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1. WO2019046185 - USE OF HIGH MOLECULAR WEIGHT POLYETHYLENE GLYCOL COMPOSITIONS TO RESTORE THE EFFICACY OF PEGYLATED THERAPEUTIC COMPOSITIONS

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[ EN ]

What is claimed is:

1. A method of reducing accelerated blood clearance of at least one pegylated therapeutic composition by anti-PEG antibodies in a subject suffering from a disease and in need of treatment thereof, the method comprising the steps of:

administering from about 0.1 to about 500 milligrams per kilogram of at least one high molecular weight polyethylene glycol composition to a subject suffering from a disease and in need of treatment with at least one pegylated therapeutic composition,

wherein the high molecular weight polyethylene glycol comprises at least one high molecular weight polyethylene glycol having a molecular weight of between about 20 kDa to about 200 kDa, and

further wherein the high molecular weight polyethylene glycol composition is administered prior to or simultaneously with the administration of the at least one pegylated therapeutic composition.

2. The method of claim 1, wherein the at least one high molecular weight

polyethylene glycol composition is administered in an amount of 0.5 to about 400 milligrams per kilogram.

3. The method of any of claims 1 or 2, wherein the at least one high molecular weight polyethylene glycol composition is administered in an amount of 1.0 to about 250 milligrams per kilogram.

4. The method of any one of claims 1-3, wherein the at least one high molecular weight polyethylene glycol has a molecular weight of about 20 kDa, about 25 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 75 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa or combinations thereof.

5. The method of any one of claims 1-4, wherein the at least one high molecular weight polyethylene glycol has a geometry that is linear, branched, star-shaped or comb-shaped.

6. The method of any one of claims 1-5, wherein the at least one high molecule weight polyethylene glycol composition is administered prior to the subject being administered the at least one pegylated therapeutic composition.

7. The method of any one of claims 1-6, wherein the high molecular weight polyethylene glycol composition is administered at least 30 seconds, at least 60 seconds, at least 90 seconds, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours or at least 24 hours prior to administration of the at least one pegylated therapeutic composition.

8. The method of any one of claims 1-7, wherein the at least one pegylated therapeutic composition comprises at least one protein, peptide, antibody, enzyme, liposome, aptamer, dendrimer, polymeric particle, micelle, inorganic nanoparticle or combinations thereof.

9. The method of claim 8, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a fully human antibody, a bi-specific antibody, a multi-specific antibody, an antibody fragment, or combinations thereof.

10. The method of claims 1-5 and 8-9, wherein the at least one high molecular weight polyethylene glycol composition is administered simultaneously with the at least one pegylated therapeutic composition.

11. The method of claim 10, wherein the at least one high molecular weight polyethylene glycol composition is co-administered with the at least one pegylated therapeutic composition.

12. A method of increasing the circulation half-life of at least one pegylated therapeutic composition to be repeatedly administered to a subject suffering from a disease, the method comprising the step of:

administering from about 1 to about 2500 milligrams per kilogram of at least one high molecular weight polyethylene glycol composition to a subject that has previously been

administered at least one pegylated therapeutic composition or that is known to possess a high titer of pre-existing anti-PEG antibodies,

wherein the high molecular weight polyethylene glycol composition comprises at least one a high molecular weight polyethylene glycol having a molecular weight of between about 20 kDa to about 200 kDa, and

wherein the high molecular weight polyethylene glycol composition is administered prior to or simultaneously with any subsequent or further administration of the at least one pegylated therapeutic composition to the subject.

13. The method of claim 12, wherein the at least one high molecular weight polyethylene glycol composition is administered in an amount of 50 to about 2200 milligrams per kilogram.

14. The method of any of claims 12 or 13, wherein the at least one high molecular weight polyethylene glycol composition is administered in an amount of 100 to about 2000 milligrams per kilogram.

15. The method of any one of claims 12-14, wherein the at least one high molecular weight polyethylene glycol has a molecular weight of about 20 kDa, about 25 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 75 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa or combinations thereof.

16. The method of any one of claims 12-15, wherein the at least one high molecular weight polyethylene glycol has a geometry that is linear, branched, star-shaped or comb-shaped.

17. The method of any one of claims 12-16, wherein the at least one high molecule weight polyethylene glycol composition is administered prior to the subject receiving any further administration of the at least one pegylated therapeutic composition.

18. The method of any one of claims 12-17, wherein the high molecular weight polyethylene glycol composition is administered at least 30 seconds, at least 60 seconds, at least 90 seconds, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours or at least 24 hours prior to administration of the at least one pegylated therapeutic composition.

19. The method of any one of claims 12-18, wherein the at least one pegylated therapeutic composition comprises at least one protein, peptide, antibody, enzyme, liposome, aptamer, dendrimer, polymeric particle, micelle, inorganic nanoparticle or combinations thereof.

20. The method of claim 19, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a fully human antibody, a bi-specific antibody, a multi-specific antibody, an antibody fragment, or combinations thereof.

21. The method of claims 12-16 and 19-20, wherein the at least one high molecular weight polyethylene glycol composition is administered simultaneously with the at least one pegylated therapeutic composition.

22. The method of claim 21, wherein the at least one high molecular weight

polyethylene glycol composition is co-administered with the at least one pegylated therapeutic composition.

