Synthetic hyperglycosylated, and hyperglycosylated protease-resistant polypeptide variants, oral formulations and methods of using the same

• US 20060204473A1
• Filed: 02/08/2006
• Published: 09/14/2006
• Est. Priority Date: 08/09/2004
• Status: Active Grant

• Current Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Original Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Inventors: Seiwert, Scott D., Hong, Jin, Blatt, Lawrence M.
• Granted Patent: US 7,597,884 B2
• Time in Patent Office: Days
• US Class Current: 424/85.500
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/555 Interferons [IFN]
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 14/565 IFN-beta
• CPC Class Codes: C07K 14/57 IFN-gamma
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides synthetic Type I interferon receptor polypeptide agonists comprising consensus or hybrid Type I interferon receptor polypeptide agonists, containing one or more native or non-native glycosylation sites. The present invention provides synthetic Type I interferon receptor polypeptide agonists comprising consensus or hybrid Type I interferon receptor polypeptide agonists, containing one or more native or non-native glycosylation sites, as well as erythropoietin and darbepoetin alfa, each of which are linked to a penetrating peptide that facilitates translocation of a substance across a biological barrier as well as pharmaceutical compositions, including oral formulations, of the same. The present invention further provides oral formulations of hyperglycosylated or protease-resistant, hyperglycosylated polypeptide variants, which polypeptide variants lack at least one protease cleavage site found in a parent polypeptide, and thus exhibit increased protease resistance compared to the parent polypeptide, which polypeptide variants further include (1) a carbohydrate moiety covalently linked to at least one non-native glycosylation site not found in the parent protein therapeutic or (2) a carbohydrate moiety covalently linked to at least one native glycosylation site found but not glycosylated in the parent protein therapeutic. The present invention further provides compositions, including oral pharmaceutical compositions, comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides containers, devices, and kits comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides therapeutic methods involving administering an effective amount of an oral pharmaceutical composition comprising a synthetic Type I interferon receptor polypeptide agonist, a hyperglycosylated polypeptide variant, or a hyperglycosylated, protease-resistant polypeptide variant to an individual in need thereof.

Claims

1. A variant of a parent Type 1 interferon, wherein the variant comprises at least one amino acid substitution compared to the parent Type 1 interferon, wherein the at least one amino acid substitution is selected from the group consisting of D31N, L31S, D31N, K31N, D102N, S102N, T102N, R102N, I102N, D108N, E108N, K108N, E138T, G138T, I138T, L138T, and P138T wherein the at least one amino acid substitution generates a glycosylation site.

2. The variant of claim 1, wherein the parent Type 1 interferon is an interferon α

(IFN α

).

3. The variant of claim 1, wherein the parent Type 1 interferon is an interferon β

(IFN β

).

4. The variant of claim 1, wherein the parent Type 1 interferon is an interferon κ

(IFN-κ

).

5. The variant of claim 1, wherein the parent Type 1 interferon is an interferon ω

(IFN ω

).

6. The variant of claim 1, wherein the parent Type 1 interferon is interferon τ

(IFN τ

).

7. The variant of claim 1, wherein the parent Type 1 interferon is a hybrid Type 1 interferon.

8. The variant of claim 2, wherein the at least one amino acid substitution is selected from the group consisting of D31N, D102N, D108N, E108N, E138T, G138T and I138T.

9. The variant of claim 2, wherein the interferon α

is interferon alfacon-1.

10. The variant of claim 9, wherein the variant is selected from the group consisting of [D102N]interferon alfacon-1, [D108N]interferon alfacon-1, [E 138N] interferon alfacon-1, [D102N, D108N] interferon alfacon-1, [D102N, E138N]interferon alfacon-1, [D108N, E138N]interferon alfacon-1, and [D102N, D108N, E138N] interferon alfacon-1.

11. The variant of claim 9, wherein the variant is selected from the group consisting of [D102N]interferon alfacon-1, [D102N, D108N]interferon alfacon-1, [D102N, D108N, E138N] interferon alfacon-1, [D108N, E138N] interferon alfacon-1, [E138N] interferon alfacon-1, and [D102N, E138N]interferon alfacon-1.

12. The variant of claim 9, wherein the variant is [D102N]interferon alfacon-1.

13. The variant of claim 9, wherein the variant is [D108N]interferon alfacon-1.

14. The variant of claim 9, wherein the variant is [D138N]interferon alfacon-1.

15. The variant of claim 9, wherein the variant is [D102N, D138N] interferon alfacon-1.

16. The variant of claim 9, wherein the variant is [D102N, E138N]interferon alfacon-1.

17. The variant of claim 9, wherein the variant is [D108N, E138N]interferon alfacon-1.

18. The variant of claim 9, wherein the variant is [D102N, D108N, E138N] interferon alfacon-1.

19. The variant of claim 9, wherein the variant comprises a consensus amino acid sequence as set forth in SEQ ID Nos:

2137-2151.

20. The variant of claim 8, wherein the parent interferon α

is interferon α

1.

21. The variant of claim 20, wherein the variant is selected from the group consisting of [D31N]interferon α

1, [D102N]interferon α

1, [D108N]interferon α

1, [G138T]interferon α

1, [D31N, D102N]interferon α

1, [D31N, D108N]interferon α

1, [D31N, G138T]interferon α

1, [D102N, D108N]interferon α

1, [D102N, G138T]interferon α

1, [D108N, G138T]interferon α

1, [D31N, D102N, D108N]interferon α

1, [D31N, D102N, G138T]interferon α

1, [D31N, D108N, G138T]interferon α

1, [D102N, D108N, G138T]interferon α

1, and [D31N, D102N, D108N, G138T]interferon α

1.

22. The variant of claim 21, wherein the variant is [D31N]interferon α

1.

23. The variant of claim 21, wherein the variant [D102N]interferon α

1.

24. The variant of claim 21, wherein the variant is [D108N]interferon α

1.

25. The variant of claim 21, wherein the variant is [G138T]interferon α

1.

26. The variant of claim 21, wherein the variant is [D31N, D102N]interferon α

1.

27. The variant of claim 21, wherein the variant is [D31N, D108N]interferon α

1.

28. The variant of claim 21, wherein the variant is [D31N, G138T]interferon α

1.

29. The variant of claim 21, wherein the variant is [D102N, D108N]interferon α

1.

