Multivalent platform molecules comprising high molecular weight polyethylene oxide

• US 6,951,939 B2
• Filed: 06/07/2001
• Issued: 10/04/2005
• Est. Priority Date: 06/08/2000
• Status: Expired due to Fees

• Current Assignee: La Jolla Pharmaceutical Company (Innoviva, Inc.)
• Original Assignee: La Jolla Pharmaceutical Company (Innoviva, Inc.)
• Inventors: Jones, David S.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/877,387
• Publication Number:
  US 20020110535A1
• Time in Patent Office: 1,580 Days
• Field of Search: 530/402, 530/409, 544/357, 560/26, 560/115, 560/158, 424/422, 424/423, 424/424, 424/426, 514/44, 436/518
• US Class Current: 544/357
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

Valency platform molecules comprising high molecular weight polyethylene oxide groups are provided, as well as conjugates thereof with biologically active molecules, and methods for their preparation. The high molecular weight polyethylene oxide group has, for example, a molecular weight of greater than 22,000 Daltons, for example at least 40,000 Daltons. In one embodiment, a composition comprising the valency platform molecules is provided, wherein the molecules have a polydispersity less than about 1.2. Conjugates of the valency platform molecule and a biologically active molecule, such as a saccharide, poly(saccharide), amino acid, poly(amino acid), nucleic acid or lipid also are provided. Also provided are pharmaceutically acceptable compositions comprising the conjugates disclosed herein and a pharmaceutically acceptable carrier, as well as methods of making and using the conjugates and compositions.

Claims

1. A composition comprising chemically defined valency platform molecules, wherein the valency platform molecules individually comprise a high molecular weight polyethylene oxide group having a molecular weight of at least about 18,000 Daltons, and wherein said valency platform molecules have a polydispersity less than 1.2.

2. The composition of claim 1, wherein the valency platform molecules individually comprise a second high molecular weight polyethylene oxide group having a molecular weight of at least about 18,000 Daltons.

3. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 22,000 Daltons.

4. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 40,000 Daltons.

5. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has the formula:

—

(CH₂CH₂O)_n—

wherein n is greater than about 500.

6. The composition of claim 5, wherein n is greater than about 600.

7. The composition of claim 5, wherein n is greater than about 700.

8. The composition of claim 5, wherein n is greater than about 800.

9. The composition of claim 1, wherein the valency platform molecules individually comprise a core group and at least three arms wherein each arm comprises a terminus.

10. The composition of claim 9, wherein the core group comprises the high molecular weight polyethylene oxide group.

11. The composition of claim 9, wherein an arm comprises the high molecular weight polyethylene oxide group.

12. The composition of claim 9, wherein the high molecular weight polyethylene oxide group is attached to the core or one of said arms.

13. The composition of claim 1, wherein the valency platform molecules individually comprise at least three reactive conjugating groups selected from the group consisting of hydroxyl, thiol, isocyanate, isothiocyanate, amine, alkyl halide, alkylmercurial halide, aldehyde, ketone, carboxylic acid halide, α

-halocarbonyl, α

,β

-unsaturated carbonyl, haloformate ester, carboxylic acid, carboxylic ester, carboxylic anhydride, O-acyl isourea, hydrazide, maleimide, imidate ester, sulfonate ester, sulfonyl halide, α

,β

-unsaturated sulfone, aminooxy, semicarbazide, and β

-aminothiol.

14. The composition of claim 1, wherein the valency platform molecules individually comprise at least 3 aminooxy groups.

15. The composition of claim 1, wherein the valency platform molecules individually comprise at least 3 carbamate groups.

16. A composition comprising conjugates comprising biologically active molecules and the valency platform molecules according to claim 1.

17. The composition of claim 16, wherein the biologically active molecules are selected from the group consisting of polysaccharides, polypeptides, nucleic acids, and lipids.

18. The composition of claim 16, wherein the conjugates are B cell toleragens.

19. The composition of claim 17, wherein the biologically active molecules comprise a nucleic acid or analog thereof, which specifically binds to an anti-double stranded DNA antibody.

20. The composition of claim 18, wherein the biologically active molecules are β

₂GPI domain 1 polypeptides or analogs thereof that specifically bind to a β

₂GPI-dependent antiphospholipid antibody.

21. The composition of claim 20, wherein the conjugates are effective for the treatment of antibody mediated thrombosis.

22. The composition of claim 17, wherein the biologically active molecules are α

₁ Gal epitopes or analogs thereof that specifically bind to an anti-α

₁ Gal antibody.

23. A pharmaceutically acceptable composition comprising the composition of claim 16 and a pharmaceutically acceptable carrier.

34. The composition of claim 22, wherein the biologically active molecules are said α

₁ Gal epitopes.

36. The composition of claim 16, wherein the average total molecular weight of the conjugates is no greater than about 200,000 Daltons.

37. The composition of claim 16, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 22,000 Daltons.

38. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 30,000 Daltons.

