VL이 링커 펩티드를 매개로 VH, 링커 펩티드 VL 순서로 연결된 scFv인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제7항에 있어서,상기 링커 펩티드는 서열번호 5의 아미노산 서열을 가지는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 암세포 표적화 영역은 표적세포인 암세포의 표적분자인 CEA를 특이적으로 인식하여 결합하는 도메인이고,그 영역은 서열번호 3의 VL와 서열번호 4의 VH가 링커 펩티드를 매개로 VL, 링커 펩티드, VH 순서로 결합된 scFv인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제9항에 있어서,상기 링커 펩티드는 서열번호 6의 아미노산 서열을 가지는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 재조합 헤르페스 심플렉스 바이러스는 gD(glycoprotein D)의 아미노산 서열 222번 위치의 아르기닌(arginine, R)과 223번 위치의 페닐알라닌(phenylalanime, F)이 각각 아스파라긴(asparagine, N)과 이소루신(isoleucine, I)로 치환된 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,재조합 헤르페스 심플렉스 바이러스는 그 당단백질 gB, gC, gD 또는 gH에 암 세포의 표적화 영역이 삽입되어 있는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 재조합 헤르페스 심플렉스 바이러스는 재조합 HSV-1 바이러스, 재조합 HSV-2 바이러스, 또는 HSV-1와 HSV-2 키메라 바이러스인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 재조합 헤르페스 심플렉스 바이러스는 HSV-1 KOS 균주로부터 유래된 재조합 HSV-1인 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 재조합 헤르페스 심플렉스 바이러스에는 헤르페스 심플렉스 바이러스의 증식을 저해하지 않으면서 그 게놈에, (i) 사이토카인, (ii) 케모카인, (iii) 면역관문(immune checkpoint)에 대한 길항제, (iv) 면역세포의 활성화를 유도할 수 있는 보조 자극 인자(co-stimulatory factor), (v) 암세포에 대한 면역반응을 억제하는 TGFβ에 대항 길항제, (vi) 고형암 종양미세환경을 구성하는 헤파란 설페이트 프로테오글리칸(heparan sulfate proteoglycan)을 분해할 수 있는 헤파라나아제(heparanase), (vii) 혈관 신생 인자 수용체인 VEGFR-2(VEGF receptor-2)의 기능을 저해할 수 있는 길항제, 및 (viii) 프로드럭(prodrug)을 암세포에 독성을 나타내는 약물(drug)으로 전환시켜주는 프로드럭 활성화 효소(prodrug-activating enzymes) 중에 선택된 것을 발현하는 발현 카세트가 추가로 삽입되어 있는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제15항에 있어서,상기 사이토카인은 IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-18, IL-24 등의 인터류킨, IFNα, IFNβ, IFNγ 등의 인터페론, TNFα 등의 종양 괴사 인자, GM-CSF 및 G-CSF 중 하나 이상이고,상기 케모카인은 CCL2, RANTES, CCL7, CCL9, CCL10, CCL12, CCL15, CCL19, CCL21, CCL20 및 XCL-1 중 하나 이상이며,상기 면역관문은 PD-1(programmed cell death-1), PD-L1(programmed cell deathligand 1), PD-L2(programmed cell death-ligand 2), CD27(cluster of differentiation 27), CD28(cluster of differentiation 28), CD70(cluster of differentiation 70), CD80(cluster of differentiation 80), CD86(cluster of differentiation 86), CD137(cluster of differentiation 137), CD276(cluster of differentiation 276), KIRs(killer-cell immunoglobulin-like receptors), LAG3(lymphocyte-activation gene 3), GITR(glucocorticoid-induced TNFR-related protein), GITRL(glucocorticoid-induced TNFR-related protein ligand) 및 CTLA-4(cytolytic T lymphocyte associated antign-4) 중 하나 이상이며,상기 보조 자극 인자는 CD2, CD7, LIGHT, NKG2C,CD27, CD28, 4-1BB, OX40, CD30, CD40, LFA-1(림프구 기능 연관 항원-1), ICOS(유도성 T 세포 