30. The variant of claim 21, wherein the variant is [D102N, G138T]interferon α

1.

31. The variant of claim 21, wherein the variant is [D108N, G138T]interferon α

1.

32. The variant of claim 21, wherein the variant is [D31N, D102N, D108N]interferon α

1.

33. The variant of claim 21, wherein the variant is [D31N, D102N, G138T] interferon α

1.

34. The variant of claim 21, wherein the variant is [D31N, D108N, G138T]interferon α

1.

35. The variant of claim 21, wherein the variant is [D102N, D108N, G138T]interferon α

1.

36. The variant of claim 21, wherein the variant is [D31N, D102N, D108N, G138T] interferon α

1.

37. The variant of claim 20 wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1407-1421.

38. The variant of claim 8, wherein the parent interferon α

is interferon α

2a.

39. The variant of claim 38, wherein the variant is selected from the group consisting of [D31N]interferon α

2a, [D102N]interferon α

2a, [D108N]interferon α

2a, [D31N, D102N]interferon α

2a, [D31N, D108N]interferon α

2a, [D102N, D108N]interferon α

2a, [D31N, D102N, D108N]interferon α

2a.

40. The variant of claim 39, wherein the variant is [D31N]interferon α

2a.

41. The variant of claim 39, wherein the variant is [D102N]interferon α

2a.

42. The variant of claim 39, wherein the variant is [D108N]interferon α

2a.

43. The variant of claim 39, wherein the variant is [D31N, D102N]interferon α

2a.

44. The variant of claim 39, wherein the variant is [D31N, D108N]interferon α

2a.

45. The variant of claim 39, wherein the variant is [D102N, D108N]interferon α

2a.

46. The variant of claim 39, wherein the variant is [D31N, D102N, D108N] interferon α

2a.

47. The variant of claim 38, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1423-1433.

48. The variant of claim 8, wherein the parent interferon α

is interferon α

2b.

49. The variant of claim 48, wherein the variant is selected from the group consisting of [D31N] interferon α

2b, [D102N]interferon α

2b, [D108N]interferon α

2b, [D31N, D102N]interferon α

2b, [D31N, D108N]interferon α

2b, [D102N, D108N]interferon α

2b, [D31N, D102N, D108N]interferon α

2b.

50. The variant of claim 49, wherein the variant is [D31N]interferon α

2b.

51. The variant of claim 49, wherein the variant is [D102N]interferon α

2b.

52. The variant of claim 49, wherein the variant is [D108N]interferon α

2b.

53. The variant of claim 49, wherein the variant is [D31N, D102N]interferon α

2b.

54. The variant of claim 49, wherein the variant is [D31N, D108N]interferon α

2b.

55. The variant of claim 49, wherein the variant is [D102N, D108N] interferon α

2b.

56. The variant of claim 49, wherein the variant is [D31N, D102N, D108N]interferon α

2b.

57. The variant of claim 48, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1439-1449.

58. The variant of claim 8, wherein the parent interferon α

is interferon α

4a.

59. The variant of claim 58, wherein the variant is selected from the group consisting of [D31N]interferon α

4a, [D102N]interferon α

4a, [E108N]interferon α

4a, [E138T]interferon α

4a, [D31N, D102N]interferon α

4a, [D31N, E108N]interferon α

4a, [D31N, E138T]interferon α

4a, [D102N, E108N]interferon α

4a, [D102N, E138T]interferon α

4a, [E108N, E138T]interferon α

4a, [D31N, D102N, E108N]interferon α

4a, [D31N, D102N, E138T]interferon α

4a, [D31N, E108N, E138T]interferon α

4a, [D102N, E108N, E138T]interferon α

4a, and [D31N, D102N, E108N, E138T]interferon α

4a.

60. The variant of claim 59, wherein the variant is [D31N]interferon α

4a.

61. The variant of claim 59, wherein the variant is [D102N]interferon α

4a]interferon α

4a.

62. The variant of claim 59, wherein the variant is [E108N]interferon α

4a.

63. The variant of claim 59, wherein the variant is [E138T]interferon α

4a.

64. The variant of claim 59, wherein the variant is [D31N, D102N]interferon α

4a.

65. The variant of claim 59, wherein the variant is [D31N, E108N]interferon α

4a.

66. The variant of claim 59, wherein the variant is [D31N, E138T]interferon α

4a.

67. The variant of claim 59, wherein the variant is [D102N, E108N]interferon α

4a.

68. The variant of claim 59, wherein the variant is [D102N, E138T]interferon α

4a.

69. The variant of claim 59, wherein the variant is [E108N, E138T] interferon α

4a.

70. The variant of claim 59, wherein the variant is [D31N, D102N, E108N]interferon α

4a.

71. The variant of claim 59, wherein the variant is [D31N, D102N, E138T]interferon α

4a.

72. The variant of claim 59, wherein the variant is [D31N, E108N, E138T] interferon α

4a.

73. The variant of claim 59, wherein the variant is [D102N, E108N, E138T]interferon α

4a.

74. The variant of claim 59, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

4a.

75. The variant of claim 58, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1455-1469.

76. The variant of claim 8, wherein the parent interferon α

is interferon α

4b.

77. The variant of claim 76, wherein the variant is selected from the group consisting of [D31N]interferon α

4b, [D102N]interferon α

4b, [E108N]interferon α

4b, [E138T]interferon α

4b, [D31N, D102N]interferon α

4b, [D31N, E108N]interferon α

4b, [D31N, E138T]interferon α

4b, [D102N, E108N]interferon α

4b, [D102N, E138T]interferon α

4b, [E108N, E138T]interferon α

4b, [D31N, D102N, E108N]interferon α

4b, [D31N, D102N, E138T]interferon α

4b, [D31N, E108N, E138T]interferon α

4b, [D102N, E108N, E138T]interferon α

4b, and [D31N, D102N, E108N, E138T]interferon α

4b.

78. The variant of claim 77, wherein the variant is [D31N]interferon α

4b.

79. The variant of claim 77, wherein the variant is [D102N]interferon α

4b.

80. The variant of claim 77, wherein the variant is [E108N]interferon α

4b.

81. The variant of claim 77, wherein the variant is [E138T]interferon α

4b.

