IP Library › Granted Patent US 8,022,043

Granted Patent B2

US 8,022,043 · App. 11/785,988 · Granted Sep 20, 2011

Ceramide derivatives as modulators of immunity and autoimmunity

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Quick Facts

Patent No.: US 8,022,043
App. No.: 11/785,988
Granted: Sep 20, 2011
Kind: B2

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Abstract

α-Galactosylceramides and glycosylceramides (“ceramide-like glycolipids”) that modulate NK T cells. The ceramide-like glycolipids vary in the cytokines induced in NK T cells and vary in the antigen-presenting cells that are capable of efficiently presenting the compounds to NK T cells. Pharmaceutical compositions of the ceramide-like glycolipids are provided, as are pharmaceutical compositions of the ceramide-like glycolipids combined with dendritic cells. Methods utilizing the ceramide-like glycolipids in vaccines, to activate NK T cells, to stimulate the immune system, and to treat mammals are also provided. The invention also provides methods of evaluating a compound for its ability to activate an NK T cell in the presence of a cell expressing a CD1d protein.

Claims (107)

1. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:

wherein

R1 is a linear or branched C 2 -C 27 alkene with at least two C═C bonds wherein R1 includes at least two C═C bonds that are conjugated with each other; and

R2 is —CH(OH)(CH 2 ) x CH 3 ,

wherein X is an integer ranging from 5-17.

2. The method of claim 1 , wherein the NK T cell exhibits increased production of a cytokine after contacting with the α-galactosylceramide.

3. The method of claim 2 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, and IFNγ.

4. The method of claim 1 , wherein the NK T cell exhibits increased CD40L expression after contacting with the α-galactosylceramide.

5. The method of claim 1 , wherein the NK T cell is in a living mammal.

6. The method of claim 5 , wherein the mammal has, or is at risk for developing, an autoimmune disease, cancer, or an infection.

7. The method of claim 5 , wherein the mammal has or is at risk for developing type 1 diabetes.

8. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:

wherein

R1 is a linear or branched C 2 -C 27 alkene with at least two C═C bonds; and

R2 is one of the following (a)-(c):

(a) —CH(OH)(OH)(CH 2 ) X CH 3 ,

(b) —CH(OH)(CH 2 ) X CH(CH 1 ) 2 ,

wherein X is an integer ranging from 5-17,

wherein the NK T cell is in a living mammal, and

wherein the α-galactosylceramide is contacted with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.

9. The method of claim 8 , wherein the dendritic cells are derived from the mammal.

10. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide of Formula I:

wherein

R1 is C(OH)—R3 where R3 is a linear or branched C 2 -C 26 alkene; and

R2 is one of the following (a)-(e):

(a) —CH 2 (CH 2 ) X CH 3 ,

(b) —CH(OH)(CH 2 ) X CH 3 ,

(d) —CH═CH(CH 2 ) X CH 3 ,

(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,

wherein X is an integer ranging from 5-17.

11. The method of claim 10 , wherein the NK T cell exhibits increased production of a cytokine after contacting with the α-galactosylceramide.

12. The method of claim 11 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, and IFNγ.

13. The method of claim 10 , wherein the NK T cell exhibits increased CD40L expression after contacting with the α-galactosylceramide.

14. The method of claim 10 , wherein the NK T cell is in a living mammal.

15. The method of claim 14 , wherein the mammal has, or is at risk for developing, an autoimmune disease, cancer, or an infection.

16. The method of claim 14 , wherein the mammal has or is at risk for developing type 1 diabetes.

17. The method of claim 14 , further comprising contacting the α-galactosylceramide with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.

18. The method of claim 17 , wherein the dendritic cells are derived from the mammal.

19. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:

wherein

R1 is a C 6 -C 27 alkane or alkene wherein (i) the C 6 -C 27 alkane or alkene is substituted with a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring or (ii) the C 6 -C 27 alkane or alkene includes, within the C 6 -C 27 alkyl or alkenyl chain, a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring; and

R2 is one of the following (a)-(e):

(a) —CH 2 (CH 2 ) X CH 3 ,

(b) —CH(OH)(CH 2 ) X CH 3 ,

(d) —CH═CH(CH 2 ) X CH 3 ,

(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,

wherein X is an integer ranging from 5-17.

20. The method of claim 19 , wherein the NK T cell exhibits increased production of a cytokine after contacting with the α-galactosylceramide.

21. The method of claim 20 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, and IFNγ.

22. The method of claim 19 , wherein the NK T cell exhibits increased CD40L expression after contacting with the α-galactosylceramide.

