Compositions and methods for diagnosing and treating retinal diseases

• US 20060252107A1
• Filed: 02/22/2006
• Published: 11/09/2006
• Est. Priority Date: 02/22/2005
• Status: Abandoned Application

• Current Assignee: Acucela Inc. (Kubota Pharmaceutical Holdings Co. Ltd.)
• Original Assignee: Acucela Inc. (Kubota Pharmaceutical Holdings Co. Ltd.)
• Inventors: Palczewski, Krzysztof, Kubota, Ryo, Gall, Anna
• Application Number:
  US11/361,027
• Publication Number:
  US 20060252107A1
• Time in Patent Office: Days
• US Class Current: 435/7.920
• CPC Class Codes: A61K 2039/6031 Proteins
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: C07D 213/20 Quaternary compounds thereof
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids

Abstract

The present invention relates generally to the preparation and use of retinoid N-retinylidene-N-retinyl-ethanolamine (A2E) conjugated to a carrier polypeptide and to the preparation and use of antibodies that bind specifically to A2E. The invention relates to the use of A2E conjugates as immunogens or vaccines and to the use of A2E specific antibodies for treatment of ophthalmic diseases. Provided herein are methods for enhancing retinal neuronal cell survival, including photoreceptor cell survival, using antibodies that specifically bind to A2E or by inducing an immune response using an A2E immunoconjugate. Enhancing survival of photoreceptor cells or decreasing accumulation of A2E in the eye using the A2E immunoconjugates or A2E specific antibodies is useful for treatment of ophthalmic diseases such as macular degeneration.

Claims

1. A compound having the following structure (1):

or a pharmaceutically acceptable acid addition salt thereof;

wherein

J is -Z¹-Y, -Z²-R⁰—

Y, -Z²-R⁰-Z³-Y, or -Z²-Y′

—

R⁰,

Z¹ is a divalent C₁-C₄₀ alkyl,

Z² is a divalent C₁-C₄₀ alkyl,

Z³ is a polyethylene glycol having the formula —

(CH₂CH₂O)_nCH₂CH₂—

wherein n=2-8, or —

R⁴—

CH₂—

, wherein R⁴ is C₁-C₄₀ alkylene or C₁-C₄₀ heteroalkylene;

R⁰ is a monovalent or divalent optionally substituted homocycle, aryl, heteroaryl, or heterocycle; and

wherein Y is a monovalent electrophilic or nucleophilic moiety suitable for covalent attachment of the compound to an amino acid,

and wherein Y′

is a divalent electrophilic or nucleophilic moiety suitable for covalent attachment of the compound to an amino acid.

2. The compound according to claim 1 wherein J is -Z¹-Y.

3. The compound according to claim 1 wherein J is -Z²-R⁰—

Y.

4. The compound according to claim 1 wherein J is -Z²-R⁰-Z³-Y.

5. The compound according to claim 4 wherein Z³ is a polyethylene glycol having the formula —

(CH₂CH₂O)_nCH₂CH₂—

wherein n=2-8.

6. The compound according to claim 4 wherein Z³ is —

R⁴—

CH₂—

, and wherein R⁴ is C₁-C₄₀ alkylene or C₁-C₄₀ heteroalkylene.

7. The compound according to claim 6 wherein R⁴ is C₁-C₄₀ alkylene.

8. The compound according to claim 6 wherein R⁴ is C₁-C₄₀ heteroalkylene.

9. The compound according to claim 8 wherein C₁-C₄₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

10. The compound according to claim 6 wherein R⁴ is C₁-C₂₀ alkylene or C₁-C₂₀ heteroalkylene.

11. The compound according to claim 10 wherein R⁴ is C₁-C₂₀ alkylene.

12. The compound according to claim 10 wherein R⁴ is C₁-C₂₀ heteroalkylene.

13. The compound according to claim 12 wherein C₁-C₂₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

14. The compound according to claim 1 wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

15. The compound according to claim 1 wherein Y is —

SH, —

NH₂, or —

C(═

O)OH.

16. The compound according to claim 1 wherein J is -Z²-Y′

—

R⁰.

17. The compound according to claim 11 wherein Y′

is —

O—

.