82. The variant of claim 77, wherein the variant is [D31N, D102N]interferon α

4b.

83. The variant of claim 77, wherein the variant is [D31N, E108N]interferon α

4b.

84. The variant of claim 77, wherein the variant is [D31N, E138T]interferon α

4b.

85. The variant of claim 77, wherein the variant is [D102N, E108N]interferon α

4b.

86. The variant of claim 77, wherein the variant is [D102N, E138T]interferon α

4b.

87. The variant of claim 77, wherein the variant is [E108N, E138T]interferon α

4b.

88. The variant of claim 77, wherein the variant is [D31N, D102N, E 108N]interferon α

4b.

89. The variant of claim 77, wherein the variant is [D31N, D102N, E138T]interferon α

4b.

90. The variant of claim 77, wherein the variant is [D31N, E108N, E138T]interferon α

4b.

91. The variant of claim 77, wherein the variant is [D102N, E108N, E138T]interferon α

4b.

92. The variant of claim 77, wherein the variant is [D31N, D102N, E 108N, E138T]interferon α

4b.

93. The variant of claim 76, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1471-1485.

94. The variant of claim 8, wherein the parent interferon α

is interferon α

5.

95. The variant of claim 94, wherein the variant is selected from the group consisting of [D31N]interferon α

5, [D102N]interferon α

5, [D108N]interferon α

5, [E138T]interferon α

5, [D31N, D102N]interferon α

5, [D31N, D108N]interferon α

5, [D31N, E138T]interferon α

5, [D102N, D108N]interferon α

5, [D102N, E138T]interferon α

5, [D108N, E138T]interferon α

5, [D31N, D102N, D108N]interferon α

5, [D31N, D102N, E138T]interferon α

5, [D31N, D108N, E138T]interferon α

5, [D102N, D108N, EI138T]interferon α

5, and [D31N, D102N, D108N, E138T] interferon α

5.

96. The variant of claim 95, wherein the variant is [D31N]interferon α

5.

97. The variant of claim 95, wherein the variant is [D102N]interferon α

5.

98. The variant of claim 95, wherein the variant is [D108N]interferon α

5.

99. The variant of claim 95, wherein the variant is [E138T]interferon α

5.

100. The variant of claim 95, wherein the variant is [D31N, D102N]interferon α

5.

101. The variant of claim 95, wherein the variant is [D31N, D108N]interferon α

5.

102. The variant of claim 95, wherein the variant is [D31N, E138T]interferon α

5.

103. The variant of claim 95, wherein the variant is [D102N, D108N]interferon α

5.

104. The variant of claim 95, wherein the variant is [D102N, E138T]interferon α

5.

105. The variant of claim 95, wherein the variant is [D108N, E138T]interferon α

5.

106. The variant of claim 95, wherein the variant is [D31N, D102N, D108N]interferon α

5.

107. The variant of claim 95, wherein the variant is [D31N, D102N, E138T]interferon α

5.

108. The variant of claim 95, wherein the variant is [D31N, D108N, E138T]interferon α

5.

109. The variant of claim 95, wherein the variant is [D102N, D108N, E138T] interferon α

5.

110. The variant of claim 95, wherein the variant is [D31N, D102N, D108N, E138T] interferon α

5.

111. The variant of claim 94, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1487-1501.

112. The variant of claim 8, wherein the parent interferon α

is interferon α

6.

113. The variant of claim 112, wherein the variant is selected from the group consisting of [D31N]interferon α

6, [D102N]interferon α

6, [D108N]interferon α

6, [G138T]interferon α

6, [D31N, D102N]interferon α

6, [D31N, D108N]interferon α

6, [D31N, G138T]interferon α

6, [D102N, D108N]interferon α

6, [D102N, G138T]interferon α

6, [D108N, E138T]interferon α

6, [D31N, D102N, D108N]interferon α

6, [D31N, D102N, G138T]interferon α

6, [D31N, D108N, G138T]interferon α

6, [D102N, D108N, G138T]interferon α

6, and [D31N, D102N, D108N, G138T] interferon α

6.

114. The variant of claim 113, wherein the variant is [D31N]interferon α

6.

115. The variant of claim 113, wherein the variant is [D102N]interferon α

6.

116. The variant of claim 113, wherein the variant is [D108N]interferon α

6.

117. The variant of claim 113, wherein the variant is [G138T]interferon α

6.

118. The variant of claim 113, wherein the variant is [D31N, D102N] interferon α

6.

119. The variant of claim 113, wherein the variant is [D31N, D108N]interferon α

6.

120. The variant of claim 113, wherein the variant is [D31N, G138T]interferon α

6.

121. The variant of claim 113, wherein the variant is [D102N, D108N] interferon α

6.

122. The variant of claim 113, wherein the variant is [D102N, G138T]interferon α

6.

123. The variant of claim 113, wherein the variant is [D108N, E138T]interferon α

6.

124. The variant of claim 113, wherein the variant is [D31N, D102N, D108N] interferon α

6.

125. The variant of claim 113, wherein the variant is [D31N, D102N, G138T] interferon α

6.

126. The variant of claim 113, wherein the variant is [D31N, D108N, G138T] interferon α

6.

127. The variant of claim 113, wherein the variant is [D102N, D108N, G138T]interferon α

6.

128. The variant of claim 113, wherein the variant is [D31N, D102N, D108N, G138T]interferon α

6.

129. The variant of claim 112, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1503-1517.

130. The variant of claim 8, wherein the parent interferon α

is interferon α

7.

131. The variant of claim 130, wherein the variant is selected from the group consisting of [D31N] interferon α

7, [D102N] interferon α

7, [E108N]interferon α

7, [E138T]interferon α

7, [D31N, D102N]interferon α

7, [D31N, E108N]interferon α

7, [D31N, E138T]interferon α

7, [D102N, E108N]interferon α

7, [D102N, E138T]interferon α

7, [D108N, E138T]interferon α

7, [D31N, D102N, E108N]interferon α

7, [D31N, D102N, E138T]interferon α

7, [D31N, E108N, E138T]interferon α

7, [D102N, E108N, E138T]interferon α

7, and [D31N, D102N, E108N, E138T] interferon α

7.

132. The variant of claim 131, wherein the variant is [D31N]interferon α

7.

133. The variant of claim 131, wherein the variant is [D102N] interferon α

7.

