RM2 antigens and use thereof

• US 10,086,054 B2
• Filed: 06/26/2014
• Issued: 10/02/2018
• Est. Priority Date: 06/26/2013
• Status: Active Grant

• Current Assignee: Academia Sinica (Government of The Republic of China)
• Original Assignee: Academia Sinica (Government of The Republic of China)
• Inventors: Wong, Chi-Huey, Wu, Chung-Yi, Chuang, Hong-Yang, Ren, Chien-Tai
• Primary Examiner(s): Olson, Eric
• Application Number:
  US14/392,341
• Publication Number:
  US 20160193310A1
• Time in Patent Office: 1,559 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/575 humoral response
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2039/6037 Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
• CPC Class Codes: A61K 2039/627 characterised by the linker
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 39/001169 Tumor associated carbohydrates
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 15/10 containing unsaturated carbon-to-carbon bonds
• CPC Class Codes: C07H 15/14 attached to a sulfur, selenium or tellurium atom of a saccharide radical
• CPC Class Codes: C07K 14/4748 Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE

Abstract

Described herein are synthetic glycan conjugates, immunogenic compositions thereof, vaccines thereof, and kits thereof. The present invention further provides methods of using the synthetic glycan conjugates, immunogenic compositions, or vaccines thereof to treat and/or prevent and/or diagnose proliferative diseases such as cancer. The provided glycan conjugate comprises a carrier and a glycan moiety of Formula (I-i) or Formula (I-ii): (structurally represented).

Claims

1. A glycan conjugate having Formula (II-a) or Formula (II-b)

2. The glycan conjugate of claim 1 having Formula (III-a) or Formula (III-b)

3. The glycan conjugate of claim 1 having Formula (IV-a) or (IV-b)

4. The glycan conjugate of claim 1 having Formula (V-a) or (V-b)

5. The glycan conjugate of claim 1 having Formula (VI-a) or Formula (VI-b)

6. The glycan conjugate of claim 1 having Formula (VII-a) or (VII-b)

7. The glycan conjugate of any one of claims 1-6, wherein w is an integer of 1 to 20, inclusive.

8. The glycan conjugate of any one of claims 1-6, wherein y is 0 or an integer of 1 to 20, inclusive.

9. The glycan conjugate of any one of claims 1-6, wherein p is 5.

10. The glycan conjugate of any one of claims 1-6, wherein R¹¹, R¹², and R¹³ are hydrogen.

11. The glycan conjugate of any one of claims 1-6, wherein R¹⁰, R¹¹, R¹², and R¹³ are hydrogen.

12. The glycan conjugate of any one of claims 1-6, wherein R¹, R², R⁴, and R⁶ are hydrogen.

13. The glycan conjugate of any one of claims 1-6, wherein R^N1 is acetyl.

14. The glycan conjugate of any one of claims 1-6, wherein R^N2 is hydrogen.

15. The glycan conjugate of any one of claims 1-6, wherein R^BN is hydrogen.

16. The glycan conjugate of any one of claims 1-6, wherein R^CN is hydrogen.

17. The glycan conjugate of any one of claims 1-6, wherein the carrier is a protein, a lipid, a lipolized protein, a virus, a peptide comprising a T cell epitope, or a dendrimer of glycopeptides.

18. The glycan conjugate of claim 17, wherein the carrier is a toxin protein selected from the group consisting of diphtheria toxin cross-reacting material 197 (DT-CRM197), diphtheria toxoid, tetanus toxoid, and outer-membrane protein (OMP).

19. The glycan conjugate of claim 18, wherein the toxin protein is DT-CRM197.

20. The glycan conjugate of claim 19, wherein the glycan conjugate is of the formula

21. A glycan conjugate mixture comprising at least two of the glycan conjugates of any one of claims 1-6.

22. A glycan conjugate mixture comprising at least two of the glycan conjugates of any one of claims 1-6 wherein the average value of w is from about 1.0 to about 100.0.

23. The glycan conjugate mixture of claim 22, wherein the average value of w is about 1.0 to about 20.0.

24. The glycan conjugate mixture of claim 22, wherein the average value of w is about 1.0.

25. The glycan conjugate mixture of claim 22, wherein the average value of w is about 3.0.

26. The glycan conjugate mixture of claim 22, wherein the average value of w is about 4.7.

27. The glycan conjugate mixture of claim 22, wherein the average value of w is about 10.0.

28. The glycan conjugate mixture of claim 22, wherein the average value of w is about 12.7.

29. An immunogenic composition, comprising

(i) a glycan conjugate of any one of claims 1-6;

and

(ii) a pharmaceutically acceptable excipient.