39. The composition of claim 16, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 40,000 Daltons.

40. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 50,000 Daltons.

41. The composition of claim 1, wherein the high molecular weight polyethylene oxide group has a molecular weight of greater than about 100,000 Daltons.

42. The composition of claim 16, wherein the high molecular weight polyethylene oxide group has the formula:

—

(CH₂CH₂O)_n—

wherein n is greater than about 500.

43. The composition of claim 42, wherein n is greater than about 600.

44. The composition of claim 42, wherein n is greater than about 700.

45. The composition of claim 42, wherein n is greater than about 800.

46. The composition of claim 5, wherein n is greater than about 900.

47. The composition of claim 5, wherein n is about 400 to 550.

48. The composition of claim 5, wherein n is 520 to 600.

49. The composition of claim 5, wherein n is 600 to 800.

50. The composition of claim 5, wherein n is 600 to 1000.

51. The composition of claim 16, wherein the valency platform molecules individually comprise a second high molecular weight polyethylene oxide group having a molecular weight of at least about 18,000 Da.

52. The composition of claim 16, wherein the valency platform molecules individually comprise a core group and at least three arms wherein each arm comprises a terminus.

53. The composition of claim 52, wherein the core group comprises the high molecular weight polyethylene oxide group.

54. The composition of claim 52, wherein an arm comprises the high molecular weight polyethylene oxide group.

55. The composition of claim 52, wherein the high molecular weight polyethylene oxide group is attached to the core or one of said arms.

56. The composition of claim 16, wherein the valency platform molecules prior to conjugation individually comprise at least three reactive conjugating groups selected from the group consisting of hydroxyl, thiol, isocyanate, isothiocyanate, amine, alkyl halide, alkylmercurial halide, aldehyde, ketone, carboxylic acid halide, α

-haloearbonyl, α

,β

-unsaturated carbonyl, haloformate ester, carboxylic acid, carboxylic ester, carboxylic anhydride, O-acyl isourea, hydrazide, maleimide, imidate ester, sulfonate ester, sulfonyl halide, α

,β

-unsaturated sulfone, aminooxy, semicarbazide, and β

-aminothiol.

57. The composition of claim 16, wherein the valency platform molecules prior to conjugation individually comprise at least 3 aminooxy groups.

58. The composition of claim 16, wherein the valency platform molecules individually comprise at least 3 carbamate groups.

99. The composition of claim 19, wherein the biologically active molecules comprise said nucleic acid.

100. The composition of claim 20, wherein the biologically active molecules are β

2GPI domain 1 polypeptides.

101. A pharmaceutically acceptable composition comprising the composition of claim 18 and a pharmaceutically acceptable carrier.

102. A pharmaceutically acceptable composition comprising the composition of claim 19 and a pharmaceutically acceptable carrier.

103. A pharmaceutically acceptable composition comprising the composition of claim 20 and a pharmaceutically acceptable carrier.

104. A pharmaceutically acceptable composition comprising the composition of claim 21 and a pharmaceutically acceptable carrier.

105. A method of making the conjugates according to claim 16 or 92, comprising covalently bonding the biologically active molecules to the valency platform molecules to form conjugates.

106. A method for treating an antibody mediated disease, comprising administering to the individual an effective amount of the composition according to claim 16 or 92.

107. The composition of claim 1, wherein said valency platform molecules have a polydispersity less than 1.07.

108. The composition of claim 9, wherein the valency platform molecules individually comprise at least three carbarnate groups and at least three aminooxy groups, wherein the aminooxy groups are protected.

109. The composition of claim 108, wherein the high molecular weight. polyethylene oxide group has a molecular weight greater than about 20,000 Daltons.

110. The composition of claim 108, wherein the high molecular weight polyethylene oxide group has a molecular weight greater than about 22,000 Daltons.

111. The composition of claim 13, wherein the valency platform molecules individually comprise at least three amine reactive conjugating functional groups.

112. The composition of claim 14, wherein the aminooxy groups are protected.

113. The composition of claim 16, wherein the valency platform molecules have a polydispersity less than 1.07.

114. The composition of claim 17, wherein the biologically active molecules are polypeptides.

115. The composition of claim 17, wherein the biologically active molecules are nucleic acids.

116. The composition of claim 52, wherein the valency platform molecules individually comprise at least three carbamate groups, and wherein the valency platform molecules prior to conjugation individually comprise at least 3 aminooxy groups.

117. The composition of claim 116, wherein the biologically active molecules are β

2GPI domain 1 polypeptides.

118. The composition of claim 116, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double stranded DNA antibody.

119. The composition of claim 116, wherein the high molecular weight polyethylene oxide group has a molecular weight of at least about 22,000 Daltons.

120. The composition of claim 119, wherein the biologically active molecules are β

2GPl domain 1 polypeptides.

121. The composition of claim 119, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double stranded DNA antibody.

122. The composition of claim 56, wherein the valency platform molecules prior to conjugation individually comprise at least three amine reactive conjugating functional groups.