134. The variant of claim 131, wherein the variant is [E108N] interferon α

7.

135. The variant of claim 131, wherein the variant is [E138T]interferon α

7.

136. The variant of claim 131, wherein the variant is [D31N, D102N] interferon α

7.

137. The variant of claim 131, wherein the variant is [D31N, E108N]interferon α

7.

138. The variant of claim 131, wherein the variant is [D31N, E138T]interferon α

7.

139. The variant of claim 131, wherein the variant is [D102N, E108N] interferon α

7.

140. The variant of claim 131, wherein the variant is [D102N, E138T]interferon α

7.

141. The variant of claim 131, wherein the variant is [D108N, E138T] interferon α

7.

142. The variant of claim 131, wherein the variant is [D31N, D102N, E108N] interferon α

7.

143. The variant of claim 131, wherein the variant is [D31N, D102N, E138T]interferon α

7.

144. The variant of claim 131, wherein the variant is [D31N, E108N, E138T]interferon α

7.

145. The variant of claim 131, wherein the variant [D102N, E108N, E138T]interferon α

7.

146. The variant of claim 131, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

7.

147. The variant of claim 130, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1519-1533.

148. The variant of claim 8, wherein the parent interferon α

is interferon α

8.

149. The variant of claim 148, wherein the variant is selected from the group consisting of [D31N]interferon α

8, [D102N]interferon α

8, [D108N]interferon α

8, [I138T]interferon α

8, [D31N, D102N]interferon α

8, [D31N, D108N]interferon α

8, [D31N, I138T]interferon α

8, [D102N, D108N]interferon α

8, [D102N, I138T]interferon α

8, [D108N, I138T]interferon α

8, [D31N, D102N, D108N]interferon α

8, [D31N, D102N, I138T]interferon α

8, [D31N, D108N, I138T]interferon α

8, [D102N, D108N, I138T]interferon α

8, and [D31N, D102N, D108N, I138T]interferon α

8.

150. The variant of claim 149, wherein the variant is [D31N]interferon α

8.

151. The variant of claim 149, wherein the variant is [D102N]interferon α

8.

152. The variant of claim 149, wherein the variant is [D108N]interferon α

8.

153. The variant of claim 149, wherein the variant is [I138T]interferon α

8.

154. The variant of claim 149, wherein the variant is [D31N, D102N]interferon α

8.

155. The variant of claim 149, wherein the variant is [D31N, D108N]interferon α

8.

156. The variant of claim 149, wherein the variant is [D31N, I138T]interferon α

8.

157. The variant of claim 149, wherein the variant is [D102N, D108N] interferon α

8.

158. The variant of claim 149, wherein the variant is [D102N, I138T]interferon α

8.

159. The variant of claim 149, wherein the variant is [D108N, I138T]interferon α

8.

160. The variant of claim 149, wherein the variant is [D31N, D102N, D108N] interferon α

8.

161. The variant of claim 149, wherein the variant is [D31N, D102N, I138T]interferon α

8.

162. The variant of claim 149, wherein the variant is [D31N, D108N, I138T] interferon α

8.

163. The variant of claim 149, wherein the variant is [D102N, D108N, I138T] interferon α

8.

164. The variant of claim 149, wherein the variant is [D31N, D102N, D108N, I138T] interferon α

8.

165. The variant of claim 148, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1535-1549.

166. The variant of claim 8, wherein the parent interferon α

is interferon α

10.

167. The variant of claim 166, wherein the variant is selected from the group consisting of [D31N]interferon α

10, [D102N]interferon 10, [E108N]interferon α

10, [E138T]interferon α

10, [D31N, D102N]interferon α

10, [D31N, E108N]interferon α

10, [D31N, E138T]interferon α

10, [D102N, E108N]interferon α

10, [D102N, E138T]interferon α

10, [D108N, E138T]interferon α

10, [D31N, D102N, E108N]interferon α

10, [D31N, D102N, E138T]interferon α

10, [D31N, E108N, E138T]interferon α

10, [D102N, E108N, E138T]interferon α

10, and [D31N, D102N, E108N, E138T]interferon α

10.

168. The variant of claim 167, wherein the variant is [D31N]interferon α

10.

169. The variant of claim 167, wherein the variant is [D102N]interferon α

10.

170. The variant of claim 167, wherein the variant is [E108N]interferon α

10.

171. The variant of claim 167, wherein the variant [E138T]interferon α

10.

172. The variant of claim 167, wherein the variant is [D31N, D102N] interferon α

10.

173. The variant of claim 167, wherein the variant is [D31N, E108N]interferon α

10.

174. The variant of claim 167, wherein the variant is [D31N, E138T]interferon α

10.

175. The variant of claim 167, wherein the variant is [D102N, E108N]interferon α

10.

176. The variant of claim 167, wherein the variant is [D102N, E138T]interferon α

10.

177. The variant of claim 167, wherein the variant is [E108N, E138T]interferon α

10.

178. The variant of claim 167, wherein the variant is [D31N, D102N, E108N]interferon α

10.

179. The variant of claim 167, wherein the variant is [D31N, D102N, E138T]interferon α

10.

180. The variant of claim 167, wherein the variant is [D31N, E108N, E138T]interferon α

10.

181. The variant of claim 167, wherein the variant is [D102N, E108N, E138T]interferon α

10.

182. The variant of claim 167, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

10.

183. The variant of claim 166, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1551-1565.

184. The variant of claim 8, wherein the parent interferon α

is interferon α

13.

185. The variant of claim 184, wherein the variant is selected from the group consisting of [D31N]interferon α

13, [D102N]interferon α

13, [D108N]interferon α

13, [G138T]interferon α

13, [D31N, D102N]interferon α

13, [D31N, D108N]interferon α

13, [D31N, G138T]interferon α

13, [D102N, D108N]interferon α

13, [D102N, G138T]interferon α

13, [D108N, E138T]interferon α

13, [D31N, D102N, D108N]interferon α

13, [D31N, D102N, G138T]interferon α

13, [D31N, D108N, G138T]interferon α

13, [D102N, D108N, G138T]interferon α

13, and [D31N, D102N, D108N, G138T]interferon α

13.

186. The variant of claim 185, wherein the variant is [D31N]interferon α

13.

