Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/28
C12P-031/06
C07P-005/00
C07P-007/00
C07P-016/00
C07P-017/00
출원번호
US-0382022
(2003-03-05)
발명자
/ 주소
Soltero,Richard
Radhakrishnan,Balasingam
Ekwuribe,Nnochiri N.
출원인 / 주소
Biocon Limited
대리인 / 주소
Moore & Van Allen PLLC
인용정보
피인용 횟수 :
2인용 특허 :
137
초록▼
Methods for synthesizing proinsulin polypeptides are described that include contacting a proinsulin polypeptide including an insulin polypeptide coupled to one or more peptides by peptide bond(s) capable of being cleaved to yield the insulin polypeptide with an oligomer under conditions sufficient t
Methods for synthesizing proinsulin polypeptides are described that include contacting a proinsulin polypeptide including an insulin polypeptide coupled to one or more peptides by peptide bond(s) capable of being cleaved to yield the insulin polypeptide with an oligomer under conditions sufficient to couple the oligomer to the insulin polypeptide portion of the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate, and cleaving the one or more peptides from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. Methods of synthesizing proinsulin polypeptide-oligomer conjugates are also provided as are proinsulin polypeptide-oligomer conjugates. Methods of synthesizing C-peptide polypeptide-oligomer conjugates and other pro-polypeptide-oligomer conjugates are also provided.
대표청구항▼
That which is claimed is: 1. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide with an oligomer comprising a hydrophilic moiety and/or a lipophilic moiety under conditions sufficient to couple the oligomer to the proinsulin polype
That which is claimed is: 1. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide with an oligomer comprising a hydrophilic moiety and/or a lipophilic moiety under conditions sufficient to couple the oligomer to the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate, wherein the proinsulin polypeptide comprises: (i) an insulin polypeptide; and (ii) one or more non-insulin polypeptides coupled to the insulin polypeptide by peptide bond(s) capable of being cleaved to yield the insulin polypeptide; and (b) cleaving the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. 2. The method of claim 1 wherein: (a) the proinsulin polypeptide comprises multiple conjugation sites; and (b) step (a) yields a proinsulin polypeptide-oligomer comprising multiple oligomers. 3. The method of claim 1 wherein: (a) the proinsulin polypeptide comprises one or more conjugation sites on the insulin polypeptide portion thereof, and (b) step (a) yields a proinsulin polypeptide-oligomer comprising one or more oligomers on the insulin polypeptide portion thereof. 4. The method of claim 3 wherein step (a) yields a proinsulin polypeptide-oligomer conjugate wherein the non-insulin polypeptide(s) are unconjugated. 5. The method of claim 1 wherein: (a) the proinsulin polypeptide comprises: (i) at least one conjugation site on the insulin polypeptide portion thereof; and (ii) at least one conjugation site on one or more non-insulin polypeptide portions thereof; and (b) step (a) yields a proinsulin polypeptide-oligomer comprising: (i) at least one oligomer coupled to the insulin polypeptide portion thereof; and (ii) at least one oligomer coupled to one or more of the non-insulin polypeptide portion(s) thereof. 6. The method of claim 1, wherein step (a) comprises: (a) contacting the oligomer with an activating agent under conditions sufficient to provide an activated oligomer capable of coupling to a nucleophilic functionality on the proinsulin polypeptide; and (b) contacting the activated oligomer with the proinsulin polypeptide under conditions sufficient to provide the proinsulin polypeptide-oligomer conjugate. 7. The method of claim 6, wherein step 0 is performed in situ. 8. The method of claim 6, wherein the molar ratio of activated oligomer to proinsulin polypeptide in step (b) is greater than about 1:1. 9. The method of claim 6, wherein the molar ratio of activated oligomer to proinsulin polypeptide in step (b) is greater than about 3:1. 10. The method of claim 6, wherein the molar ratio of activated oligomer to proinsulin polypeptide in step (b) is greater than about 4:1. 