24. A conjugate comprising a chemically defined valency platform molecule and a polypeptide comprising a β

₂GPI domain 1 polypeptide, wherein the conjugate comprises a high molecular weight polyethylene oxide group having a molecular weight of at least about 18,000 Daltons.

25. The conjugate of claim 24, wherein the valency platform molecule comprises at least 3 aminooxy groups.

26. The conjugate of claim 24, wherein the valency platform molecule comprises at least 3 carbamate groups.

27. The conjugate of claim 24, wherein the high molecular weight polyethylene oxide group has a molecular weight greater than about 22,000 Daltons.

28. The conjugate of claim 24, wherein the valency platform molecule comprises a core group and at least three arms, wherein each arm comprises a terminus.

29. The conjugate of claim 24, wherein the polypeptide specifically binds to a β

₂GPI-dependent antiphospholipid antibody.

30. The conjugate of claim 29, wherein the polypeptide lacks a T cell epitope capable of activating T cells in an individual having β

₂GPI dependent antiphospholipid antibodies.

31. The conjugate of claim 24, wherein the β

₂GPI domain 1 polypeptide comprises at least five contiguous amino acids of FIG. 19 (SEQ ID NO;

     2).

32. The conjugate of claim 24, wherein the β

₂GPI domain 1 polypeptide comprises amino acids Nos. 2-63 of SEQ ID NO;

2.

33. The conjugate of claim 24, wherein the conjugate is selected from the group consisting of compounds 200, 202, 203, and 205 shown in FIG. 7 and compound 300 shown in FIG. 16, wherein D1 in said structures is a polypeptide consisting of amino acids No. 2-63 of SEQ ID NO:

2.

35. The conjugate of claim 24, wherein the conjugate is effective for the treatment of antibody mediated thrombosis.

123. A composition comprising conjugates according to claim 24, wherein the valency platform molecules have a polydispersity less than 1.2.

124. The conjugate of claim 28, wherein the core group comprises the high molecular weight polyethylene oxide group.

125. The conjugate of claim 28, wherein an arm comprises the high molecular weight polyethylene oxide group.

59. A composition comprising chemically defined valency platform molecules, wherein the chemically defined valency platform molecules individually comprise a first and a second polyethylene oxide group, wherein the first and the second polyethylene oxide groups each have a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 18,000 Da, and wherein said valency platform molecules have a polydispersity less than 1.2.

60. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 20,000 Da.

61. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 22,000 Da.

62. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 30,000 Da.

63. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 40,000 Da.

64. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 35,200 Da.

65. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 39,600 Da.

66. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 44,000 Da.

67. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 22,900-26,400 Da.

68. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 24,200-30,800 Da.

69. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 26,400-44,000 Da.

70. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 26,400-39,600 Da.

71. The composition of claim 59, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 26,400-35,200 Da.

72. The composition of claim 59, wherein the first and the second polyethylene oxide groups each have a molecular weight of greater than about 10,000 Da.

73. The composition of claim 59, wherein the first and the second polyethylene oxide groups each have a molecular weight of about 5,000-10,000 Da.

74. The composition of claim 59, wherein the first and the second polyethylene oxide groups each have a molecular weight of about 8,000-20,000 Da.

75. The composition of claim 59, wherein the first and the second polyethylene oxide groups each have a molecular weight of about 10,000-20,000 Da.

76. The composition of claim 59, wherein the chemically defined valency platform molecules individually comprise a third and a fourth polyethylene oxide group.

77. The composition of claim 76, wherein the first, second, third, and fourth polyethylene oxide groups each have a molecular weight of about 8,000-20,000 Da.

78. The composition of claim 76, wherein the molecular weight of the first, second, third, and fourth polyethylene oxide groups in each valency platform molecule in combination is 26,400-44,000 Da.

79. A composition comprising conjugates comprising biologically active molecules and the valency platform molecules of claim 78, wherein the biologically active molecules are β

₂GPI domain I polypeptides.

92. A composition comprising conjugates comprising biologically active molecules and the valency platform molecules according to claim 59.

93. The composition of claim 92, wherein the biologically active molecules are β

₂GPI domain I polypeptides or analogs thereof that specifically bind to β

₂GPI-dependent antiphospholipid antibodies.

94. The composition of claim 93, wherein the biologically active molecules are β

₂GPI domain I polypeptides.

95. The composition of claim 92, wherein the biologically active molecules are selected from the group consisting of polysaccharides, polypeptides, nucleic acids, and lipids.

96. The composition of claim 92, wherein the biologically active molecules are polypeptides.

126. The composition of claim 59, wherein the valency platform molecules individually comprise a core group and at least three arms wherein each arm comprises a terminus.

127. The composition of claim 126, wherein the core group comprises at least one of the first and second polyethylene oxide groups.

128. The composition of claim 126, wherein an arm comprises at least one of the first and second polyethylene oxide groups.