187. The variant of claim 185, wherein the variant is [D102N]interferon α

13,

188. The variant of claim 185, wherein the variant is [D108N]interferon α

13.

189. The variant of claim 185, wherein the variant is [G138T]interferon α

13.

190. The variant of claim 185, wherein the variant is [D31N, D102N]interferon α

13.

191. The variant of claim 185, wherein the variant is [D31N, D108N]interferon α

13.

192. The variant of claim 185, wherein the variant is [D31N, G138T]interferon α

13.

193. The variant of claim 185, wherein the variant is [D102N, D108N]interferon α

113.

194. The variant of claim 185, wherein the variant is [D102N, G138T]interferon α

13.

195. The variant of claim 185, wherein the variant is [D108N, E138T]interferon α

13.

196. The variant of claim 185, wherein the variant is [D31N, D102N, D108N]interferon α

13.

197. The variant of claim 185, wherein the variant is [D31N, D102N, G138T]interferon α

13.

198. The variant of claim 185, wherein the variant is [D31N, D108N, G138T]interferon α

113.

199. The variant of claim 185, wherein the variant is [D102N, D108N, G138T]interferon α

13.

200. The variant of claim 185, wherein the variant is [D31N, D102N, D108N, G138T]interferon α

13.

201. The variant of claim 184, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1567-1581.

202. The variant of claim 8, wherein the parent interferon α

is interferon α

14.

203. The variant of claim 202, wherein the variant is selected from the group consisting of [D108N]interferon α

14, [E138T]interferon α

14, and [D108N, E138T]interferon α

14.

204. The variant of claim 203, wherein the variant is [D108N]interferon α

14.

205. The variant of claim 203, wherein the variant is [E138T]interferon α

14.

206. The variant of claim 203, wherein the variant is [D108N, E138T]interferon α

14.

207. The variant of claim 202, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1585-1592.

208. The variant of claim 8, wherein the parent interferon α

is interferon α

16.

209. The variant of claim 208, wherein the variant is selected from the group consisting of [D31N]interferon α

16, [D102N]interferon α

16, [D108N]interferon α

16, [E138T]interferon α

16, [D31N, D102N] interferon α

16, [D31N, D108N]interferon α

16, [D31N, E 138T] interferon α

16, [D102N, D108N] interferon α

16, [D102N, E138T]interferon α

16, [D108N, E138T]interferon α

16, [D31N, D102N, D108N]interferon α

16, [D31N, D102N, E138T]interferon α

16, [D31N, D108N, E138T]interferon α

16, [D102N, D108N, E138T]interferon α

16, and [D31N, D102N, D108N, E138T]interferon α

16.

210. The variant of claim 209, wherein the variant is [D31N]interferon α

16.

211. The variant of claim 209, wherein the variant is [D102N]interferon α

16.

212. The variant of claim 209, wherein the variant is [D108N]interferon α

16.

213. The variant of claim 209, wherein the variant is [E138T]interferon α

16.

214. The variant of claim 209, wherein the variant is [D31N, D102N]interferon α

16.

215. The variant of claim 209, wherein the variant is [D31N, D108N] interferon α

16.

216. The variant of claim 209, wherein the variant is [D31N, E138T]interferon α

16.

217. The variant of claim 209, wherein the variant is [D102N, D108N]interferon α

16.

218. The variant of claim 209, wherein the variant is [D102N, E138T]interferon α

16.

219. The variant of claim 209, wherein the variant is [D108N, E138T]interferon α

16.

220. The variant of claim 209, wherein the variant is [D31N, D102N, D108N]interferon α

16.

221. The variant of claim 209, wherein the variant is [D31N, D102N, E138T]interferon α

16.

222. The variant of claim 209, [D31N, D108N, E138T]interferon α

16.

223. The variant of claim 209, wherein the variant is [D31N, D102N, D108N, E138T]interferon α

16.

224. The variant of claim 208, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1599-1613.

225. The variant of claim 8, wherein the parent interferon α

is interferon α

17.

226. The variant of claim 225, wherein the variant is selected from the group consisting of [D31N]interferon α

17, [D102N]interferon α

17, [E108N]interferon α

17, [E138T]interferon α

17, [D31N, D102N]interferon α

17, [D31N, E108N]interferon α

17, [D31N, E138T]interferon α

17, [D102N, E108N]interferon α

17, [D102N, E138T]interferon α

17, [D108N, E138T]interferon α

17, [D31N, D102N, E108N]interferon α

17, [D31N, D102N, E138T]interferon α

17, [D31N, E108N, E138T]interferon α

17, [D102N, E108N, E138T]interferon α

17, and [D31N, D102N, E108N, E138T]interferon α

17.

227. The variant of claim 226, wherein the variant is [D31N]interferon α

17.

228. The variant of claim 226, wherein the variant is [D102N]interferon α

17.

229. The variant of claim 226, wherein the variant is [E108N]interferon α

17.

230. The variant of claim 226, wherein the variant is [E138T]interferon α

17.

231. The variant of claim 226, wherein the variant is [D31N, D102N] interferon α

17.

232. The variant of claim 226, wherein the variant is [D31N, E 108N]interferon α

17.

233. The variant of claim 226, wherein the variant is [D31N, E138T]interferon α

17.

234. The variant of claim 226, wherein the variant is [D102N, E108N]interferon α

17.

235. The variant of claim 226, wherein the variant is [D102N, E138T]interferon α

17.

236. The variant of claim 226, wherein the variant is [D108N, E138T]interferon α

17.

237. The variant of claim 226, wherein the variant is [D31N, D102N, E108N]interferon α

17.

238. The variant of claim 226, wherein the variant is [D31N, D102N, E138T]interferon α

17.

239. The variant of claim 226, wherein the variant is [D31N, E108N, E138T]interferon α

17.

240. The variant of claim 226, wherein the variant is [D102N, E108N, E138T]interferon α

17.

241. The variant of claim 226, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

17.

242. The variant of claim 225, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1615-1629.

243. The variant of claim 8, wherein the parent interferon α

is interferon α

21.

