# US 10,421,979 B2 · Retargeted herpesvirus with a glycoprotein H fusion

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- Number: US 10,421,979 B2
- Document ID: US10421979B2
- Status: Granted
- Kind: B2
- Application number: 15/548,731
- Filed: 2016-02-11
- Published: 2018-01-04
- Granted: 2019-09-24
- Earliest claimed: 2015-02-11
- Assignees: Alma Mater Studiorum - Università di Bologna
- Applicants: Alma Mater Studiorum Universita'di Bologna
- Inventors: Maria Gabriella Campadelli; Valentina Gatta
- Web page: https://patentgrep.com/patent/US10421979B2

## CPC

- C12N 15/869: Herpesviral vectors
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61P 31/22: for herpes viruses
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/86: Viral vectors
- A61K 2039/5254: {avirulent or attenuated}
- A61K 2039/5256: {expressing foreign proteins}
- C12N 2710/16032: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2710/16632: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to the field of disease therapy. More specifically, it relates to a retargeted herpesvirus having a heterologous polypeptide fused to glycoprotein H, wherein the polypeptide targets diseased cells. It also relates to a nucleic acid comprising the genome of the herpesvirus of the invention, a vector comprising this nucleic acid and a cell comprising the nucleic acid or the vector. It further relates to killing cells using the herpesvirus of the invention and to methods for growing it in vitro.

## Claims

### Claim 1

A recombinant infectious herpesvirus comprising a heterologous polypeptide ligand inserted into mature glycoprotein H (gH)
(i) between amino acid 23 and amino acid 24 of the gH according to SEQ ID NO: 1 or a corresponding region of a homologous gH, or
(ii) within the region starting at amino acid 116 and ending at amino acid 136 of the gH according to SEQ ID NO: 1 or a corresponding region of a homologous gH.

### Claim 2 (depends on 1)

The recombinant infectious herpesvirus of claim 1, wherein one or more gH amino acids of the N-terminal region are deleted.

### Claim 3 (depends on 1)

The recombinant infectious herpesvirus of claim 1, wherein said herpesvirus has a reduced virulence compared to a wildtype, or has a higher replicative capacity in diseased cells than in non-diseased cells.

### Claim 4 (depends on 1)

The recombinant infectious herpesvirus of claim 1, comprising an altered glycoprotein D (gD) having reduced specific binding to gD's cellular ligands compared to wildtype gD or having no specific binding to gD's cellular ligands, or which lacks gD.

### Claim 5

A recombinant infectious herpesvirus comprising a heterologous polypeptide ligand fused to the N-terminus of mature glycoprotein H (gH) or of a truncated gH, or inserted into gH, and further comprising a heterologous polypeptide ligand fused to the N-terminus of mature gD or of a truncated gD, or inserted into gD.

### Claim 6 (depends on 1)

The recombinant infectious herpesvirus of claim 1, further comprising a heterologous detectable marker and/or one or more expression cassettes expressing one or more of the following
i) one or more therapeutic proteins,
ii) one or more heterologous or autologous antigens, epitopes/neoepitopes or string of epitopes/neoeptitopes, or
iii) one or more prodrug-converting enzymes.

### Claim 7 (depends on 1)

The recombinant infectious herpesvirus of claim 1, wherein the heterologous polypeptide ligand fused to or inserted into gH binds to a molecule or part thereof accessible on the surface of a cell.

### Claim 8 (depends on 1)

The recombinant infectious herpesvirus of claim 1 for use in medicine.

### Claim 9 (depends on 4)

The recombinant infectious herpesvirus of claim 4, comprising an altered glycoprotein D (gD), wherein gD has an amino acid deletion starting at any of amino acid residues 26 to 33 and ending at any of amino acid residues 31 to 63, and/or starting at any of amino acid residues 65 to 86 and ending at any of amino acid residues 235 to 243 of the gD according to SEQ ID NO: 4 or a corresponding region of a homologous gD.

### Claim 10 (depends on 7)

The recombinant infectious herpesvirus of claim 7, wherein the cell is a diseased cell.

### Claim 11 (depends on 5)

The recombinant infectious herpesvirus of claim 5, wherein the heterologous polypeptide ligand is inserted within the N-terminal region starting at any one of amino acids 19 to 23 and ending at any one of amino acids 48 to 88 or starting at amino acid 116 and ending at amino acid 136 of the gH according to SEQ ID NO: 1 or a corresponding region of a homologous gH.

### Claim 12 (depends on 5)

The recombinant infectious herpesvirus of claim 5, wherein the heterologous polypeptide ligand is inserted N-terminally of the H1A domain of gH.