23. The method of claim 19 , wherein the NK T cell is in a living mammal.

24. The method of claim 23 , wherein the mammal has, or is at risk for developing, an autoimmune disease, cancer, or an infection.

25. The method of claim 23 , wherein the mammal has or is at risk for developing type 1 diabetes.

26. The method of claim 23 , further comprising contacting the α-galactosylceramide with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.

27. The method of claim 26 , wherein the dendritic cells are derived from the mammal.

28. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:

wherein

R1 is selected from the group consisting of —C(═O)OCH 2 CH 3 , —(CH 2 ) 6 CH 3 , —(CH 2 ) 4 Cl, —(CH 2 ) 16 CH 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 4 CH 3 , —(CH 2 ) 8 CH 3 , —(CH 2 ) 10 CH 3 , and —(CH 2 ) 12 CH 3 ; and

R2 is —CH(OH)(CH 2 ) 13 CH 3 .

29. The method of claim 28 , wherein the NK T cell exhibits increased production of a cytokine after contacting with the α-galactosylceramide.

30. The method of claim 29 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, and IFNγ.

31. The method of claim 28 , wherein the NK T cell exhibits increased CD40L expression after contacting with the α-galactosylceramide.

32. The method of claim 28 , wherein the NK T cell is in a living mammal.

33. The method of claim 32 , wherein the mammal has, or is at risk for developing, an autoimmune disease, cancer, or an infection.

34. The method of claim 32 , wherein the mammal has or is at risk for developing type 1 diabetes.

35. The method of claim 32 , further comprising contacting the α-galactosylceramide with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.

36. The method of claim 35 , wherein the dendritic cells are derived from the mammal.

37. The method of claim 10 , wherein R1 includes at least two C═C bonds.

38. The method of claim 37 , wherein R1 includes at least two C═C bonds that are conjugated with each other.

39. The method of claim 19 , wherein R1 includes at least two C═C bonds.

40. The method of claim 39 , wherein R1 includes at least two C═C bonds that are conjugated with each other.

41. The method of claim 1 , wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .

42. The method of claim 1 , wherein the α-galactosylceramide having the following formula:

43. The method of claim 1 , wherein the α-galactosylceramide having the following formula:

44. A method of activating a NK T cell, the method comprising contacting the NK T cell with an α-galactosylceramide comprising Formula I:

wherein

R1 is selected from the group consisting of

where ( ) represent the point of attachment of R1 to the compound of Formula I; and

R2 is one of the following (a)-(e):

(a) —CH 2 (CH 2 ) X CH 3 ,

(b) —CH(OH)(CH 2 ) X CH 3 ,

(d) —CH═CH(CH 2 ) X CH 3 ,

(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,

wherein X is an integer ranging from 5-17.

45. The method of claim 44 , wherein the NK T cell exhibits increased production of a cytokine after contacting with the α-galactosylceramide.

46. The method of claim 45 , wherein the cytokine is selected from the group consisting of IL-2, IL-4, and IFNγ.

47. The method of claim 44 , wherein the NK T cell exhibits increased CD40L expression after contacting with the α-galactosylceramide.

48. The method of claim 44 , wherein the NK T cell is in a living mammal.

49. The method of claim 48 , wherein the mammal has, or is at risk for developing, an autoimmune disease, cancer, or an infection.

50. The method of claim 48 , wherein the mammal has or is at risk for developing type 1 diabetes.

51. The method of claim 48 , further comprising contacting the α-galactosylceramide with dendritic cells ex vivo before the α-galactosylceramide is contacted with the NK T cell and then injecting the dendritic cells into the mammal.

52. The method of claim 51 , wherein the dendritic cells are derived from the mammal.

53. An α-galactosylceramide of Formula I:

wherein

R 1 is a linear or branched C 2 -C 27 alkene with at least two C═C bond, wherein said at least two C═C bonds are conjugated with each other, or R 1 is C(OH)—R 3 , wherein R3 is a linear or branched C 2 -C 26 alkene with at least two C═C bond, and wherein said at least two C═C bonds are conjugated with each other; and

R2 is one of the following (a)-(e):

(a) —CH 2 (CH 2 ) X CH 3 ,

(b) —CH(OH)(CH 2 ) X CH 3 ,

(d) —CH═CH(CH 2 ) X CH 3 ,

(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,

wherein X is an integer ranging from 5-17.

54. The α-galactosylceramide of claim 53 , wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .

Assignments (5)

MERGER AND CHANGE OF NAME Recorded Feb 26, 2019

From: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.; ALBERT EINSTEIN COLLEGE OF MEDICINE

To: ALBERT EINSTEIN COLLEGE OF MEDICINE

Reel/Frame 048438/0275 →