244. The variant of claim 243, wherein the variant is selected from the group consisting of [D31N] interferon α

21, [D102N]interferon α

21, [E108N]interferon α

21, [E138T]interferon α

21, [D31N, D102N]interferon α

21, [D31N, E108N]interferon α

21, [D31N, E138T]interferon α

21, [D102N, E108N]interferon α

21, [D102N, E138T]interferon α

21, [D108N, E138T]interferon α

21, [D31N, D102N, E108N]interferon α

21, [D31N, D102N, E138T]interferon α

21, [D31N, E108N, E138T] interferon α

21, [D102N, E108N, E138T] interferon α

21, and [D31N, D102N, E108N, E138T]interferon α

21.

245. The variant of claim 244, wherein the variant is [D31N]interferon α

21.

246. The variant of claim 244, wherein the variant is [D102N]interferon α

21.

247. The variant of claim 244, wherein the variant is [E108N]interferon α

21.

248. The variant of claim 244, wherein the variant is [E138T]interferon α

21.

249. The variant of claim 244, wherein the variant is [D31N, D102N] interferon α

21.

250. The variant of claim 244, wherein the variant is [D31N, E108N]interferon α

21.

251. The variant of claim 244, wherein the variant is [D31N, E138T]interferon α

21.

252. The variant of claim 244, wherein the variant [D102N, E108N]interferon α

21.

253. The variant of claim 244, wherein the variant is [D102N, E138T]interferon α

21.

254. The variant of claim 244, wherein the variant is [D108N, E138T]interferon α

21.

255. The variant of claim 244, wherein the variant is [D31N, D102N, E108N] interferon α

21.

256. The variant of claim 244, wherein the variant is selected from the group consisting of [D31N, D102N, E138T] interferon α

21.

257. The variant of claim 244, wherein the variant is [D31N, E108N, E138T]interferon α

21.

258. The variant of claim 244, wherein the variant is [D102N, E108N, E138T]interferon α

21.

259. The variant of claim 244, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

21.

260. The variant of claim 243, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1631-1645.

261. The variant of claim 8, wherein the parent interferon α

is interferon α

H.

262. The variant of claim 261, wherein the variant is selected from the group consisting of [D108N]interferon α

H, [E138T]interferon α

H, and [D108N, E138T] interferon α

H.

263. The variant of claim 262, wherein the variant is [D108N]interferon α

H.

264. The variant of claim 262, wherein the variant is [E138T]interferon α

H.

265. The variant of claim 262, wherein the variant is [D108N, E138T] interferon α

H.

266. The variant of claim 261, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1649-1656.

267. The variant of claim 8, wherein the parent interferon α

is interferon α

I.

268. The variant of claim 267, wherein the variant is selected from the group consisting of [D31N]interferon α

I, [D102N] interferon α

1, [E108N]interferon α

I, [E138T]interferon α

I, [D31N, D102N]interferon α

1, [D31N, E108N]interferon α

1, [D31N, E138T]interferon α

1, [D102N, E108N]interferon α

I, [D102N, E138T]interferon α

I, [D108N, E138T]interferon α

1, [D31N, D102N, E108N]interferon α

1, [D31N, D102N, E138T]interferon α

1, [D31N, E108N, E138T]interferon α

1, [D102N, E108N, E138T]interferon α

I, and [D31N, D102N, E108N, E138T] interferon α

1.

269. The variant of claim 268, wherein the variant is [D31N] interferon α

I.

270. The variant of claim 268, wherein the variant is [D102N]interferon α

I.

271. The variant of claim 268, wherein the variant is [E108N]interferon α

1.

272. The variant of claim 268, wherein the variant is [E138T]interferon α

1.

273. The variant of claim 268, wherein the variant is [D31N, D102N] interferon α

I.

274. The variant of claim 268, wherein the variant is [D31N, E108N]interferon α

I.

275. The variant of claim 268, wherein the variant is [D31N, E138T]interferon α

I.

276. The variant of claim 268, wherein the variant is [D102N, E108N]interferon α

I.

277. The variant of claim 268, wherein the variant is [D102N, E138T]interferon α

I.

278. The variant of claim 268, wherein the variant is [D108N, E138T] interferon α

I.

279. The variant of claim 268, wherein the variant is [D31N, D102N, E108N] interferon α

I.

280. The variant of claim 268, wherein the variant is [D31N, D102N, E138T]interferon α

I.

281. The variant of claim 268, wherein the variant is [D31N, E108N, E138T] interferon α

I.

282. The variant of claim 268, wherein the variant is [D102N, E108N, E138T] interferon α

I.

283. The variant of claim 268, wherein the variant is [D31N, D102N, E108N, E138T] interferon α

I.

284. The variant of claim 267, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1663-1677.

285. The variant of claim 8, wherein the parent interferon α

is interferon α

J1.

286. The variant of claim 285, wherein the variant is selected from the group consisting of [D31N]interferon α

J1, [D102N]interferon α

J1, [E108N] interferon α

J1;

[E138T]interferon α

J1, [D31N, D102N]interferon α

J1, [D31N, E108N]interferon α

J1, [D31N, E138T]interferon α

J1, [D102N, E108N]interferon α

J1, [D102N, E138T]interferon α

J1, [D108N, E138T]interferon α

J1, [D31N, D102N, E108N]interferon α

J1, [D31N, D102N, E138T]interferon α

J1, [D31N, E108N, E138T]interferon α

J1, [D102N, E108N, E138T]interferon α

J1, and [D31N, D102N, E108N, E138T]interferon α

J1.

287. The variant of claim 286, wherein the variant is [D31N]interferon α

J1.

288. The variant of claim 286, wherein the variant is [D102N]interferon α

J1.

289. The variant of claim 286, wherein the variant is [E108N]interferon α

J1.

290. The variant of claim 286, wherein the variant is [E138T]interferon α

J1.

291. The variant of claim 286, wherein the variant is [D31N, D102N]interferon α

J1.

292. The variant of claim 286, wherein the variant is [D31N, E108N]interferon α

J1.

293. The variant of claim 286, wherein the variant is [D31N, E138T]interferon α

J1.

294. The variant of claim 286, wherein the variant is [D102N, E108N]interferon α

J1.

295. The variant of claim 286, wherein the variant is [D102N, E138T]interferon α

J1.

296. The variant of claim 286, wherein the variant is [D108N, E138T]interferon α

J1.

297. The variant of claim 286, wherein the variant is [D31N, D102N, E108N] interferon α

J1.

298. The variant of claim 286, wherein the variant is [D31N, D102N, E138T]interferon α

J1.