23. A method of restoring the pharmacokinetics of at least one pegylated therapeutic composition that will be repeatedly administered to a subject suffering from a disease, the method comprising the step of:

administering from about 1 to about 2500 milligrams per kilogram of at least one high molecular weight polyethylene glycol composition to a subject that has previously been

administered at least one pegylated therapeutic composition,

wherein the high molecular weight polyethylene glycol composition comprises at least one high molecular weight polyethylene glycol having a molecular weight of between about 20 kDa to about 200 kDa,

wherein the high molecular weight polyethylene glycol composition is administered prior to or simultaneously with any subsequent or further administration of at least one pegylated therapeutic composition to the subject,

further wherein the high molecular weight polyethylene glycol composition reduces the binding of anti-polyethylene glycol antibodies to the at least one pegylated therapeutic composition, and

still further wherein the administration of the at least one high molecular weight polyethylene glycol composition restores the pharmacokinetics of the at least one pegylated therapeutic composition.

24. The method of claim 23, wherein the subject has a high titer of anti-polyethylene glycol antibodies.

25. The method of claim 23, wherein the at least one pegylated therapeutic composition has an improved circulation half-life.

26. The method of claim 23, wherein the at least one high molecular weight

polyethylene glycol composition is administered in an amount of 50 to about 2200 milligrams per kilogram.

27. The method of any of claims 23-26, wherein the at least one high molecular weight polyethylene glycol composition is administered in an amount of 100 to about 2000 milligrams per kilogram.

28. The method of any one of claims 23-27, wherein the at least one high molecular weight polyethylene glycol has a molecular weight of about 20 kDa, about 25 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 75 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa or combinations thereof.

29. The method of any one of claims 23-28, wherein the at least one high molecular weight polyethylene glycol has a geometry that is linear, branched, star-shaped or comb-shaped.

30. The method of any one of claims 23-29, wherein the at least one high molecule weight polyethylene glycol composition is administered prior to the subject receiving any further administration of the at least one pegylated therapeutic composition.

31. The method of any one of claims 23-30, wherein the high molecular weight polyethylene glycol composition is administered at least 30 seconds, at least 60 seconds, at least 90 seconds, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours or at least 24 hours prior to administration of the at least one pegylated therapeutic composition.

32. The method of any one of claims 23-31, wherein the at least one pegylated therapeutic composition comprises at least one protein, peptide, antibody, enzyme, liposome, aptamer, dendrimer, polymeric particle, micelle, inorganic nanoparticle or combinations thereof.

33. The method of claim 32, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a fully human antibody, a bi-specific antibody, a multi-specific antibody, an antibody fragment, or combinations thereof.

34. The method of claims 23-29 and 32-33, wherein the at least one high molecular weight polyethylene glycol composition is administered simultaneously with the at least one pegylated therapeutic composition.

35. The method of claim 34, wherein the at least one high molecular weight polyethylene glycol composition is co-administered with the at least one pegylated therapeutic composition.

36. A method of reducing the formation of anti-PEG antibodies in a suffering from a disease and in need of treatment or continued treatment thereof, the method comprising the step of:

administering from about 1 to about 2500 milligrams per kilogram of at least one high molecular weight polyethylene glycol composition, about 10 to 2500 milligrams per kilogram of at

least one low molecular weight polyethylene glycol composition or about 10 to 2500 milligrams per kilogram of a combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition to a subject that either has previously not been administered at least one pegylated therapeutic composition or that has previously been administered at least one pegylated therapeutic composition,

wherein the high molecular weight polyethylene glycol composition comprises at least one high molecular weight polyethylene glycol having a molecular weight of between about 20 kDa to about 200 kDa,

wherein the low molecular weight polyethylene glycol composition comprises at least one high molecular weight polyethylene glycol having a molecular weight of between about 200 Da to about 19 kDa,

37. The method of claim 36, wherein the at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered in an amount of 50 to about 2200 milligrams per kilogram.

38. The method of any of claims 36-37, wherein at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered in an amount of 100 to about 2000 milligrams per kilogram.

39. The method of any one of claims 36-38, wherein the at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered prior to the subject receiving any treatment with at least one pegylated therapeutic composition.

40. The method of any one of claims 36-38, wherein at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered prior to the subject receiving any further administration of the at least one pegylated therapeutic composition.

41. The method of any one of claims 36-40, wherein the at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered at least 30 seconds, at least 60 seconds, at least 90 seconds, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours or at least 24 hours prior to administration of the at least one pegylated therapeutic composition.

42. The method of any one of claims 36-41, wherein the at least one pegylated therapeutic composition comprises at least one protein, peptide, antibody, enzyme, liposome, aptamer, dendrimer, polymeric particle, micelle, inorganic nanoparticle or combinations thereof.

43. The method of claim 42, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a fully human antibody, a bi-specific antibody, a multi-specific antibody, an antibody fragment, or combinations thereof.

44. The method of claims 36-43, wherein the at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is administered simultaneously with the at least one pegylated therapeutic composition.

45. The method of claim 44, wherein the at least one high molecular weight polyethylene glycol composition, at least one low molecular weight polyethylene glycol composition or combination of at least one high molecular weight polyethylene glycol composition and at least one low molecular weight polyethylene glycol composition is co-administered with the at least one pegylated therapeutic composition.