129. The composition of claim 126, wherein at least one of the first and second polyethylene oxide groups is attached to the core or one of said arms.

130. The composition of claim 126, wherein the valency platform molecules individually comprise at least three carbamate groups and at least three aminooxy groups, wherein the aminooxy groups are protected.

131. The composition of claim 130, wherein the total of the molecular weights of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 20,000 Daltons.

132. The composition of claim 130, wherein the total of the molecular weights of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 22,000 Daltons.

133. The composition of claim 130, wherein all polyethylene oxide groups in each valency platform molecule are in the arms.

134. The composition of claim 59, wherein the valency platform molecules individually comprise at least three reactive conjugating groups selected from the group consisting of hydroxyl, thiol, isocyanate, isothiocyanate, amine, alkyl halide, alkylmercurial halide, aldehyde, ketone, carboxylic acid halide, α

-halocarbonyl, α

,β

-unsaturated carbonyl, haloformate ester, carboxylic acid, carboxylic ester, carboxylic anhydride, O-acyl isourea, hydrazide, maleimide, imidate ester, sulfonate ester, sulfonyl halide, α

,β

-unsaturated sulfone, aminooxy, semicarbazide, and β

-aminothiol.

135. The composition of claim 134, wherein the valency platform molecules individually comprise at least three amine reactive conjugating functional groups.

136. The composition of claim 59, wherein the valency platform molecules individually comprise at least 3 aminooxy groups.

137. The composition of claim 136, wherein the aminooxy groups are protected.

138. The composition of claim 59, wherein the valency platform molecules individually comprise at least 3 carbamate groups.

139. The composition of claim 59, wherein the valency platform molecules have a polydispersity less than 1.07.

140. The composition of claim 76, wherein the valency platform molecules individually comprise a core group and four arms, wherein each arm comprises one of said first, second, third, and fourth polyethylene glycol groups.

141. The composition of claim 92, wherein the biologically active molecules are nucleic acids.

142. The composition of claim 92, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double stranded DNA antibody.

143. A pharmaceutically acceptable composition comprising the composition of claim 142 and a pharmaceutically acceptable carrier.

144. The composition of claim 92, wherein the conjugates are B cell toleragens.

145. A pharmaceutically acceptable composition comprising the composition of claim 144 and a pharmaceutically acceptable carrier.

146. The composition of claim 92, wherein the biologically active molecules are α

Gal epitopes.

147. The composition of claim 92, wherein the valency platform molecules individually comprise a core group and at least three arms wherein each arm comprises a terminus.

148. The composition of claim 147, wherein the core group comprises at least one of the first and second polyethylene oxide groups.

149. The composition of claim 147, wherein an arm comprises at least one of the polyethylene oxide groups.

150. The composition of claim 147, wherein at least one of the first and second polyethylene oxide groups is attached to the core or one of said arms.

151. The composition of claim 147, wherein the valency platform molecules individually comprise at least three carbamate groups, and wherein the valency platform molecules prior to conjugation individually comprise at least 3 aminooxy groups

152. The composition of claim 151, wherein the biologically active molecules are β

2GPI domain 1 polypeptides.

153. The composition of claim 151, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double stranded DNA antibody.

154. The composition of claim 151, wherein the total of the molecular weights of all polyethylene oxide groups in each valency platform molecule in combination is greater than about 22,000 Daltons.

155. The composition of claim 154, wherein the biologically active molecules are β

2GPI domain 1 polypeptides.

156. The composition of claim 154, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double, stranded DNA antibody.

157. The composition of claim 151, wherein the molecular weight of all polyethylene oxide groups in each valency platform molecule in combination is 26,400-44,000 Da.

158. The composition of claim 157, wherein the biologically active molecules are β

2GPI domain 1 polypeptides.

159. The composition of claim 157, wherein the biologically active molecules comprise a nucleic acid which specifically binds to an anti-double stranded DNA antibody.

160. The composition of claim 92, wherein the valency platform molecules prior to conjugation individually comprise at least three reactive conjugating groups selected from the group consisting of hydroxyl, thiol, isocyanate, isothiocyanate, amine, alkyl halide, alkylmercurial halide, aldehyde, ketone, carboxylic acid halide, α

-halocarbonyl, α

,β

-unsaturated carbonyl, haloformate ester, carboxylic acid, carboxylic ester, carboxylic anhydride, O-acyl isourea, hydrazide, maleimide, imidate ester, sulfonate ester, sulfonyl halide, α

,β

-unsaturated sulfone, aminooxy, semicarbazide, and β

-aminothiol.

161. The composition of claim 160, wherein the valency platform molecules prior to conjugation individually comprise at least three amine reactive conjugating functional groups.

162. The composition of claim 92, wherein the valency platform molecules prior to conjugation individually comprise at least 3 aminooxy groups.

163. The composition of claim 92, wherein the valency platform molecules individually comprise at least 3 carbamate groups.