299. The variant of claim 286, wherein the variant is [D31N, E108N, E138T]interferon α

J1.

300. The variant of claim 286, wherein the variant is [D102N, E108N, E138T]interferon α

J1.

301. The variant of claim 286, wherein the variant is [D31N, D102N, E108N, E138T]interferon α

J1.

302. The variant of claim 285, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1678-1693.

303. The variant of claim 3, wherein the at least one amino acid substitution is selected from the group consisting of L31S, S102N, and E138T.

304. The variant of claim 303, wherein the variant is selected from the group consisting of [L31S]interferon-β

, [S102N]interferon-β

, [E138T]interferon-β

, [L31S, S102N]interferon-β

, [L31S, E138T]interferon-β

, [S102N, E138T]interferon-β

, and [L31S, S102N, E138T]interferon-β

.

305. The variant of claim 304, wherein the variant is [L31S]interferon-β

.

306. The variant of claim 304, wherein the variant is [S102N]interferon-β

.

307. The variant of claim 304, wherein the variant is [E138T]interferon-β

.

308. The variant of claim 304, wherein the variant is [L31S, S102N]interferon-β

.

309. The variant of claim 304, wherein the variant is [L31S E138T]interferon-β

.

310. The variant of claim 304, wherein the variant is [S102N, E138T]interferon-β

.

311. The variant of claim 304, wherein the variant is [L31S, S102N, E138T]interferon-β

.

312. The variant of claim 303, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1695-1706.

313. The variant of claim 4, wherein the at least one amino acid substitution is selected from the group consisting of L31S, T102N, K108N, and P138T.

314. The variant of claim 313, wherein the variant is selected from the group consisting of [L31S]interferon κ

, [T102N]interferon κ

, [K108N]interferon K, [P138T]interferon κ

, [L31S, T102N]interferon κ

, [L31S, K108N]interferon κ

, [L31S, P138T]interferon κ

, [T102N, K108N]interferon κ

, [T102N, P138T]interferon κ

, [K108N, P138T]interferon κ

, [L31S, T102N, K108N]interferon κ

, [L31S, T102N, P138T]interferon κ

, [L31S, K108N, P138T]interferon κ

, [T102N, K108N, P138T]interferon κ

, and [L31S, T102N, K108N, P138T]interferon κ

.

315. The variant of claim 314, wherein the variant is [L31S]interferon κ

.

316. The variant of claim 314, wherein the variant is [T102N]interferon κ

.

317. The variant of claim 314, wherein the variant is [K108N]interferon κ

.

318. The variant of claim 314, wherein the variant is [P138T] interferon κ

.

319. The variant of claim 314, wherein the variant is [L31S, T102N]interferon κ

.

320. The variant of claim 314, wherein the variant is [L31S, K108N]interferon κ

.

321. The variant of claim 314, wherein the variant is [L31S, P138T]interferon K.

322. The variant of claim 314, wherein the variant is [T102N, K108N]interferon κ

.

323. The variant of claim 314, wherein the variant is [T102N, P138 T] interferon κ

.

324. The variant of claim 314, wherein the variant is [K108N, P138T] interferon κ

.

325. The variant of claim 314, wherein the variant is [L31S, T102N, K108N]interferon κ

.

326. The variant of claim 314, wherein the variant is [L31S, T102N, P138T] interferon κ

.

327. The variant of claim 314, wherein the variant is [L31S, K108N, P138T]interferon κ

.

328. The variant of claim 314, wherein the variant is [T102N, K108N, P138T] interferon κ

.

329. The variant of claim 314, wherein the variant is [L31S, T102N, K108N, P138T]interferon κ

.

330. The variant of claim 313, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1711-1725.

331. The variant of claim 5, wherein the at least one amino acid substitution is selected from the group consisting of D31N, R102N, and G138T.

332. The variant of claim 331, wherein the variant is selected from the group consisting of [D31N]interferon ω

, [R102N]interferon ω

, [G138T]interferon ω

, [D31N, R102N]interferon ω

, [D31N, G138T]interferon ω

, [R102N, G138T]interferon (o, [D31N, R102N, G138T]interferon ω

.

333. The variant of claim 332, wherein the variant is [D31N] interferon ω

.

334. The variant of claim 332, wherein the variant is [R102N]interferon ω

.

335. The variant of claim 332, wherein the variant is [G138T]interferon ω

.

336. The variant of claim 332, wherein the variant is [D31N, R102N] interferon co.

337. The variant of claim 332, wherein the variant is [D31N, G138T]interferon ω

.

338. The variant of claim 332, wherein the variant is [R102N, G138T]interferon ω

.

339. The variant of claim 332, wherein the variant is [D31N, R102N, G138T]interferon ω

.

340. The variant of claim 331, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1727-1738.

341. The variant of claim 6, wherein the at least one amino acid substitution is selected from the group consisting of K31N, I102N, E108N, and L138T.

342. The variant of claim 341, wherein the variant is selected from the group consisting of [K31N]interferon τ

, [1102N]interferon τ

, [E108N]interferon T, [L138T] interferon τ

, [K31N, I102N] interferon τ

, [K31N, E108N]interferon τ

, [K31N, L138T]interferon τ

, [I102N, E108N]interferon τ

, [I102N, L138T]interferon τ

, [E108N, L138T]interferon r, [K31N, I102N, E108N]interferon τ

, [K31N, I102N, L138T]interferon τ

, [K31N, E108N, L138T]interferon τ

, [I102N, E108N, L138T]interferon τ

, and [K31N, I102N, E108N, L138T]interferon τ

.

343. The variant of claim 342, wherein the variant is [K31N]interferon τ

.

344. The variant of claim 342, wherein the variant is [I102N]interferon τ

.

345. The variant of claim 342, wherein the variant is [E108N]interferon τ

.

346. The variant of claim 342, wherein the variant is [L138T]interferon τ

.

347. The variant of claim 342, wherein the variant is [K31N, I102N]interferon τ

.

348. The variant of claim 342, wherein the variant is [K31N, E108N]interferon τ

.

349. The variant of claim 342, wherein the variant is [K31N, L138T]interferon τ

.

350. The variant of claim 342, wherein the variant is [I102N, E108N]interferon τ

.