공동자극인자), CD3γ, CD3δ 및 CD3ε 중 하나 이상이며,상기 프로드럭 활성화 효소(prodrug-activating enzymes)는 시토신 디아민나아제(Cytosine deaminase), 랫드 사이토크롬 P450(rat cytochrome P450, CYP2B1), 카르복실에스터라제(carboxylesterase), 세균 니트로리덕타아제(bacterial nitroreductase) 및 대장균에서 분리된 PNP(purine nucleoside phosphorylase) 중 하나 이상인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 융합 단백질의 발현 카세트는 상기 바이러스 게놈에, UL3와 UL4 유전자 사이, UL26과 UL27 유전자 사이, UL37과 UL38 유전자 사이, UL48과 UL49 유전자 사이, UL53과 UL54 유전자 사이, US1과 US2 사이에 삽입되어 있는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제15항에 있어서,상기 발현 카세트가 상기 바이러스 게놈에, UL3와 UL4 유전자 사이, UL26과 UL27 유전자 사이, UL37과 UL38 유전자 사이, UL48과 UL49 유전자 사이, UL53과 UL54 유전자 사이, US1과 US2 사이에 삽입되어 있되, 상기 융합 단백질의 발현 카세트와는 다른 위치에 삽입되어 있는 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 융합 단백질은 NH2-암세포 표적화 도메인-HVEM 세포외 도메인-COOH 순이거나 그 역순인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
- 제1항에 있어서,상기 융합 단백질은 암세포 표적화 영역과 HVEM의 세포외 도메인이 링커 펩타이드를 매개로 연결되고, 상기 융합 단백질은 NH2-암세포 표적화 영역-링커 펩타이드-HVEM 세포외 도메인-COOH 순이거나 그 역순인 것을 특징으로 하는 재조합 헤르페스 심플렉스 바이러스.
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CA3144881A CA3144881A1 (en) | 2019-08-22 | 2020-08-24 | Recombinant herpes simplex virus having expression cassette capable of expressing fusion protein formed from cancer cell targeting region and hvem extracellular domain, and use thereof |
CN202080059083.5A CN114302957A (zh) | 2019-08-22 | 2020-08-24 | 具有能够表达由癌细胞靶向区与hvem胞外结构域形成的融合蛋白的表达盒的重组单纯疱疹病毒和其用途 |
EP20854496.5A EP4019626A4 (en) | 2019-08-22 | 2020-08-24 | RECOMBINANT HERPES SIMPLEX VIRUS HAVING EXPRESSION CASSETTE CAPABLE OF EXPRESSING FUSION PROTEIN FORMED FROM CANCER CELL TARGET REGION AND EXTRACELLULAR DOMAIN HVEM AND USE THEREOF |
JP2022512751A JP2022545120A (ja) | 2019-08-22 | 2020-08-24 | 癌細胞標的化領域とhvemの細胞外ドメインとの融合タンパク質を発現可能な発現カセットを有する組換え単純ヘルペスウイルス及びその用途 |
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KR100937774B1 (ko) | 2007-09-17 | 2010-01-20 | 재단법인 한국원자력의학원 | 헤르페스바이러스의 세포 감염 효율을 증가시키는 수용성재조합 단백질 sHveA 및 유전자 치료에 이의 적용 |
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Also Published As
Publication number | Publication date |
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EP4019626A1 (en) | 2022-06-29 |
KR102405246B1 (ko) | 2022-06-08 |
JP2022545120A (ja) | 2022-10-25 |
US11421017B2 (en) | 2022-08-23 |
EP4019626A4 (en) | 2023-03-29 |
US20210054052A1 (en) | 2021-02-25 |
CN114302957A (zh) | 2022-04-08 |
CA3144881A1 (en) | 2021-02-25 |
AU2020333370B2 (en) | 2024-05-09 |
AU2020333370A1 (en) | 2022-03-03 |
KR20210023751A (ko) | 2021-03-04 |
KR20210111237A (ko) | 2021-09-10 |
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