11. The method of claim 1, wherein the oligomer comprises a polyethylene glycol moiety. 12. The method of claim 1, wherein the oligomer consists essentially of a polyethylene glycol moiety. 13. The method of claim 1, wherein: (a) the insulin polypeptide comprises an A-chain polypeptide and a B-chain polypeptide, and (b) the one or more non-insulin polypeptides comprise a connecting peptide coupled at a first end to the C-terminus of the B-chain polypeptide and coupled at a second end to the N-terminus of the A-chain polypeptide. 14. The method of claim 13 wherein: (a) the B-chain comprises a conjugation site at B29, and (b) the insulin polypeptide-oligomer conjugate is conjugated at the B29 conjugation site. 15. The method of claim 13 wherein: (a) the proinsulin polypeptide has a single lysine at B29, and (b) the insulin polypeptide-oligomer conjugate is a B29 monoconjugate. 16. The method of claim 1, wherein the connecting peptide is a C-peptide polypeptide. 17. The method of claim 16 wherein: (a) the G-peptide comprises a lysine, and (b) step (a) yields a proinsulin polypeptide-oligomer in which the lysine(s) of the C-peptide are coupled to oligomer(s). 18. The method of claim 1, wherein the connecting peptide is C-peptide. 19. The method of claim 1, wherein the connecting peptide is devoid of lysine residues. 20. The method of claim 1, wherein the proinsulin polypeptide further comprises a leader peptide coupled to the N-terminus of the B-chain polypeptide. 21. The method of claim 1 wherein: (a) the leader peptide comprises a lysine, and (b) step (a) yields a proinsulin polypeptide-oligomer in which the lysine(s) of the leader peptide are coupled to oligomer(s). 22. The method of claim 1, wherein the leader peptide is devoid of lysine residues. 23. The method of claim 1 wherein step (a) yields a proinsulin polypeptide-oligomer comprising an oligomer coupled at an N-terminus of the leader peptide. 24. The method of claim 1, wherein the one or more non-insulin polypeptides further comprise a leader peptide coupled to the N-terminus of the B-chain polypeptide. 25. The method of claim 24 wherein: (a) the leader peptide comprises a lysine, and (b) step (a) yields a proinsulin polypeptide-oligomer in which the lysine(s) of the C-peptide are coupled to oligomer(s). 26. The method of claim 24, wherein the leader peptide is devoid of lysine residues. 27. The method of claim 1, wherein: (a) the insulin polypeptide comprises an A-chain polypeptide and a B-chain polypeptide, and (b) the C-terminus of the B-chain polypeptide is coupled to the N-terminus of the A-chain polypeptide. 28. The method of claim 1, wherein the proinsulin polypeptide is proinsulin. 29. The method of claim 1, wherein the proinsulin polypeptide is proinsulin coupled at the N-terminus of the B-chain to a leader peptide by a cleavable peptide bond. 30. The method of claim 1, wherein the insulin polypeptide is insulin. 31. The method of claim 30, wherein the oligomer is coupled to the lysine at the B29 position of the insulin. 32. The method of claim 1, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human; GlyA21 GlnB3 insulin, human; AlaA21 insulin, human; AlaA21 GlnB3 insulin, human; GlnB3 insulin, human; GlnB30 insulin, human; GlyA21 GluB30 insulin, human; GlyA21 GlnB3 GluB30 insulin, human; GlnB3 GluB30 insulin, human; AspB28 insulin, human; LysB28 insulin, human; LeuB28 insulin, human; ValB28 insulin, human; Ala B28 insulin, human; AspB28 ProB29 insulin, human; LysB28 ProB29 insulin, human; LeuB28 Pro B29 insulin, human; ValB28 ProB29 insulin, human; and AlaB28 ProB29 insulin, human. 33. The method of claim 1, wherein the oligomer is present as a substantially monodispersed mixture. 34. The method of claim 1, wherein the oligomer is present as a monodispersed mixture. 35. The method of claim 1, wherein the hydrophilic moiety is a polyalkylene glycol moiety. 36. The method of claim 35, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety. 37. The method of claim 35, wherein the polyalkylene glycol moiety has between 1 and 50 polyalkylene glycol subunits. 38. The method of claim 35, wherein the polyalkylene glycol moiety has between 3 and 50 polyalkylene glycol subunits. 39. The method of claim 35, wherein the polyalkylene glycol moiety has between 2 and 10 polyalkylene glycol subunits. 