Administration of kynurenine depleting enzymes for tumor therapy

Patent metadata

Field	Value
Publication number	US-10772913-B2
Application number	US-201916373588-A
Country	US
Kind code	B2
Filing date	Apr 2, 2019
Priority date	Aug 30, 2013
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Methods and compositions related to the use of a protein with kynureninase activity are described. For example, in certain aspects there may be disclosed a modified kynureninase capable of degrading kynurenine. Furthermore, certain aspects of the invention provide compositions and methods for the treatment of cancer with kynurenine depletion using the disclosed proteins or nucleic acids.

First claim

What is claimed is:

1. An isolated polypeptide comprising a kynureninase enzyme having an amino acid sequence that is at least 90% identical to SEQ ID NO: 8, and having one or more substitutions relative to SEQ ID NO: 8, wherein the one or more substitutions comprise a substitution of the Phe found at position 306 of SEQ ID NO: 8, wherein the enzyme is formulated in a pharmaceutically acceptable carrier.

2. The enzyme of claim 1 , wherein the enzyme has an amino acid sequence that is at least 95% identical to SEQ ID NO: 8.

3. The enzyme of claim 1 , wherein the at least one substitution comprises Phe306Met.

4. The enzyme of claim 1 , wherein the at least one substitution comprises Phe306Leu.

5. The enzyme of claim 1 , further comprising a heterologous peptide segment.

6. The enzyme of claim 5 , wherein the heterologous peptide segment is an XTEN peptide, an IgG Fc, an albumin, or an albumin binding peptide.

7. The enzyme of claim 1 , wherein the enzyme is coupled to polyethylene glycol (PEG).

8. The enzyme of claim 7 , wherein the enzyme is coupled to PEG by way of one or more Lys or Cys residues.

9. The enzyme of claim 1 , wherein the kynureninase has greater catalytic activity towards kynurenine than 3′-OH kynurenine.

10. The enzyme of claim 1 , wherein the kynureninase has a k cat /K M for kynurenine of at least 0.5 M −1 /s −1 .

11. A nucleic acid encoding the enzyme of claim 1 .

12. The nucleic acid of claim 11 , wherein the nucleic acid is codon optimized for expression in bacteria, fungus, insects, or mammals.

13. An expression vector comprising the nucleic acid of claim 11 .

14. A host cell comprising the nucleic acid of claim 11 .

15. The host cell of claim 14 , wherein the host cell is a bacterial cell, a fungal cell, an insect cell, or a mammalian cell.

16. A pharmaceutical composition comprising the expression vector of claim 13 .

17. The pharmaceutical composition of claim 16 , wherein the enzyme has an amino acid sequence that is at least 95% identical to SEQ ID NO: 8.

18. The pharmaceutical composition of claim 16 , wherein the kynureninase has greater catalytic activity towards kynurenine than 3′-OH kynurenine.

19. The pharmaceutical composition of claim 16 , wherein the kynureninase has a k cat /K M for kynurenine of at least 0.5 M −1 /s −1 .

Assignees

• Univ Texas

Inventors

• Georgiou George
• Stone Everett

Classifications

• A61K40/4244

  Enzymes · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K2121/00

  Preparations for use in therapy · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12Y307/01003

  Kynureninase (3.7.1.3) · CPC title