30. The immunogenic composition of claim 29 further comprising an adjuvant.

31. The immunogenic composition of claim 30, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

32. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to any one of claims 1-6.

33. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to any one of claims 1-6.

34. The method of claim 32, wherein the proliferative disease is cancer.

35. The method of claim 34, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

36. The method of claim 35, wherein the cancer is prostate cancer.

37. A kit comprising a glycan conjugate according to any one of claims 1-6 and instructions for use thereof.

38. A method of preparing the glycan conjugate of claim 1, comprising coupling a compound of the following formulae:

39. The method of claim 38, wherein L^2C is a crosslinking reagent capable of crosslinking an amine group and —

SH.

40. The method of claim 39, wherein L^2C is of one of the following formulae:

41. The method of any one of claim 38-40, wherein the molar ratio of the compound of Formula (C-1) to the compound of Formula (C-2) is from about 1 to about 100.

42. The method of claim 41, wherein the coupling is carried out in the presence of phosphate buffered saline (PBS).

43. The method of any one of claims 38-40, further comprising deprotecting a compound of the following formulae:

44. The method of claim 43, wherein the deprotection is carried out in the presence of LiOH.

45. The method of claim 43, wherein the deprotection is carried out in the presence of LiOH, then Ac₂O and NaHCO₃, then LiOH.

46. The method of claim 43, further comprising

(a) activating a compound of Formula (C-4a) or Formula (C-4b) to give a compound of Formula (C-1a) or Formula (C-1b);

and

(b) activating the carrier to give a compound of Formula (C-2).

47. An immunogenic composition, comprising

(i) a glycan conjugate of claim 7;

and

(ii) a pharmaceutically acceptable excipient.

48. The immunogenic composition of claim 47 further comprising an adjuvant.

49. The immunogenic composition of claim 48, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

50. An immunogenic composition, comprising

(i) a glycan conjugate of claim 8;

and

(ii) a pharmaceutically acceptable excipient.

51. The immunogenic composition of claim 50 further comprising an adjuvant.

52. The immunogenic composition of claim 51, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

53. An immunogenic composition, comprising

(i) a glycan conjugate of claim 9;

and

(ii) a pharmaceutically acceptable excipient.

54. The immunogenic composition of claim 53 further comprising an adjuvant.

55. The immunogenic composition of claim 54, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

56. An immunogenic composition, comprising

(i) a glycan conjugate of claim 9;

and

(ii) a pharmaceutically acceptable excipient.

57. The immunogenic composition of claim 56 further comprising an adjuvant.

58. The immunogenic composition of claim 57, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

59. An immunogenic composition, comprising

(i) a glycan conjugate of claim 10;

and

(ii) a pharmaceutically acceptable excipient.

60. The immunogenic composition of claim 59 further comprising an adjuvant.

61. The immunogenic composition of claim 60, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

62. An immunogenic composition, comprising

(i) a glycan conjugate of claim 11;

and

(ii) a pharmaceutically acceptable excipient.

63. The immunogenic composition of claim 62 further comprising an adjuvant.

64. The immunogenic composition of claim 63, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

65. An immunogenic composition, comprising

(i) a glycan conjugate of claim 12;

and

(ii) a pharmaceutically acceptable excipient.

66. The immunogenic composition of claim 65 further comprising an adjuvant.

67. The immunogenic composition of claim 66, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

68. An immunogenic composition, comprising

(i) a glycan conjugate of claim 13;

and

(ii) a pharmaceutically acceptable excipient.

69. The immunogenic composition of claim 68 further comprising an adjuvant.

70. The immunogenic composition of claim 69, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

71. An immunogenic composition, comprising

(i) a glycan conjugate of claim 14;

and

(ii) a pharmaceutically acceptable excipient.

72. The immunogenic composition of claim 71 further comprising an adjuvant.

73. The immunogenic composition of claim 72, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

74. An immunogenic composition, comprising

(i) a glycan conjugate of claim 15;

and

(ii) a pharmaceutically acceptable excipient.

75. The immunogenic composition of claim 74 further comprising an adjuvant.

76. The immunogenic composition of claim 75, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

77. An immunogenic composition, comprising

(i) a glycan conjugate of claim 16;

and

(ii) a pharmaceutically acceptable excipient.