40. The method of claim 35, wherein the polyalkylene glycol moiety has between 4 and 10 polyalkylene glycol subunits. 41. The method of claim 35, wherein the polyalkylene glycol moiety has at least 2 polyalkylene glycol subunits. 42. The method of claim 1, wherein the lipophilic moiety is an alkyl or fatty acid moiety. 43. The method of claim 1, wherein the lipophilic moiety has between 1 and 28 carbon atoms. 44. The method of claim 1, wherein the lipophilic moiety has between 2 and 24 carbon atoms. 45. The method of claim 1, wherein the lipophilic moiety has between 3 and 18 carbon atoms. 46. The method of claim 1, wherein the lipophilic moiety has between 4 and 12 carbon atoms. 47. The method of claim 1, wherein the lipophilic moiety has between 5 and 7 carbon atoms. 48. The method of claim 1, wherein the lipophilic moiety has between 4 and 14 carbon atoms. 49. The method of claim 1, wherein the cleaving of the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate comprises contacting the proinsulin polypeptide-oligomer conjugate with one or more enzymes that are capable of cleaving the bond(s) between the one or more non-insulin polypeptides and the insulin polypeptide under conditions sufficient to cleave the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate. 50. The method of claim 49, wherein the one or more enzymes are selected from the group consisting of trypsin, carboxy peptidase B, and mixtures thereof. 51. The method of claim 1, wherein the connecting peptide has a terminal amino acid residue at the first end, and wherein the cleaving of the connecting peptide from the proinsulin polypeptide-oligomer conjugate comprises: (a) contacting the proinsulin polypeptide-oligomer conjugate with a first enzyme under conditions sufficient to provide a terminal amino acid residue-insulin polypeptide-oligomer conjugate; and (b) contacting the terminal amino acid residue-insulin polypeptide-oligomer conjugate with a second enzyme under conditions sufficient to provide the insulin polypeptide-oligomer conjugate. 52. The method of claim 51, wherein the terminal amino acid residue is an arginine residue. 53. The method of claim 52, wherein the insulin polypeptide is insulin, and wherein the connecting peptide is human C-peptide. 54. The method of claim 51, wherein the contacting of the proinsulin polypeptide-oligomer conjugate with a first enzyme and the contacting of the terminal amino acid residue-insulin polypeptide-oligomer conjugate with a second enzyme occur substantially concurrently. 55. The method of claim 54, wherein the first enzyme and the second enzyme are provided in a mixture comprising the first enzyme and the second enzyme. 56. The method of claim 51, wherein the first enzyme is trypsin, and wherein the second enzyme is carboxy peptidase B. 57. The method of claim 1, further comprising chemically modifying one or more of the oligomer(s) of the insulin polypeptide-oligomer conjugate. 58. The method of claim 1, further comprising activating one or more of the oligomer(s) of the insulin polypeptide-oligomer conjugate. 59. The method of claim 1, further comprising lengthening one or more of the oligomer(s) of the insulin polypeptide-oligomer conjugate. 60. The method of claim 1, further comprising shortening one or more of the oligomer(s) of the insulin polypeptide-oligomer conjugate. 61. The method of claim 1, wherein the yield of insulin polypeptide-oligomer conjugate is greater than 75 percent. 62. The method of claim 1, wherein the yield of insulin polypeptide-oligomer conjugate is greater than 85 percent. 63. The method of claim 1, wherein the yield of insulin polypeptide-oligomer conjugate is greater than about 90 percent. 64. The method of claim 1, wherein the yield of insulin polypeptide-oligomer conjugate is greater than 95 percent. 65. The method of claim 1, wherein the yield of insulin polypeptide-oligomer conjugate is greater than 99 percent. 66. A method of synthesizing an insulin molecule, comprising synthesizing an insulin polypeptide-oligomer conjugate according to claim 1 and hydrolyzing the oligomer(s) from the polypeptide-oligomer conjugate to yield the insulin molecule. 