Methods and compositions for modulating the immune system with arginase I
Methods and compositions comprising recombinant Arginase I proteins which are capable of depleting the plasma arginine levels in a subject are disclosed. The methods and compositions can be used to modulate the activity of the immune system in a subject. Modulation of the immune system is useful in the treatment of immune disorders and in preventing rejection of a transplanted organ, tissue, or cell. The methods and compositions can also be used to treat a bone condition of a subject.
1. A method of treating multiple sclerosis in a subject in need thereof, the method comprising administering to the subject suffering from multiple sclerosis a therapeutically-effective amount of a purified pegylated Arginase I or a functional fragment thereof, wherein the purified pegylated Arginase I or functional fragment thereof treats the multiple sclerosis by inhibiting T-cell polarization.
2. The method of claim 1 , wherein the purified pegylated Arginase I is a purified pegylated recombinant Arginase I.
3. The method of claim 2 , wherein the purified pegylated Arginase I is a purified pegylated recombinant human Arginase I.
4. The method of claim 3 , wherein the purified pegylated recombinant human Arginase I comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.
5. The method of claim 1 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is from about 1 mg/Kg to about 10 mg/Kg.
6. The method of claim 1 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is from about 10 mg/Kg to about 100 mg/Kg.
7. The method of claim 1 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is greater than 100 mg/Kg.
8. The method of claim 1 , wherein the purified pegylated Arginase I provides an arginine plasma concentration in the subject that is lower than 120 μM.
9. The method of claim 8 , wherein the purified pegylated Arginase I provides an arginine plasma concentration in the subject that is lower than 80 μM.
10. The method of claim 9 , wherein the purified pegylated Arginase I provides an arginine plasma concentration in the subject that is lower than 10 μM.
11. The method of claim 1 , wherein the administration is intravenous administration.
12. The method of claim 1 , wherein the therapeutically-effective amount of a purified pegylated Arginase I is in a unit dosage form.
13. The method of claim 1 , wherein the subject is a human.
14. The method of claim 1 , wherein the purified pegylated Arginase I is partially purified.
15. The method of claim 1 , wherein the purified pegylated Arginase I is substantially pure.
16. The method of claim 1 , wherein the purified pegylated Arginase I is at least 95% pure.
17. The method of claim 16 , wherein the purified pegylated Arginase I is at least 99% pure.
18. A method of treating inflammation associated with a T-cell mediated autoimmune disease, the method comprising:
administering to a subject suffering from the inflammation associated with the T-cell mediated autoimmune disease a therapeutically-effective amount of a purified pegylated Arginase I, or a functional fragment thereof, wherein the administration of the purified pegylated Arginase I, or the functional fragment thereof, treats the inflammation by inhibiting T-cell polarization.
19. The method of claim 18 , wherein the purified pegylated Arginase I is a recombinant Arginase I.
20. The method of claim 19 , wherein the purified pegylated Arginase I is purified pegylated recombinant human Arginase I.
21. The method of claim 18 , wherein the purified pegylated Arginase I modulates cytokine release.
22. The method of claim 21 , wherein the cytokine is Interleukin 6.
23. The method of claim 21 , wherein the cytokine is Interferon gamma.
24. The method of claim 18 , wherein the purified pegylated Arginase I comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.
25. The method of claim 18 , wherein the autoimmune disorder is multiple sclerosis.
26. The method of claim 18 , wherein the autoimmune disorder is rheumatoid arthritis.
27. The method of any one of claim 25 or 26 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is from about 1 mg/kg to about 10 mg/kg of the subject's body mass.
28. The method of any one of claim 25 or 26 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is from about 10 mg/kg to about 100 mg/kg of the subject's body mass.
29. The method of any one of claim 25 or 26 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is greater than 100 mg/kg of the subject's body mass.
30. The method of claim 18 , wherein the administration of the purified pegylated Arginase I provides a plasma level of arginine in the subject that is no greater than 10 μM.
31. The method of claim 18 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is administered to the subject at least once over a period of 24 hours.
32. The method of claim 18 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is administered to the subject at least once over a period of 48 hours.
33. The method of claim 18 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is administered to the subject at least once over a period of 1 week.
34. The method of claim 18 , wherein the therapeutically-effective amount of the purified pegylated Arginase I is administered to the subject at least once over a period of 2 weeks.
35. The method of claim 18 , wherein the subject is a human.
36. The method of claim 21 , wherein the cytokine is Interleukin 17A.
37. The method of claim 36 , wherein the T-cell mediated autoimmune disease is mediaded by a Th17 cell.
38. The method of claim 4 , wherein the pegylated recombinant human Arginase I comprises SEQ ID NO: 1.
39. The method of claim 24 , wherein the pegylated recombinant human Arginase I comprises SEQ ID NO: 1.