IP Library › Granted Patent US 12,441,992
Granted Patent B2
US 12,441,992 · App. 17/338,508 · Granted Oct 14, 2025

Method of treating AML with PEGylated l-asparaginase

Inventor: Thierry Abribat (Sainte Foy les Lyon, FR)
Assignee: Jazz Pharmaceuticals II SAS
C12N9/82A61K38/50A61K47/60C12N9/96C12Y305/01001Y02A50/30
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Quick Facts
Patent No.
US 12,441,992
App. No.
17/338,508
Granted
Oct 14, 2025
Kind
B2
Abstract

Disclosed is L-asparagine aminohydrolase and polyethylene glycol conjugate. The polyethylene glycol has a molecular weight less than or equal to about 5000 Da and the protein is an L-asparaginase from Erwinia . The conjugate has a high level of in vitro activity and an unexpected increase in half-life in vivo. Methods of producing the conjugate and methods of using the conjugate in therapy in treatment of cancer, particularly Acute Lymphoblastic Leukemia (ALL). The method is disclosed for use of the conjugate as a second line therapy for patients who have developed hypersensitivity or have had a disease relapse after treatment with other L-asparaginase preparations.

Claims (52)

1. A method of treating acute myelocytic leukemia (AML) in a human patient, comprising: administering to the human patient an effective amount of a conjugate comprising four L-asparaginase monomers, wherein each of the monomers has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and is conjugated to at least one polyethylene glycol (PEG) molecule,

wherein each of the at least one PEG molecule has a molecular weight of about 2000 Da to about 5000 Da;

wherein each of the monomers comprises accessible amino groups, wherein about 100% of the accessible amino groups in the monomers are covalently linked to the PEG molecule;

and

wherein the human patient had previous hypersensitivity to an Escherichia coli L-asparaginase or a PEGylated form of an Escherichia coli L-asparaginase.

2. The method of claim 1 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

3. The method of claim 1 , wherein said conjugate has a longer in vivo half-life as compared to SEQ ID NO:1 not conjugated to PEG.

4. The method of claim 1 , wherein said conjugate has at least 75% in vitro activity compared to SEQ ID NO:1 not conjugated to PEG.

5. The method of claim 1 , wherein said conjugate has at least 80% in vitro activity compared to SEQ ID NO:1 not conjugated to PEG.

6. The method of claim 1 , wherein said conjugate has at least 85% in vitro activity compared to SEQ ID NO:1 not conjugated to PEG.

7. The method of claim 1 , wherein said conjugate elicits a lower immunogenic response in the human patient compared to SEQ ID NO:1 not conjugated to PEG.

8. The method of claim 1 , wherein said conjugate does not cross-react with antibodies to the Escherichia coli L-asparaginase.

9. The method of claim 1 , wherein said monomers are recombinant proteins.

10. The method of claim 1 , wherein said conjugate is administered at an amount of 5 U/kg to 25 U/kg.

11. The method of claim 1 , wherein said conjugate is administered at an amount of 25 U/kg.

12. The method of claim 1 , wherein said conjugate is administered intravenously.

13. The method of claim 1 , wherein said conjugate is administered intramuscularly.

14. The method of claim 1 , wherein said conjugate is administered once per week.

15. The method of claim 1 , wherein said conjugate is administered twice per week.

16. The method of claim 1 , wherein said conjugate is administered as a monotherapy.

17. The method of claim 1 , wherein said conjugate is not administered with an asparagine synthetase inhibitor.

18. The method of claim 1 , wherein said hypersensitivity is selected from the group consisting of allergic reaction, anaphylactic shock, and silent hypersensitivity.

19. The method of claim 1 , wherein said human patient has had an acute myelocytic leukemia relapse.

20. The method of claim 19 , wherein said acute myelocytic leukemia relapse occurs after treatment with Escherichia coli L-asparaginase or PEGylated form thereof.

21. The method of claim 18 , wherein the PEG is covalently linked to one or more amino groups of the L-asparaginase.

22. The method of claim 21 , wherein the PEG is covalently linked to the one or more amino groups by an amide bond.

23. The method of claim 18 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

24. The method of claim 18 , wherein said conjugate has a longer in vivo half-life as compared to SEQ ID NO:1 not conjugated to PEG.