164. The composition of claim 92, wherein the valency platform molecules have a polydispersity less than 1.07.

165. A pharmaceutically acceptable composition comprising the composition of claim 94 and a pharmaceutically acceptable carrier.

166. The composition of claim 94, wherein the conjugates are effective for the treatment of antibody mediated thrombosis.

167. A pharmaceutically acceptable composition comprising the composition of claim 166 and a pharmaceutically acceptable carrier.

80. A chemically defined valency platform molecule having the formula:

or an aminooxy protected form thereof;

wherein the molecular weight of the polyethylene oxide groups in combination is 26,400-44,000 Da.

98. A pharmaceutically acceptable composition comprising conjugates comprising biologically active molecules and the valency platform molecules according to any one of claims 80-91 and a pharmaceutically acceptable carrier.

168. The composition according to claim 98, wherein the biologically active molecules are polypeptides.

169. The composition according to claim 98, wherein the biologically active molecules are nucleic acids.

81. A chemically defined valency platform molecule having the formula:

R_c[O—

C(═

O)—

NR₁-G₂-(ONH₂)_n]_y

or an aminooxy protected form thereof;

wherein y is 2 to 16;

n is 1 to 32;

R₁ is H;

R_c is a hydrocarbyl group having from 1 to 200 carbon atoms;

each G₂ independently comprises a polyethylene oxide group having a molecular weight of 44 to 22,000 Da;

wherein each G₂ further comprises an amide group;

with the proviso that the formula comprises at least a first and a second G₂ group, wherein the molecular weight of the polyethylene oxide groups in the first and the second G₂ groups are greater than about 5,000 Da; and

wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

82. A chemically defined valency platform molecule having the structure of one of the following formulae:

R^c[O—

C(═

O)—

NR¹-G₂-(ONH₂)_n]_y;

R^c[C(═

O)—

NR¹-G₂-(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)-G₂-(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)—

O-G₂-(ONH₂)_n]_y;

R^c[R¹C═

N—

O-G₂-(ONH₂)_n]_y;

or

R^c[S-G₂-(ONH₂)_n]_y

or an aminooxy protected form thereof;

wherein;

y is 1 to 16;

n is 1 to 32;

R¹ is H, alkyl, heteroalkyl, aryl, heteroaryl or G₂-(ONH₂)_n;

R^c is an organic moiety comprising atoms selected from the group consisting of H, C, N, O, P, Si and S atoms, and optionally comprising one or more polyethylene oxide groups; and

G₂ is an organic moiety comprising atoms selected from the group consisting of H, C, N, O, P, Si and S atoms, and optionally comprising one or more polyethylene oxide groups;

with the proviso that at least one of the R^c or G₂ groups comprises a high molecular weight polyethylene oxide group having a molecular weight of greater than about 18,000 Da.

83. A chemically defined valency platform molecule having the structure of one of the following formulae:

R^c[O—

C(═

O)—

NR¹-G₂-(ONH₂)_n]_y;

R^c[C(═

O)—

NR¹-G₂-(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)-G₂-(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)—

O-G₂-(ONH₂)_n]_y;

R^c[R¹C═

N—

O-G₂-(ONH₂)_n]_y;

or

R^c[S-G₂-(ONH₂)_n]_y

or an aminooxy protected form thereof;

wherein;

y is 1 to 16;

n is 1 to 32;

R¹ is H, alkyl, heteroalkyl, aryl, heteroaryl or G₂-(ONH₂)_n;

R^c is an organic moiety comprising atoms selected from the group consisting of H, C, N, O, P, Si and S atoms, and optionally comprising one or more polyethylene oxide groups; and

G₂ is an organic moiety comprising atoms selected from the group consisting of H, C, N, O, P, Si and S atoms, and optionally comprising one or more polyethylene oxide groups;

with the proviso that the valency platform molecule comprises at least 2 polyethylene oxide groups each having a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

84. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein;

n is an integer from 1 to 10;

y¹, y², and y³ are independently 1 or 2;

J independently denotes either an oxygen atom or a covalent bond;

R^c is selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; and

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein R^c optionally further comprises one or more polyethylene oxide groups;

each G¹, G², and G³ is independently selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein each G¹, G², and G³ may independently further comprise one or more polyethylene oxide groups;

each R^N is independently selected from the group consisting of;

hydrogen;

linear or branched alkyl groups having from 1 to 15 carbon atoms;

alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;

aromatic groups having from 6 to 20 carbon atoms;

heteroaromatic groups having from 3 to 20 carbon atoms;

each Z is independently selected from the group consisting of;

—

H

—

C(═

O)OR^CARB

—

C(═

O)R^ESTER

—

C(═

O)NR^AR^B

—

C(═

O)NR^AB

wherein;

each R^CARB is independently an organic group comprising from 1 to about 20 carbon atoms;

each R^ESTER is independently an organic group comprising from 1 to about 20 carbon atoms;

each monovalent R^A and R^B and each divalent R^AB is independently H or an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group;

with the proviso that at least one of the R^c, G¹, G², or G³ groups comprises a high molecular weight polyethylene oxide group having a molecular weight of greater than about 18,000 Da.

85. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein;

n is an integer from 1 to 10;

y¹, y², and y³ are independently 1 or 2;

J independently denotes either an oxygen atom or a covalent bond;

R^c is selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; and

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein R^c optionally further comprises one or more polyethylene oxide groups;

each G¹, G², and G³ is independently selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein each G¹, G², and G³ may independently further comprise one or more polyethylene oxide groups;

each R^N is independently selected from the group consisting of;

hydrogen;

linear or branched alkyl groups having from 1 to 15 carbon atoms;

alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;

aromatic groups having from 6 to 20 carbon atoms;

heteroaromatic groups having from 3 to 20 carbon atoms;

each Z is independently selected from the group consisting of;

—

H

—

C(═

O)OR^CARB

—

C(═

O)R^ESTER

—

C(═

O)NR^AR^B

—

C(═

O)NR^AB

wherein;

each R^CARB is independently an organic group comprising from 1 to about 20 carbon atoms;

each R^ESTER is independently an organic group comprising from 1 to about 20 carbon atoms;

each monovalent R^A and R^B and each divalent R^AB is independently H or an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group;

with the proviso that the valency platform molecule comprises at least 2 polyethylene oxide groups each having a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

86. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein;

n is an integer from 1 to 10;

y¹, y², and y³ are independently 1 or 10;

J independently denotes either an oxygen atom or a covalent bond;

R^C is selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; and

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein R^C optionally further comprises one or more polyethylene oxide groups;

each G¹, G², and G³ is independently selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein each G¹, G², and G³ may independently further comprise one or more polyethylene oxide groups;

each R^N is independently selected from the group consisting of;

hydrogen;

linear or branched alkyl groups having from 1 to 15 carbon atoms;

alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;

aromatic groups having from 6 to 20 carbon atoms;

heteroaromatic groups having from 3 to 20 carbon atoms;

each Z is independently selected from the group consisting of;

—

H

—

C(═

O)OR^CARB

—

C(═

O)R^ESTER

—

C(═

O)NR^AR^B

—

C(═

O)NR^AB

wherein;

each R^CARB is independently an organic group comprising from 1 to about 20 carbon atoms;

each R^ESTER is independently an organic group comprising from 1 to about 20 carbon atoms;

each monovalent R^A and R^B and each divalent R^AB is independently H or an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group;

with the proviso that at least one of the R^C, G¹, G², or G³ groups comprises a high molecular weight polyethylene oxide group having a molecular weight of greater than about 18,000 Da.

87. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein;

n is an integer from 1 to 10;

y¹, y², and y³ are independently a positive integer from 1 to 10;

J independently denotes either an oxygen atom or a covalent bond;

R^C is selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein R^c optionally further comprises one or more polyethylene oxide groups;

each G¹, G², and G³ is independently selected from the group consisting of;

hydrocarbyl groups having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms;

and wherein each G¹, G², and G³ may independently further comprise one or more polyethylene oxide groups;

each R^N is independently selected from the group consisting of;

hydrogen;

linear or branched alkyl groups having from 1 to 15 carbon atoms;

alkyl groups comprising an alicyclic structure and having from 1 to 15 carbon atoms;

aromatic groups having from 6 to 20 carbon atoms;

heteroaromatic groups having from 3 to 20 carbon atoms;

each Z is independently selected from the group consisting of;

—

H

—

C(═

O)OR^CARB

—

C(═

O)R^ESTER

—

C(═

O)NR^AR^B

—

C(═

O)NR^AB

wherein;

each R^CARB is independently an organic group comprising from 1 to about 20 carbon atoms;

each R^ESTER is independently an organic group comprising from 1 to about 20 carbon atoms;

each monovalent R^A and R^B and each divalent R^AB is independently H or an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive coniugating functional group;

with the proviso that the valency platform molecule comprises at least 2 polyethylene oxide groups each having a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

88. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein

each of G^[1] and G^[2], if present, is independently a linear, branched or multiply-branched chain comprising 1-2,000 chain atoms selected from the group C, N, O, Si, P and S;

and wherein G^[1] and G^[2], if present, optionally further comprises one or more polyethylene oxide groups;

each T^[1] and each T^[2], if present, is independently chosen from the group NHR^SUB, C(═