52. The compound of claim 1 wherein J is Z²-R⁰-Z³-Y, and -Z²-R⁰-Z³- has the following structure (I):

wherein n=0-12 when A is a direct bond;

wherein n=1-10 when A is —

O—

, —

NH—

, —

S—

, —

S—

S—

, —

C(═

O)NH, —

NHC(═

O)—

, —

NHC(═

O)NH—

, —

OC(═

O)—

, or —

C(═

O)O—

;

and wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

53. The compound of claim 1 wherein J is Z²-R⁰-Z³-Y, and Z²-R⁰-Z³- has the following structure (II):

wherein n=0-12 when A is a direct bond;

wherein n=1-10 when A is —

O—

, —

NH—

, —

S—

, —

S—

S—

, —

C(═

O)NH, —

NHC(═

O)—

, —

NHC(═

O)NH—

, —

OC(═

O)—

, or —

C(═

O)O—

; and

wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

54. The compound of claim 1 wherein J is -Z²-Y′

—

R⁰, and -Z²-Y′

—

R⁰ has the following structure (III);

55. The compound of claim 1 wherein J is Z²-R⁰—

Y, and -Z²-R⁰—

Y has the following structure (IV);

56. The compound according to claim 1 wherein compound 1 has either structure 1(a)

or structure 1(b)

57. The compound of claim 1 wherein compound 1 has the structure 1(c):

63. An immunogen comprising at least one molecule of the compound according to any one of claims 1, 18 and 35, wherein the compound is conjugated to a carrier polypeptide.

64. The immunogen of claim 63 wherein the carrier polypeptide is selected from keyhole limpet hemocyanin, bovine serum albumin, ovalbumin, tetanus toxoid, diphtheria toxoid, E. coli heat-labile enterotoxin B subunit, polyglutamate, glucose oxidase, rabbit serum albumin, sperm whale myoglobin, human thyroglobulin, and Pasteurella haemolytica leukotoxin polypeptide.

67. A composition comprising the immunogen according to claim 63 and a physiologically acceptable excipient.

68. The composition of claim 67 further comprising an adjuvant.

81. A method for producing an antibody that specifically binds to retinoid N-retinylidene-N-retinyl-ethanolamine (A2E) comprising administering to an animal an immunogen that comprises a compound according to any one of claims 1, 18, and 35 that is conjugated to a carrier polypeptide.

82. The method of claim 81 further comprising administering an adjuvant to the animal.

84. A method for inducing an immune response in an animal comprising administering to the animal a composition that comprises the immunogen according to claim 63.

107. A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject the immunogen according to claim 63.

108. The method according claim 107 wherein the carrier polypeptide is selected from keyhole limpet hemocyanin, bovine serum albumin, ovalbumin, tetanus toxoid, diphtheria toxoid, E. Coli heat-labile enterotoxin B subunit, polyglutamate, glucose oxidase, rabbit serum albumin, sperm whale myoglobin, human thyroglobulin, and Pasteurella haemolytica leukotoxin polypeptide.

117. The method according to claim 107 wherein the ophthalmic disease or disorder is selected from macular degeneration, glaucoma, diabetic retinopathy, retinal detachment, retinal blood vessel occlusion, retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, diabetic maculopathy, hemorrhagic retinopathy, retinopathy of prematurity, optic neuropathy, proliferative vitreoretinopathy, retinal dystrophy, ischemia-reperfusion related retinal injury, hereditary optic neuropathy, metabolic optic neuropathy, Stargardt'"'"'s macular dystrophy, Sorsby'"'"'s fundus dystrophy, Best disease, uveitis, a retinal injury, a retinal disorder associated with Parkinson'"'"'s disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, and a retinal disorder associated with AIDS, a retinal disorder associated with Alzheimer'"'"'s disease, and a retinal disorder associated with multiple sclerosis.

18. A compound having the following structure (2):

or a pharmaceutically acceptable acid addition salt thereof,

wherein

J is -Z¹-Y, -Z²-R⁰—

Y, -Z²-R⁰-Z³-Y, or -Z²-Y′

—

R⁰,

Z¹ is a divalent C₁-C₄₀ alkyl,

Z² is a divalent C₁-C₄₀ alkyl,

Z³ is a polyethylene glycol having the formula —

(CH₂CH₂O)_nCH₂CH₂—

wherein n=2-8, or —

R⁴—

CH₂—

, wherein R⁴ is C₁-C₄₀ alkylene or C₁-C₄₀ heteroalkylene;

R⁰ is an monovalent or divalent optionally substituted homocycle, aryl, heteraryl, or heterocycle; and

wherein Y is a monovalent electrophilic or nucleophilic moiety suitable for covalent attachment of the compound to an amino acid,

and wherein Y′

is a divalent electrophilic or nucleophilic moiety suitable for covalent attachment of the compound to an amino acid.