### Claim 13 (depends on 5)

The recombinant infectious herpesvirus of claim 5, comprising an altered glycoprotein D (gD) having reduced specific binding to gD's cellular ligands compared to wildtype gD or having no specific binding to gD's cellular ligands, or which lacks gD.

### Claim 14 (depends on 5)

The recombinant infectious herpesvirus of claim 5, comprising an altered glycoprotein D (gD), wherein gD has an amino acid deletion starting at any of amino acid residues 26 to 33 and ending at any of amino acid residues 31 to 63, and/or starting at any of amino acid residues 65 to 86 and ending at any of amino acid residues 235 to 243 of the gD according to SEQ ID NO: 4 or a corresponding region of a homologous gD.

### Claim 15 (depends on 5)

The recombinant infectious herpesvirus of claim 5, wherein one or more gH amino acids of the N-terminal region are deleted.

### Claim 16 (depends on 5)

The recombinant infectious herpesvirus of claim 5, wherein said herpesvirus has a reduced virulence compared to the wildtype, or has a higher replicative capacity in diseased cells than in non-diseased cells.

### Claim 17 (depends on 5)

The recombinant infectious herpesvirus of claim 5, further comprising a heterologous detectable marker and/or one or more expression cassettes expressing one or more of the following:
i) one or more therapeutic proteins;
ii) one or more heterologous or autologous antigens, epitopes/neoepitopes or string of epitopes/neoeptitopes; or
iii) one or more prodrug-converting enzymes.

### Claim 18 (depends on 5)

The recombinant infectious herpesvirus of claim 5, wherein the heterologous polypeptide ligand fused to or inserted into gH and/or gD binds to a molecule or part thereof accessible on the surface of a cell.

### Claim 19 (depends on 18)

The recombinant infectious herpesvirus of claim 18, wherein the cell is a diseased cell.

### Claim 20 (depends on 5)

The recombinant infectious herpesvirus of claim 5 for use in medicine.

### Claim 21

A recombinant infectious herpesvirus comprising a heterologous polypeptide ligand fused to the N-terminus of mature glycoprotein H (gH) or of a truncated gH, or inserted into gH, and further comprising an altered glycoprotein D (gD), wherein gD has an amino acid deletion starting at any of amino acid residues 26 to 33 and ending at any of amino acid residues 31 to 63, and/or starting at any of amino acid residues 65 to 86 and ending at any of amino acid residues 235 to 243 of the gD according to SEQ ID NO: 4 or a corresponding region of a homologous gD.

### Claim 22 (depends on 21)

The recombinant infectious herpesvirus of claim 21, wherein the heterologous polypeptide ligand is inserted within the N-terminal region starting at any one of amino acids 19 to 23 and ending at any one of amino acids 48 to 88 or starting at amino acid 116 and ending at amino acid 136 of the gH according to SEQ ID NO: 1 or a corresponding region of a homologous gH.

### Claim 23 (depends on 21)

The recombinant infectious herpesvirus of claim 21, wherein the heterologous polypeptide ligand is inserted N-terminally of the H1A domain of gH.

### Claim 24 (depends on 21)

The recombinant infectious herpesvirus of claim 21, wherein one or more gH amino acids of the N-terminal region are deleted.

### Claim 25 (depends on 21)

The recombinant infectious herpesvirus of claim 21, wherein said herpesvirus has a reduced virulence compared to the wildtype, or has a higher replicative capacity in diseased cells than in non-diseased cells.

### Claim 26 (depends on 21)

The recombinant infectious herpesvirus of claim 21, comprising a heterologous polypeptide ligand fused to the N-terminus of mature gD or of a truncated gD, or inserted into gD.

### Claim 27 (depends on 21)

The recombinant infectious herpesvirus of claim 21, further comprising a heterologous detectable marker and/or one or more expression cassettes expressing one or more of the following:
i) one or more therapeutic proteins;
ii) one or more heterologous or autologous antigens, epitopes/neoepitopes or string of epitopes/neoeptitopes; or
iii) one or more prodrug-converting enzymes.

### Claim 28 (depends on 21)

The recombinant infectious herpesvirus of claim 21, wherein the heterologous polypeptide ligand fused to or inserted into gH and/or gD binds to a molecule or part thereof accessible on the surface of a cell.

### Claim 29 (depends on 28)

The recombinant infectious herpesvirus of claim 28, wherein the cell is a diseased cell.

### Claim 30 (depends on 21)

The recombinant infectious herpesvirus of claim 21 for use in medicine.