O)NHNHR^SUB, NHNHR^SUB, C(═

O)OH, C(═

O)OR^ESTER, C(═

O)OC(═

O)R^B, C(═

O)X, S(═

O)₂X, C(═

NR^SUB)OR^SUB, NCO, NCS, OC(═

O)X, C(═

O)OC(═

NR^SUB)NHR^SUB, C(═

O)H, C(═

O)R^B, SH, OH, C(═

O)CH₂X, R^ALKX, S(═

O)₂OR^ALKX, NR¹R² wherein R¹R² is —

C(═

O)CH═

CHC(═

O)—

, C(═

O)CR^B═

CR^B₂, R^ALK—

Hg—

X, S(═

O)CR^B═

CR^B₂, and ONH₂;

wherein

each X is independently a halogen of atomic number greater than 16 and less than 54 or other leaving group;

each R^ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;

each R^SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (6-20C), or alkaryl (7-30C);

each R^ESTER is independently N-succinimidyl, p-nitrophenyl, pentafluorophenyl, tetrafluorophenyl, pentachlorophenyl, 2,4,5-trichlorophenyl, 2,4-dinitrophenyl, cyanomethyl, 5-chloro,8-quinolone, 1-piperidine, or N-benzotriazole;

each R^B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;

each L^[2], if present, is independently chosen from the group O, NR^SUB and S;

each J^[2], if present, is independently chosen from the group C(═

O) and C(═

S);

each Z^[2], if present, is independently a radical comprising 1-200 atoms selected from the group C, H, N, O, Si, P and S, and forming attachment sites for at least p^[2] functional groups, wherein the attachment sites are alkyl, alkenyl, or aromatic carbon atoms;

and wherein Z^[2], if present, optionally further comprises one or more polyethylene oxide groups;

n^[1], if present, is 1 to 32;

n^[2], if present, is 1 to 32; and

p^[2], if present, is 1 to 8;

with the proviso that the product n^[2]×

p^[2] be greater than 1 and less than 33;

with the proviso that at least one of the G^[1], G^[2], or Z^[2] groups comprises a high molecular weight polyethylene oxide group having a molecular weight of greater than about 18,000 Da.

89. A chemically defined valency platform molecule having the structure of one of the following formulae;

wherein

each of G^[1] and G^[2], if present, is independently a linear, branched or multiply-branched chain comprising 1-2,000 chain atoms selected from the group C, N, O, Si, P and S;

and wherein G^[1] and G^[2], if present, optionally further comprises one or more polyethylene oxide groups;

each T^[1] and each T^[2], if present, is independently chosen from the group NHR^SUB, C(═

O)NHNHR^SUB, NHNHR^SUB, C(═

O)OH, C(═

O)OR^ESTER, C(═

O)OC(═

O)R^B, C(═

O)X, S(═

O)₂X, C(═

NR^SUB)OR^SUB, NCO, NCS, OC(═

O)X, C(═

O)OC(═

NR^SUB)NHR^SUB, C(═

O)H, C(═

O)R^B, SH, OH, C(═

O)CH₂X, R^ALKX, S(═

O)₂OR^ALKX, NR¹R² wherein R¹R² is —

C(═

O)CH═

CHC(═

O)—

, C(═

O)CR^B═

CR^B₂, R^ALK—

Hg—

X, S(═

O)CR^B═

CR^B₂, and ONH₂;

wherein

each X is independently a halogen of atomic number greater than 16 and less than 54 or other leaving group;

each R^ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;

each R^SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (6-20C), or alkaryl (7-30C);

each R^ESTER is independently N-succinimidyl, p-nitrophenyl, pentafluorophenyl, tetrafluorophenyl, pentachlorophenyl, 2,4,5-trichlorophenyl, 2,4-dinitrophenyl, cyanomethyl, 5-chloro,8-quinolone, 1-piperidine, or N-benzotriazole;

each R^B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;

each L^[2], if present, is independently chosen from the group O, NR^SUB and S;

each J^[2], if present, is independently chosen from the group C(═

O) and C(═

S);

each Z^[2], if present, is independently a radical comprising 1-200 atoms selected from the group C, H, N, O, Si, P and S, and forming attachment sites for at least p^[2] functional groups, wherein the attachment sites are alkyl, alkenyl, or aromatic carbon atoms;

and wherein Z^[2], if present, optionally further comprises one or more polyethylene oxide groups;

n^[1], if present, is 1 to 32;

n^[2], if present, is 1 to 32;

p^[2], if present, is 1 to 8;

with the proviso that the product n^[2]×

p^[2] be greater than 1 and less than 33;

with the proviso that the valency platform molecule comprises at least 2 polyethylene oxide groups each having a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

90. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein

each of G^[6] and G^[7], if present, is independently a linear, branched or multiply-branched chain comprising 1-2,000 chain atoms selected from the group C, N, O, Si, P and S;

and wherein G^[6] and G^[7], if present, optionally further comprises one or more polyethylene oxide groups;

each T^[6] and each T^[7], if present, is independently chosen from the group NHR^SUB, C(═