25. The method of claim 18 , wherein said conjugate has at least 75% in vitro activity compared to SEQ ID NO:1 not conjugated to PEG.

26. The method of claim 18 , wherein said conjugate elicits a lower immunogenic response in the human patient compared to SEQ ID NO:1 not conjugated to PEG.

27. The method of claim 18 , wherein said conjugate does not cross-react with antibodies to the Escherichia coli L-asparaginase.

28. The method of claim 18 , wherein said monomers are recombinant proteins.

29. The method of claim 18 , wherein said conjugate is administered at an amount of about 5 U/kg to 25 U/kg.

30. The method of claim 18 , wherein said conjugate is administered intravenously or intramuscularly.

31. The method of claim 18 , wherein said conjugate is administered once per week or twice per week.

32. The method of claim 18 , wherein said conjugate is administered as a monotherapy.

33. The method of claim 18 , wherein said conjugate is not administered with an asparagine synthetase inhibitor.

34. The method of claim 18 , wherein said human patient has had an acute myelocytic leukemia relapse.

35. The method of claim 34 , wherein said acute myelocytic leukemia relapse occurs after treatment with Escherichia coli L-asparaginase or PEGylated form thereof.

36. The method of claim 1 , wherein each of the monomers comprises the amino acid sequence of SEQ ID NO: 1.

37. A method of treating acute myelocytic leukemia (AML) in a human patient, comprising: administering to the human patient an effective amount of a conjugate comprising four L-asparaginase monomers, wherein each of the monomers has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and is conjugated to at least one polyethylene glycol (PEG) molecule,

wherein each of the at least one PEG molecule has a molecular weight of about 2000 Da;

wherein each of the monomers comprises accessible amino groups, and wherein about 100% of the accessible amino groups are covalently linked to the PEG molecule; and wherein the human patient had previous hypersensitivity to an Escherichia coli L-asparaginase or a PEGylated form of an Escherichia coli L-asparaginase.

38. The method of claim 37 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

39. The method of claim 37 , wherein each of the monomers comprises the amino acid sequence of SEQ ID NO: 1.

40. The method of claim 39 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

41. A method of treating acute myelocytic leukemia (AML) in a human patient, comprising: administering to the human patient an effective amount of a conjugate comprising four L-asparaginase monomers, wherein each of the monomers has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and is conjugated to at least one polyethylene glycol (PEG) molecule,

wherein each of the at least one PEG molecule has a molecular weight of about 5000 Da;

wherein each of the monomers comprises accessible amino groups, and wherein about 100% of the accessible amino groups are covalently linked to the PEG molecule; and wherein the human patient had previous hypersensitivity to an Escherichia coli L-asparaginase or a PEGylated form of an Escherichia coli L-asparaginase.

42. The method of claim 41 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

43. The method of claim 41 , wherein each of the monomer comprises the amino acid sequence of SEQ ID NO: 1.

44. The method of claim 43 , wherein the PEG molecule is monomethoxy-polyethylene glycol.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 20, 2021
From: ABRIBAT, THIERRY
To: ALIZE PHARMA II SAS
Reel/Frame 057238/0398 →
CHANGE OF NAME Recorded Aug 20, 2021
From: ALIZE PHARMA II
To: JAZZ PHARMACEUTICALS II SAS
Reel/Frame 057250/0021 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 3, 2021
From: ABRIBAT, THIERRY
To: ALIZE PHARMA II SAS
Reel/Frame 056434/0772 →
CHANGE OF NAME Recorded Jun 3, 2021
From: ALIZE PHARMA II SAS
To: JAZZ PHARMACEUTICALS II SAS
Reel/Frame 056476/0482 →
Continuity (6)
Continuation 16877324 · May 18, 2020
Division 15886216 · Feb 1, 2018
Continuation 14819305 · Aug 5, 2015
Continuation 13382276
Provisional Application 61223320 · Jul 6, 2009
Related Publication 20210348151A1 · Nov 11, 2021
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