351. The variant of claim 342, wherein the variant is [I102N, L138T]interferon T.

352. The variant of claim 342, wherein the variant is [E108N, L138T]interferon τ

.

353. The variant of claim 342, wherein the variant is [K31N, I102N, E108N] interferon τ

.

354. The variant of claim 342, wherein the variant is [K31N, I102N, L138T] interferon τ

.

355. The variant of claim 342, wherein the variant is [K31N, E108N, L138T]interferon τ

.

356. The variant of claim 342, wherein the variant is [I102N, E108N, L138T]interferon r.

357. The variant of claim 342, wherein the variant is [K31N, I102N, E108N, L138T] interferon τ

.

358. The variant of claim 341, wherein the variant comprises an amino acid sequence as set forth in any one of SEQ ID Nos:

1743-1757.

359. The variant of claim 1, wherein the variant comprises a carbohydrate moiety covalently linked to a non-native glycosylation site.

364. The variant of any of claims 1, 2, 10, 11, 21, 39, 49, 59, 77, 95, 113, 131, 149, 167, 185, 203, 209, 226, 244, 262, 268, 286, 304, 314, 332, and 342 wherein the variant comprises a carrier peptide set forth in Table 9.

365. A pharmaceutical composition comprising the variant of claim 1;

and a pharmaceutically acceptable excipient.

367. The composition of claim 365, wherein the pharmaceutically-acceptable excipient is suitable for oral delivery.

369. The composition of claim 367 or 368, wherein the pharmaceutically-acceptable excipient is suitable for parenteral delivery.

370. A polynucleotide comprising a nucleotide sequence encoding a variant of any one of claims 1, 2, 10, 11, 21, 39, 49, 59, 77, 95, 113, 131, 149, 167, 185, 203, 209, 226, 244, 262, 268, 286, 304, 314, 332, and 342.

371. The polynucleotide of claim 370, wherein the polynucleotide comprises codons corresponding to mammalian codon usage bias.

372. A polynucleotide comprising a nucleotide sequence encoding a variant of either of claims 1 or 7, wherein the polynucleotide has been selected or screened from a population of shuffled polynucleotides encoding the amino acid substitutions D31N, L31S, D31N, K31N, D102N, S102N, T102N, R102N, I102N, D108N, E108N, K108N, E138T, G138T, I138T, L138T, and P138T.

374. An expression vector comprising the polynucleotide of claims 370 or 373 operably linked to a promoter functional in a eukaryotic cell.

375. A host cell comprising the polynucleotide of claims 370 or 373.

376. A host cell comprising the expression vector of claim 374.

377. The host cell of claim 375, wherein the host cell is a eukaryotic cell.

378. The host cell of claim 376, wherein the host cell is a eukaryotic cell.

379. A method for producing a variant of claim 1, the method comprising:

culturing the host cell of claim 377 or 378 under conditions that favor production of the variant; and

isolating the synthetic Type I interferon receptor polypeptide agonist from the culture.

380. A method of treating a disorder amenable to treatment with a Type 1 interferon, the method comprising administering to an individual in need thereof a therapeutically effective amount of a variant according to claim 1.

381. A method of prophylactically treating a disorder amenable to treatment with a Type 1 interferon, the method comprising administering to an individual in need thereof a prophylactically effective amount of a variant according to claim 1.

382. The method of treating a disorder of claim 380, wherein the disorder is a fibrotic disorder.

383. The method of treating a disorder of claim 380, wherein the disorder is cancer.

384. The method of treating a disorder of claim 380, wherein the disorder is multiple sclerosis.

385. The method of treating a disorder of claim 380, wherein the variant is a variant of a parent interferon-β

.

386. The method of treating a disorder of claim 383, wherein the cancer is selected from the group consisting of malignant melanoma, renal cell carcinoma, multiple myeloma and leukemia.

387. The method of treating a disorder of claim 380 or 381, wherein the disorder is a viral infection.

388. The method of treating a disorder of claim 387, wherein the viral infection is caused by a virus of family Flaviviridae.

389. The method of treating a disorder of claim 388, wherein the virus of family Flaviviridae is selected from the group consisting of yellow fever virus, West Nile virus, dengue fever virus, and hepatitis C virus.

390. The method of treating a disorder of claim 389, wherein the virus of family Flaviviridae is hepatitis C virus.

391. The method of claims 380 or 381, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual at a dosing interval selected from the group consisting of once a week, twice a week, and three times a week.

392. The method of claim 391, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual at a dosing interval of once a week.

393. The method of claim 387, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual on one occasion.

394. The method of claim 380-385, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual by subcutaneous injection.

395. The method of claims 380-385, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual intravenously.

396. The method of claims 380-385, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual orally.

397. The method of claim 385, wherein the therapeutically effective amount of a variant according to claim 1 is administered to the individual intramuscularly.

398. The method of any of claims 380-385, wherein the individual is a human.

360. A polypeptide, wherein the polypeptide comprises a carrier peptide set forth in Table 9.

361. The polypeptide of claim 360, wherein the polypeptide is a native Type 1 interferon comprising an amino acid sequence as set forth in any one of SEQ ID Nos:

1406, 1422, 1438, 1454, 1470, 1486, 1502, 1518, 1534, 1550, 1566, 1582, 1598, 1614, 1630, 1646, 1662, 1678, 1694, 1710, 1726, 1742, and 1758.

362. The polypeptide of claim 360, wherein the polypeptide binds erythropoietin receptor.

363. The polypeptide of claim 362, wherein the polypeptide comprises an amino acid sequence as set forth in SEQ ID Nos:

1774-1775.

366. A pharmaceutical composition comprising the variant of claims 360 or 363;

and a pharmaceutically acceptable excipient.

368. The composition of claim 366, wherein the pharmaceutically-acceptable excipient is suitable for oral delivery.

373. A polynucleotide comprising a nucleic acid sequence as set forth in any one of SEQ ID Nos:

1784-1798, 1801-1815, 1817-1831, 1833-1847, 1849-1863, 1865-1879, 1881-1895, 1897-1911, 1913-1927, 1929-1943, 1945-1959, 1961-1975, 1977-1991, 1993-2007, 2009-2023, 2025-2039, 2041-2055, 2057-2071, 2073-2087, 2089-2103, 2105-2119, 2121-2135, and 2137-2153.