O)NHNHR^SUB, NHNHR^SUB, C(═

O)OH, C(═

O)OR^ESTER, C(═

O)OC(═

O)R^B, C(═

O)X, S(═

O)₂X, C(═

NR^SUB)OR^SUB, NCO, NCS, OC(═

O)X, C(═

O)OC(═

NR^SUB)NHR^SUB, C(═

O)H, C(═

O)R^B, SH, OH, C(═

O)CH₂X, R^ALKX, S(═

O)₂OR^ALKX, NR¹R² wherein R¹R² is —

C(═

O)CH═

CHC(═

O)—

, C(═

O)CR^B═

CR^B₂, R^ALK—

Hg—

X, S(═

O)CR^B═

CR^B₂, and ONH₂;

wherein

each X is independently a halogen of atomic number greater than 16 and less than 54 or other leaving group;

each R^ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;

each R^SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (1-20C), or alkaryl (1-30C);

each R^ESTER is independently N-hydroxysuccinimidyl, p-nitrophenoxy, or pentafluorophenoxy;

each R^B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;

n^[6], if present, is 1 to 32;

p^[6], if present, is 1 to 8;

with the proviso that the product n^[6]×

p^[6] be greater than 1 and less than 33;

n^[7], if present, is 1 to 32;

^[7], if present, is 1 to 8;

with the proviso that the product n^[7]×

p^[7] be greater than 1 and less than 33;

each Q^[6] and each Q^[7], if present, is independently a radical comprising 1-100 atoms selected from the group C, H, N, O, Si, P and S, and wherein each Q^[6] and Q^{8 7]} moiety, if present, forms attachment sites for at least p^[6] or p^[7]/2 functional groups, respectively, wherein the attachment sites are alkyl, alkenyl, or aromatic carbon atoms;

and wherein Q^[6] and Q^[7], if present, optionally further comprises one or more polyethylene oxide groups; and

wherein p^[7]/2 is an integer;

with the proviso that at least one of the G^[6], G^[7], Q^[6], or Q^[7] groups comprises a high molecular weight polyethylene oxide group having a molecular weight of greater than about 18,000 Da.

91. A chemically defined valency platform molecule having the structure of one of the following formulae:

wherein

each of G^[6] and G^[7], if present, is independently a linear, branched or multiply-branched chain comprising 1-2,000 chain atoms selected from the group C, N, O, Si, P and S;

and wherein G^[6] and G^[7], if present, optionally further comprises one or more polyethylene oxide groups;

each T^[6] and each T^[7], if present, is independently chosen from the group NHR^SUB, C(═

O)NHNHR^SUB, NHNHR^SUB, C(═

O)OH, C(═

O)OR^ESTER, C(═

O)OC(═

O)R^B, C(═

O)X, S(═

O)₂X, C(═

NR^SUB)OR^SUB, NCO, NCS, OC(═

O)X, C(═

O)OC(═

NR^SUB)NHR^SUB, C(═

O)H, C(═

O)R^B, SH, OH, C(═

O)CH₂X, R^ALKX, S(═

O)₂OR^ALKX, NR¹R² wherein R¹R² is —

C(═

O)CH═

CHC(═

O)—

, C(═

O)CR^B═

CR^B₂, R^ALK—

Hg—

X, S(═

O)CR^B═

CR^B₂, and ONH₂;

wherein

each X is independently a halogen of atomic number greater than 16 and less than 54 or other leaving group;

each R^ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;

each R^SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (1-20C), or alkaryl (1-30C);

each R^ESTER is independently N-hydroxysuccinimidyl, p-nitrophenoxy, or pentafluorophenoxy;

each R^B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;

n^[6], if present, is 1 to 32;

p^[6], if present, is 1 to 8;

with the proviso that the product n^[6]×

p^[6] be greater than 1 and less than 33;

n^[7], if present, is 1 to 32;

p^[7], if present, is 1 to 8;

with the proviso that the product n^[7]×

p^[7] be greater than 1 and less than 33;

each Q^[6] and each Q^[7], if present, is independently a radical comprising 1-100 atoms selected from the group C, H, N, O, Si, P and S, and wherein each Q^[6] and Q^{8 7]} moiety, if present, forms attachment sites for at least p^[6] or p^[7]/2 functional groups, respectively, wherein the attachment sites are alkyl, alkenyl, or aromatic carbon atoms;

and wherein Q^[6] and Q^[7], if present, optionally further comprises one or more polyethylene oxide groups; and

wherein p^[7]/2 is an integer;

with the proviso that the valency platform molecule comprises at least 2 polyethylene oxide groups each having a molecular weight of greater than about 5,000 Da, and wherein the total of the molecular weights of all polyethylene oxide groups in the valency platform molecule in combination is greater than about 18,000 Da.

97. A conjugate of a valency platform molecule and a biologically active molecule, having the formula:

wherein the molecular weight of the polyethylene oxide groups in combination is 26,400-44,000 Da; and

wherein D1 in said structures is a polypeptide consisting of amino acids No. 2-63 of SEQ ID NO;

2.

170. A method for treating an antibody mediated disease, comprising administering to the individual an effective amount of the composition according to claim 97.