78. The immunogenic composition of claim 77 further comprising an adjuvant.

79. The immunogenic composition of claim 78, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

80. An immunogenic composition, comprising

(i) a glycan conjugate of claim 17;

and

(ii) a pharmaceutically acceptable excipient.

81. The immunogenic composition of claim 80 further comprising an adjuvant.

82. The immunogenic composition of claim 81, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

83. An immunogenic composition, comprising

(i) a glycan conjugate of claim 18;

and

(ii) a pharmaceutically acceptable excipient.

84. The immunogenic composition of claim 83 further comprising an adjuvant.

85. The immunogenic composition of claim 84, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

86. An immunogenic composition, comprising

(i) a glycan conjugate of claim 19;

and

(ii) a pharmaceutically acceptable excipient.

87. The immunogenic composition of claim 86 further comprising an adjuvant.

88. The immunogenic composition of claim 87, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

89. An immunogenic composition, comprising

(i) a glycan conjugate of claim 20;

and

(ii) a pharmaceutically acceptable excipient.

90. The immunogenic composition of claim 89 further comprising an adjuvant.

91. The immunogenic composition of claim 90, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

92. An immunogenic composition, comprising

(i) a glycan conjugate mixture of claim 21 and

(ii) a pharmaceutically acceptable excipient.

93. The immunogenic composition of claim 92 further comprising an adjuvant.

94. The immunogenic composition of claim 93, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

95. An immunogenic composition, comprising

(i) a glycan conjugate mixture of claim 22 and

(ii) a pharmaceutically acceptable excipient.

96. The immunogenic composition of claim 95 further comprising an adjuvant.

97. The immunogenic composition of claim 96, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

98. An immunogenic composition, comprising

(i) a glycan conjugate mixture of claim 23, and

(ii) a pharmaceutically acceptable excipient.

99. The immunogenic composition of claim 98 further comprising an adjuvant.

100. The immunogenic composition of claim 99, wherein the adjuvant is C34, 7DW8-5, C17, C23, C30, α

-galactoceramide, Aluminum salt, Squalene, MF59, or QS-21.

101. A kit comprising a glycan conjugate according to claim 21, and instructions for use thereof.

102. A kit comprising a glycan conjugate according to claim 22, and instructions for use thereof.

103. A kit comprising an immunogenic composition of claim 29, and instructions for use thereof.

104. A kit comprising an immunogenic composition of claim 30, and instructions for use thereof.

105. A kit comprising an immunogenic composition of claim 31, and instructions for use thereof.

106. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 17.

107. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 18.

108. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 19.

109. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 20, wherein w is an integer of 1 to 20 and y is an integer of 1 to 20.

110. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 21.

111. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 22.

112. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 23.

113. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 29.

114. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 30.

115. A method of treating a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 31.

116. The method of claim 106, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

117. The method of claim 116, wherein the cancer is prostate cancer.

118. The method of claim 107, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

119. The method of claim 118, wherein the cancer is prostate cancer.

120. The method of claim 108, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

121. The method of claim 120, wherein the cancer is prostate cancer.

122. The method of claim 109, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

123. The method of claim 122, wherein the cancer is prostate cancer.

124. The method of claim 110, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

125. The method of claim 124, wherein the cancer is prostate cancer.

126. The method of claim 111, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

127. The method of claim 126, wherein the cancer is prostate cancer.

128. The method of claim 112, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

129. The method of claim 128, wherein the cancer is prostate cancer.

130. The method of claim 113, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

131. The method of claim 130, wherein the cancer is prostate cancer.

132. The method of claim 114, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

133. The method of claim 132, wherein the cancer is prostate cancer.

134. The method of claim 115, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

135. The method of claim 134, wherein the cancer is prostate cancer.

136. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 17.

137. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 18.

138. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 19.

139. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate according to claim 20, wherein w is an integer of 1 to 20, and y is an integer of 1 to 20.

140. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 21.

141. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 22.

142. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of a glycan conjugate mixture according to claim 23.

143. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 29.

144. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 30.

145. A method of diagnosing a proliferative disease in a subject comprising administering to the subject an effective amount of an immunogenic composition according to claim 31.

146. The method of claim 33, wherein the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer, liver cancer, buccal cancer, stomach cancer, colon cancer, nasopharyngeal cancer, dermal cancer, renal cancer, brain tumor, prostate cancer, ovarian cancer, cervical cancer, intestinal cancer, and bladder cancer.

147. The method of claim 146, wherein the cancer is prostate cancer.