19. The compound according to claim 18 wherein J is -Z¹-Y.

20. The compound according to claim 18 wherein J is -Z²-R⁰—

Y.

21. The compound according to claim 18 wherein J is -Z²-R⁰-Z³-Y.

22. The compound according to claim 21 wherein Z³ is a polyethylene glycol having the formula —

(CH₂CH₂O)_nCH₂CH₂—

wherein n=2-8.

23. The compound according to claim 21 wherein Z³ is —

R⁴—

CH₂—

, and wherein R⁴ is C₁-C₄₀ alkylene or C₁-C₄₀ heteroalkylene.

24. The compound according to claim 23 wherein R⁴ is C₁-C₄₀ alkylene.

25. The compound according to claim 23 wherein R⁴ is C₁-C₄₀ heteroalkylene.

26. The compound according to claim 25 wherein C₁-C₄₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

27. The compound according to claim 23 wherein R⁴ is C₁-C₂₀ alkylene or C₁-C₂₀ heteroalkylene.

28. The compound according to claim 27 wherein R⁴ is C₁-C₂₀ alkylene.

29. The compound according to claim 27 wherein R⁴ is C₁-C₂₀ heteroalkylene.

30. The compound according to claim 29 wherein C₁-C₂₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

31. The compound according to claim 18 wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

32. The compound according to claim 18 wherein Y is —

SH, —

NH₂, or —

C(═

O)OH.

33. The compound according to claim 18 wherein J is -Z²-Y′

—

R⁰.

34. The compound according to claim 33 wherein Y′

is —

O—

.

58. The compound of claim 18 wherein J is -Z²-R⁰-Z³-Y, and -Z²-R⁰-Z³ has the structure (V):

wherein n=0-12 when A is a direct bond;

wherein n=1-10 when A is —

O—

, —

NH—

, —

S—

, —

S—

S—

, —

C(═

O)NH, —

NHC(═

O)—

, —

NHC(═

O)NH—

, —

OC(═

O)—

, or —

C(═

O)O—

; and

wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

59. The compound of claim 18 wherein J is -Z²-R⁰-Z³-Y, and -Z²-R⁰-Z³ has the following structure (VI):

wherein n=0-12 when A is a direct bond;

wherein n=1-10 when A is —

O—

, —

NH—

, —

S—

, —

S—

S—

, —

C(═

O)NH, —

NHC(═

O)—

, —

NHC(═

O)NH—

, —

OC(═

O)—

, or —

C(═

O)O—

; and

wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

60. The compound of claim 18 wherein J is -Z²-Y′

—

R⁰, and -Z²-Y′

—

R⁰ has the following structure (VII);

61. The compound of claim 18 wherein J is -Z²-R⁰—

Y, and -Z²-R⁰—

Y has the following structure (VIII);

62. The compound according to claim 18 wherein compound 2 has the structure 2(a)

or structure 2(b)

35. A compound having the following structure (3):

or a pharmaceutically acceptable acid addition salt thereof,

wherein L is a divalent linker group -R₁-, -R₂-, or -R₃-, and

R₁ is divalent C₁-C₆ alkyl;

R₂ is C₁-C₄₀ alkylene or C₁-C₄₀ heteroalkylene; and

R₃ is a polyethylene glycol having the formula —

(CH₂CH₂O)_nCH₂CH₂—

wherein n=2-12;

and wherein Y is an electrophilic or nucleophilic moiety suitable for reaction of the compound with an amino acid.

36. The compound of claim 35 wherein L is -R₁-.

37. The compound of claim 35 wherein L is -R₂-.

38. The compound of claim 35 wherein L is -R₃-.

39. The compound of claim 37 wherein -R₂- is C₁-C₄₀ alkylene.

40. The compound of claim 37 wherein -R₂- is C₁-C₄₀ heteroalkylene.

41. The compound of claim 37 wherein -R₂- is C₁-C₂₀ alkylene or C₁-C₂₀ heteroalkylene.

42. The compound of claim 37 wherein -R₂- is C₁-C₂₀ alkylene.

43. The compound of claim 37 wherein -R₂- is C₁-C₂₀ heteroalkylene.

44. The compound according to claim 40 wherein C₁-C₄₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

45. The compound according to claim 43 wherein C₁-C₂₀ heteroalkylene comprises amide, disulfide, —

O—

, —

S—

, or sulfonamide.

