RNA VIRUSES EXPRESSING IL-12 FOR IMMUNOVIROTHERAPY

• US 20190315825A1
• Filed: 06/28/2019
• Published: 10/17/2019
• Est. Priority Date: 02/25/2016
• Status: Active Application

• Current Assignee: Deutsches Krebsforschungszentrum, Ruprecht-Karls-Universität Heidelberg
• Original Assignee: Deutsches Krebsforschungszentrum
• Inventors: UNGERECHTS, Guy, ENGELAND, Christine, VEINALDE, Ruta
• Application Number:
  US16/456,773
• Publication Number:
  US 20190315825A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/5434 IL-12
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3007 Carcino-embryonic Antigens
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C12N 2760/18043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2760/18432 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2760/18443 viral genome or elements thereof as genetic vector

Abstract

The present invention relates to a recombinant virus of the family Paramyxoviridae, comprising at least one expressible polynucleotide encoding an IL-12 polypeptide, wherein said IL-12 polypeptide is an IL-12 fusion polypeptide comprising a p35 subunit of an IL-12 and a p40 subunit of an IL-12; to a polynucleotide encoding the same, and to a kit comprising the same. Moreover, the present invention relates to a method for treating cancer in a subject afflicted with cancer, comprising contacting said subject with a recombinant virus of the family Paramyxoviridae of the invention, and thereby, treating cancer in a subject afflicted with cancer.

Claims

1. A recombinant virus of the family Paramyxoviridae, comprising an expressible polynucleotide encoding an IL-12 polypeptide, wherein said IL-12 polypeptide is an IL-12 fusion polypeptide comprising a p35 subunit of an IL-12 and a p40 subunit of an IL-12.

2. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said p35 subunit and said p40 subunit of said IL-12 fusion polypeptide are from the same species.

3. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said IL-12 fusion polypeptide comprises the structure p35-linker-p40.

4. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said linker is -(glycine₄-serine)_n-, with n=1 to 10.

5. The recombinant virus of the family Paramyxoviridae of claim 1, further comprising at least one expressible polynucleotide encoding a further activator of the immune response.

6. The recombinant virus of the family Paramyxoviridae of claim 5, wherein said further activator of the immune response is a secreted immunoglobulin.

7. The recombinant virus of the family Paramyxoviridae of claim 5, wherein said further activator of the immune response is an Fc domain of an antibody.

8. The recombinant virus of the family Paramyxoviridae of claim 5, wherein said further activator of the immune response is a secreted soluble activator of the immune response.

9. The recombinant virus of the family Paramyxoviridae of claim 5, wherein said further activator of the immune response is a secreted soluble anti-PD-L1 antibody.

10. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said recombinant virus is a recombinant Morbillivirus.

11. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said recombinant virus is derived from a measles virus strain Edmonston A or B.

12. The recombinant virus of the family Paramyxoviridae of claim 1, wherein the at least one expressible polynucleotide encoding an IL-12 polypeptide is comprised in a polynucleotide encoding the recombinant virus of the family Paramyxoviridae.

13. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said polynucleotide encoding the recombinant virus of the family Paramyxoviridae comprises the nucleic acid sequence of any one of SEQ ID NOs:

4 to 7, 14, and 15.

14. A medicament comprising

(a) (i) a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 and not comprising an expressible polynucleotide encoding a CTLA-4 antagonist, a PD-1 antagonist, a CD80 antagonist, a CD86 antagonist, or a PD-L1 antagonist;

(ii) a recombinant virus of the family Paramyxoviridae according to claim 1,

(iii) a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (i) and/or (ii),

(iv) a host cell comprising the recombinant virus of the family Paramyxoviridae according to (i) or (ii) and/or a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (iii);

or

(v) any combination of (i) to (iv); and

(b) at least one pharmacologically acceptable excipient.

15. A method for treating cancer in a subject afflicted with cancer, comprising

a) contacting said subject with

(i) a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 and not comprising an expressible polynucleotide encoding a CTLA-4 antagonist, a PD-1 antagonist, a CD80 antagonist, a CD86 antagonist, or a PD-L1 antagonist;

(ii) a recombinant virus of the family Paramyxoviridae according of claim 1,

(iii) a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (i) and/or (ii),

(iv) a host cell comprising the recombinant virus of the family Paramyxoviridae according to (i) or (ii) and/or a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (iii);

or

(v) any combination of (i) to (iv); and

, thereby,

b) treating cancer in a subject afflicted with cancer.

16. The method of claim 15, wherein said recombinant virus of the family Paramyxoviridae of (i) is a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 polypeptide and not comprising an expressible polynucleotide encoding a ligand for an immune checkpoint blockade protein.

17. The method of claim 15, wherein said recombinant virus of the family Paramyxoviridae of (i) is a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 polypeptide as the only expressible polynucleotide encoding an activator of the immune response.

18. The method of claim 15, wherein said cancer is a solid cancer, a metastasis, or a relapse thereof.

19. The method of claim 15, wherein treating cancer is reducing tumor burden.

20. The method of claim 15, wherein said cancer is malignant melanoma, head and neck cancer, hepatocellular carcinoma, pancreatic carcinoma, prostate cancer, renal cell carcinoma, gastric carcinoma, colorectal carcinoma, lymphomas or leukemias.

21. The recombinant virus of the family Paramyxoviridae of claim 1, wherein said p35 subunit and said p40 subunit of said IL-12 fusion polypeptide are a mouse p35 subunit and a mouse p40 subunit or a variant thereof, or a human p35 subunit and a human p40 subunit or a variant thereof.