Method for Treating Cancer with a Coxsackievirus B3 (CVB3) Variant

• US 20190099460A1
• Filed: 09/29/2017
• Published: 04/04/2019
• Est. Priority Date: 09/29/2017
• Status: Active Grant

• Current Assignee: Technische Universitã¤T Berlin (Tu)
• Original Assignee: Technische Universitã¤T Berlin (Tu)
• Inventors: FECHNER, Henry, HAZINI, Ahmet, BRUECKNER, Vanessa
• Granted Patent: US 10,639,337 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 2770/32321 Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2770/32332 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2770/32371 Demonstrated in vivo effect
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a Coxsackie B3 group virus or a modified form thereof, wherein the cells of the cancer express a heparan sulfate (HS) receptor on their surface and the virus binds to said HS receptor, enters and accumulates in the cancer cells, whereby at least some cancer cells undergo viral lysis.

Claims

1. A method for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a Coxsackie B3 group (CVB3) virus or a modified form thereof, wherein the cells in the tumor and/or the cancer cells of the tumor express a heparan sulfate (HS) receptor on their surface, wherein the virus binds to said HS receptor, enters and accumulates in the HS expressing cells, and causes the infected cells to undergo viral lysis.

2. The method according to claim 1, wherein the CVB3 virus comprise at lease one or several alterations in amino acid sequence selected from the group comprising the amino acid residues K78, A80, A91 and I92 in the viral capsid protein 1 (VP1) and/or the amino acid residue M34 and Y237 in the viral capsid protein 3 (VP3).

3. The method according to claim 2, wherein the Coxsackie B3 group virus is selected from the group of CVB3 Nancy, 31-1-93, H3 and PD, all being characterized by at least one modification in the VP1 and/or VP3 surface protein.

4. The method according to claim 2, wherein the CVB3 virus is CVB3 PD-0 or a modified form thereof.

5. The method according to claim 1, wherein the range of viral dose is between about 5×

10⁵ to about 3×

10⁸ plaque forming units (PFU), preferably between about 3×

10⁶ to about 3×

10⁷ PFU and further preferred between about 3×

10⁶ to about 3×

10⁸ PFU.

6. The method according to claim 1, wherein the cancer is selected from the group of colorectal carcinoma, esophageal cancer, breast cancer, lung cancer, pancreatic cancer, prostata cancer, gastric cancer and liver cancer.

7. The method according to claim 1, wherein the HS receptor is a N- and/or a 6-O-sulfated heparan.

8. The method according to claim 1, wherein cells of the tumor substantially lacking or have expression of the Coxsackievirus and adenovirus receptor (CAR) and/or the decay-accelerating factor (DAF) on their surface.

17. A pharmacological composition for use in treating cancer in a subject in need thereof, comprising:

i) a therapeutically effective amount of a Coxsackie B3 group (CVB3) virus or a modified form thereof according to claim 1, capable of lytically infecting said cancer; and

ii) at least one pharmaceutically acceptable excipient, diluent or carrier.

9. A method for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a nucleic acid molecule or fragment thereof derived from a Coxsackie B3 group (CVB3) virus, wherein the cells in the tumor and/or the cancer cells of the tumor express a heparan sulfate (HS) receptor on their surface, wherein the nucleic acid molecule is transferred into the tumor and/or into the cancer cells, produces viral particles, which cause the transfected cells to undergo viral lysis, thereby releasing further virus particles which bind to HS receptor on cancer cells, enter these, accumulate in the HS expressing cells, and eventually causes lysis of the infected cells.

10. The method according to claim 9, wherein the CVB3 virus is a recombinant virus and comprises at least one additional nucleic acid molecule in its genomic sequence.

11. The method according to claim 10, wherein the at least one additional nucleic acid molecule is selected from the group of therapeutic, transgenic or small RNAs.

12. The method according to claim 9, wherein the CVB3 virus is selected from the group of CVB3 Nancy, 31-1-93, H3 and PD, which are all characterized by at lease one or several alterations in amino acid sequence selected from the group comprising the amino acid residues K78, A80, A91, and I92 in the viral capsid protein 1 (VP1).

13. The method according to claim 9, wherein the CVB3 virus is CVB3 PD or a modified form thereof.

14. The method according to claim 9, wherein the nucleic acid sequence of CVB3 PD comprise RNA residues giving rise to amino acid residues K78, A80, A91, and I92 in the viral capsid protein 1 (VP1).

15. The method according to claim 9, wherein the cancer is selected from the group of colorectal carcinoma, esophageal cancer, breast cancer, lung cancer, pancreatic cancer, prostata cancer, gastric cancer and liver cancer.

16. The method according to claim 9, wherein the HS receptor is N- and/or 6-O-sulfated.

18. A pharmacological composition for use in treating cancer in a subject in need thereof, comprising:

i) a therapeutically effective amount of a nucleic acid molecule derived from the CVB3 virus or a modified form thereof according to claim 9, capable of lytically infecting said cancer; and

ii) at least one pharmaceutically acceptable excipient, diluent or carrier.