46. The compound of claim 35 wherein R₃ is a polyethylene glycol moiety having the formula —

(CH₂CH₂O)_nCH₂CH₂—

, wherein n=1 to 4.

47. The compound of claim 35 wherein Y is —

OH, —

SH, —

NH₂, —

C(═

O)OH, oxo, hydrazide, N-hydroxy-succinimidyl ester, N-hydroxy-sulfosuccinimidyl ester, or pentafluorophenoxycarbonyl.

48. The compound of claim 35 wherein R₃ is —

(CH₂CH₂O)₂CH₂CH₂— and

Y is —

NH₂.

49. The compound of claim 35 wherein R₃ is —

(CH₂CH₂O)₂CH₂CH₂— and

Y is —

SH.

50. The compound of claim 35 wherein R₃ is —

(CH₂CH₂O)₄CH₂CH₂— and

Y is —

C(═

O)OH.

51. The compound of claim 35 wherein compound 3 has the

structure 3(a)

the structure 3(b)

structure 3(c)

65-66. -66. (canceled)

69. An isolated antibody, or an antigen-binding fragment thereof, that binds specifically to retinoid N-retinylidene-N-retinyl-ethanolamine (A2E).

70. The antibody of claim 69 wherein the antibody is a polyclonal antibody or a monoclonal antibody.

72. The antibody of claim 70 wherein the monoclonal antibody is selected from a mouse monoclonal antibody, a human monoclonal antibody, a rat monoclonal antibody, and a hamster monoclonal antibody.

73. The antibody of claim 69 wherein the antibody is a chimeric antibody or a humanized antibody.

75. The antibody of claim 69 wherein the antigen binding fragment thereof is selected from an Fab, Fab′

, F(ab′

)₂, Fd, and Fv.

77. The antibody of claim 69 wherein the antibody comprises a single chain antibody.

78. The antibody of claim 69 wherein the antibody is a recombinant antibody.

79. A host cell that expresses the antibody of claim 69.

80. A composition comprising an antibody, or antigen-binding fragment thereof, according to claim 69 and a physiologically acceptable excipient.

71. (canceled)

76. (canceled)

83. (canceled)

85-86. -86. (canceled)

87. The method according to 84 wherein the composition further comprises an adjuvant.

88. (canceled)

89. A method for detecting the presence of retinoid N-retinylidene-N-retinyl-ethanolamine (A2E) in a biological sample comprising:

(a) contacting a biological sample with an antibody, or antigen-binding fragment thereof, that specifically binds to A2E, under conditions and for a time sufficient to permit formation of an antibody/A2E complex; and

(b) detecting a level of antibody/A2E complex, and thereby detecting the presence of A2E in a sample.

91. The method of claim 89 wherein the biological sample is selected from blood, serum, vitreous fluid, aqueous humor, intraocular fluid, and tears.

94. The method of claim 89 wherein the antibody is detectably labeled.

90. (canceled)

92-93. -93. (canceled)

95. The method of 94 wherein the antibody is detectably labeled with a fluorophore, a radionuclide, an enzyme, or biotin.

96-101. -101. (canceled)

102. A method for treating an ophthalmic disease or disorder in a subject comprising administering to the subject a composition comprising an antibody that specifically binds to retinoid N-retinylidene-N-retinyl-ethanolamine (A2E) and a physiologically acceptable excipient.

103. The method of claim 102 wherein the ophthalmic disease or disorder is selected from macular degeneration, glaucoma, diabetic retinopathy, retinal detachment, retinal blood vessel occlusion, retinitis pigmentosa, optic neuropathy, inflammatory retinal disease, diabetic maculopathy, hemorrhagic retinopathy, retinopathy of prematurity, optic neuropathy, proliferative vitreoretinopathy, retinal dystrophy, ischemia-reperfusion related retinal injury, hereditary optic neuropathy, metabolic optic neuropathy, Stargardt'"'"'s macular dystrophy, Sorsby'"'"'s fundus dystrophy, Best disease, uveitis, a retinal injury, a retinal disorder associated with Parkinson'"'"'s disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, and a retinal disorder associated with AIDS, a retinal disorder associated with Alzheimer'"'"'s disease, and a retinal disorder associated with multiple sclerosis.

104-106. -106. (canceled)

109. (canceled)

110. The method according to 107 further comprising administering an adjuvant.

111-116. -116. (canceled)

118-120. -120. (canceled)