Granted Patent
B2
US 12,364,775 · App. 18/316,899 · Granted Jul 22, 2025
Viral vectors for cancer therapy
Inventors:
Suma Krishnan (Pittsburgh, PA); Trevor Parry (San Diego, CA); Dana Michelle Previte (Sewickley, PA); Mary Jane Duermeyer (Glenshaw, PA)
Assignee:
Krystal Biotech, Inc.
A61K48/0066A61K38/193A61K38/2013A61K38/208A61P35/00C12N7/00C12N15/86C12N2710/16622C12N2710/16633C12N2710/16643C12N2710/16662C12N2710/16671
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Abstract
The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding an immunomodulatory polypeptide (e.g., a pro-inflammatory cytokine such as a human IL-2 or IL-12 polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for the treatment of cancer, such as lung cancer); and articles of manufacture or kits thereof.
Claims (42)
1. A method of providing therapeutic relief of one or more signs or symptoms of lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
(a) a herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises a polynucleotide encoding an Interleukin (IL)-12 polypeptide and a polynucleotide encoding an IL-2 polypeptide; and
(b) a pharmaceutically acceptable excipient,
wherein the pharmaceutical composition is administered intratracheally, intratumorally, or via inhalation to the subject,
wherein the IL-12 polypeptide comprises an IL-12 subunit alpha polypeptide and an IL-12 subunit beta polypeptide connected by a linker polypeptide, and
wherein the recombinant herpes simplex virus genome further comprises a first promoter operably linked to the polynucleotide encoding the IL-12 polypeptide and a second promoter operably linked to the polynucleotide encoding IL-2 polypeptide.
2. The method of claim 1 , wherein the subject is a human.
3. The method of claim 1 , wherein the pharmaceutical composition is administered intratumorally or via inhalation.
4. The method of claim 1 , wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome or a recombinant herpes simplex virus type 2 (HSV-2) genome.
5. The method of claim 1 , wherein the recombinant herpes simplex virus genome does not comprise an inactivating mutation in one or both copies of the ICP34.5 gene.
6. The method of claim 1 , wherein the recombinant herpes simplex virus genome does not comprise an inactivating mutation in the ICP47 gene.
7. The method of claim 1 , wherein the herpes simplex virus is not oncolytic.
8. The method of claim 1 , wherein the herpes simplex virus has reduced cytotoxicity as compared to a corresponding wild-type herpes simplex-virus.
9. The method of claim 1 , wherein the IL-2 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3.
10. The method of claim 1 , wherein the recombinant herpes simplex virus genome does not comprise a polynucleotide encoding a Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) polypeptide.
11. The method of claim 1 , wherein the herpes simplex virus is replication defective.
12. The method of claim 1 , wherein the IL-12 subunit alpha polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5.
13. The method of claim 1 , wherein the IL-12 subunit beta polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 6.
14. The method of claim 1 , wherein the linker polypeptide is a cleavable linker polypeptide.
15. The method of claim 1 , wherein the recombinant herpes simplex virus genome comprises the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within the same viral gene locus.
16. The method of claim 1 , wherein the recombinant herpes simplex virus genome comprises the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within different viral gene loci.
17. A method of providing therapeutic relief of one or more signs or symptoms of lung cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
(a) a population of herpes simplex viruses, wherein the population of herpes simplex viruses comprises recombinant herpes simplex virus genomes comprising a polynucleotide encoding an IL-12 polypeptide and a polynucleotide encoding an IL-2 polypeptide; and
(b) a pharmaceutically acceptable excipient,
wherein the pharmaceutical composition is administered intratracheally, intratumorally, or via inhalation to the subject,
wherein the IL-12 polypeptide comprises an IL-12 subunit alpha polypeptide and an IL-12 subunit beta polypeptide connected by a linker polypeptide, and
wherein the recombinant herpes simplex virus genomes further comprise a first promoter operably linked to the polynucleotide encoding the IL-12 polypeptide and a second promoter operably linked to the polynucleotide encoding the IL-2 polypeptide.
18. The method of claim 17 , wherein the subject is a human.
19. The method of claim 17 , wherein the recombinant herpes simplex virus genomes are recombinant HSV-1 genomes or recombinant HSV-2 genomes.
20. The method of claim 17 , wherein the recombinant herpes simplex virus genomes do not comprise an inactivating mutation in one or both copies of the ICP34.5 gene.
21. The method of claim 17 , wherein the recombinant herpes simplex virus genomes do not comprise an inactivating mutation in the ICP47 gene.
22. The method of claim 17 , wherein the population of herpes simplex viruses is not oncolytic.
23. The method of claim 17 , wherein the population of herpes simplex viruses has reduced cytotoxicity as compared to a corresponding population of wild-type herpes simplex viruses.
24. The method of claim 17 , wherein the IL-2 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3.
25. The method of claim 17 , wherein the pharmaceutical composition is administered intratumorally or via inhalation.
26. The method of claim 17 , wherein the recombinant herpes simplex virus genomes do not comprise a polynucleotide encoding a GM-CSF polypeptide.
27. The method of claim 17 , wherein the population of herpes simplex viruses is replication defective.
28. The method of claim 17 , wherein the recombinant herpes simplex virus genomes comprise the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within the same viral gene locus.
29. The method of claim 17 , wherein the recombinant herpes simplex virus genomes comprise the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within different viral gene loci.
30. The method of claim 17 , wherein the IL-12 subunit alpha polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5.
31. The method of claim 17 , wherein the IL-12 subunit beta polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 6.
32. The method of claim 17 , wherein the linker polypeptide is a cleavable linker polypeptide.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 20, 2023
From: KRISHNAN, SUMA; PARRY, TREVOR; PREVITE, DANA MICHELLE; DUERMEYER, MARY JANE
To: KRYSTAL BIOTECH, INC.
Reel/Frame 064323/0948 →
Continuity (3)
Provisional Application
63170103
· Apr 2, 2021
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