67. A method of synthesizing insulin, comprising synthesizing an insulin polypeptide-oligomer conjugate according to claim 1 and hydrolyzing the oligomer(s) from the polypeptide-oligomer conjugate to yield insulin. 68. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide comprising an insulin polypeptide coupled to one or more non-insulin polypeptides by peptide bond(s) capable of being cleaved to yield the insulin polypeptide with an oligomer comprising the structure of Formula I: description="In-line Formulae" end="lead"A-L j-Gk-R-G'm-R'-G"n-T (I)description="In-line Formulae" end="tail" wherein: A is an activatable moiety; L is an optional linker moiety; G, G' and G" are each optional spacer moieties; R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety, and wherein, (i) R and R' are both present, or (ii) Rand G are absent and L is coupled to G' if present or to R' if G' is not present, or (iii) R' and G" are absent and T is coupled to G' if present or to R if G' is not present; T is a terminating moiety; and j, k, m and n are individually 0 or 1; under conditions sufficient to couple the oligomer to the insulin polypeptide portion of the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate; and (b) cleaving the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. 69. The method of claim 68, wherein R and R' are both present. 70. The method of claim 68, wherein R and G are absent and L is coupled to G' if present or to R' if G' is not present. 71. The method of claim 70 wherein R' is a polyethylene glycol moiety. 72. The method of claim 68, wherein R' and G" are absent and T is coupled to G' if present or to R if G' is not present. 73. The method of claim 68, wherein A is selected from the group consisting of--C(O)--OH, C(S)--OH,--C(S)--SH,--OH,--SH, and NH2. 74. The method of claim 68, wherein L is selected from the group consisting of alkyl moieties and fatty acid moieties. 75. The method of claim 68, wherein G, G' and G" are individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties. 76. The method of claim 68, wherein T is selected from the group consisting of alkyl and alkoxy. 77. The method of claim 68, wherein: A is a carboxylic acid moiety; R is an alkyl moiety having between 3 and 8 carbon atoms; R' is polyethylene glycol having between 4 and 10 polyethylene glycol subunits; T is lower alkyl or lower alkoxy; and j, k, m and n are 0. 78. The method of claim 68, wherein: A is a carboxylic acid moiety; R is an alkyl moiety having between 3 and 8 carbon atoms; R' is polyethylene glycol having 7 polyethylene glycol subunits; T is methoxy; and j, k, m and n are 0. 79. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide comprising an insulin polypeptide coupled to one or more non-insulin polypeptides by peptide bond(s) capable of being cleaved to yield the insulin polypeptide with an oligomer comprising the structure of Formula II: description="In-line Formulae" end="lead"A-X(CH 2)mY(C2H4O)nR (II)description="In-line Formulae" end="tail" wherein: A is--C(O)--OH, C(S)--OH,--C(S)--SH,--OH,--SH, or NH 2; X is an oxygen atom or a covalent bond, with the proviso that X is not an oxygen atom when A is--OH; Y is an ester, an ether, a carbamate, a carbonate, or an amide bonding moiety; m is between 0 and 30; n is between 0 and 50; m and n are not both 0; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety; under conditions sufficient to couple the oligomer to the insulin polypeptide portion of the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate; and (b) cleaving the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. 80. The method of claim 79, wherein m is between 3 and 16. 81. The method of claim 79, wherein m is between 4 and 14. 82. The method of claim 79, wherein m is between 5 and 10. 83. The method of claim 79, wherein n is between 3 and 18. 84. The method of claim 79, wherein n is between 4 and 14. 85. The method of claim 79, wherein n is between 5 and 10. 86. The method of claim 79, wherein R is lower alkyl. 87. The method of claim 79, wherein R is C1 to C3 alkyl. 88. The method of claim 79, wherein R is methyl. 89. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide comprising an insulin polypeptide coupled to one or more non-insulin polypeptides by peptide bond(s) capable of being cleaved to yield the insulin polypeptide with an oligomer comprising the structure of Formula III: description="In-line Formulae" end="lead"A-(CH 2)m(OC2H4)nOR (III)description="In-line Formulae" end="tail" wherein: A is--C(O)--OH, C(S)--OH,--C(S)--SH,--OH,--SH, or NH 2; m is between 0 and 25; n is between 0 and 25; m and n are not both 0; and R is alkyl; under conditions sufficient to couple the oligomer to the insulin polypeptide portion of the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate; and (b) cleaving the one or more non-insulin polypeptides from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. 90. The method of claim 89, wherein m is between 3 and 16. 91. The method of claim 89, wherein m is between 4 and 14. 92. The method of claim 89, wherein m is between 5 and 10. 93. The method of claim 89, wherein n is between 3 and 18. 94. The method of claim 89, wherein n is between 4 and 14. 95. The method of claim 89, wherein n is between 5 and 10. 96. The method of claim 89, wherein R is lower alkyl. 97. The method of claim 89, wherein R is C1 to C 3 alkyl. 98. The method of claim 89, wherein R is methyl. 99. A method of synthesizing an insulin polypeptide-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide comprising an insulin polypeptide having an A-chain polypeptide and a B-chain polypeptide, which comprises a lysine residue; a connecting peptide coupled at a first end to the C-terminus of the B-chain polypeptide and coupled at a second end to the N-terminus of the A-chain polypeptide; and a leader peptide coupled to the N-terminus of the B-chain polypeptide with an oligomer comprising the structure of Formula IV: wherein: m is between 0 and 30. n is between 0 and 50. m and n are not both 0; and R is alkyl; under conditions sufficient to couple the oligomer to the lysine residue of the B-chain polypeptide of the insulin polypeptide portion of the proinsulin polypeptide and provide a proinsulin polypeptide-oligomer conjugate; and (b) enzymatically cleaving the connecting peptide and the leader peptide from the proinsulin polypeptide-oligomer conjugate to provide the insulin polypeptide-oligomer conjugate. 100. The method of claim 99, wherein m is between 3 and 16. 101. The method of claim 99, wherein m is between 4 and 14. 102. The method of claim 99, wherein m is between 5 and 10. 103. The method of claim 99, wherein n is between 3 and 18. 104. The method of claim 99, wherein n is between 4 and 14. 105. The method of claim 99, wherein n is between 5 and 10. 106. The method of claim 99, wherein R is lower alkyl. 107. The method of claim 99, wherein R is C1 to C 3 alkyl. 108. The method of claim 99, wherein R is methyl. 109. A method of synthesizing an insulin-oligomer conjugate comprising: (a) contacting a proinsulin polypeptide, which comprises proinsulin coupled at its N-terminus to a leader peptide, with an oligomer comprising the structure of Formula V: under conditions sufficient to couple the oligomer to the B29 lysine residue of the proinsulin and provide a proinsulin polypeptide-oligomer conjugate; and (b) enzymatically cleaving the C-peptide and the leader peptide from the proinsulin polypeptide-oligomer conjugate to provide the insulin-oligomer conjugate. 110. The method of claim 109, wherein the enzymatically cleaving of the C-peptide and the leader peptide from the proinsulin polypeptide-oligomer conjugate comprises: (a) contacting the proinsulin polypeptide-oligomer conjugate with a first enzyme under conditions sufficient to provide an (Arg 31)-insulin-oligomer conjugate; and (b) contacting the (Arg3)-insulin polypeptide-oligomer conjugate with a second enzyme under conditions sufficient to provide the insulin polypeptide-oligomer conjugate. 111. The method of claim 110, wherein the first enzyme is trypsin. 112. The method of claim 110, wherein the second enzyme is carboxy peptidase B. 113. A method of synthesizing an insulin polypeptide-acyl oligomer conjugate comprising enzymatically cleaving one or more non-insulin polypeptides from a proinsulin polypeptide-acyl oligomer conjugate to provide the insulin polypeptide-acyl oligomer conjugate. 114. A method of synthesizing an insulin-acyl oligomer conjugate comprising enzymatically cleaving a leader peptide and a C-peptide from a proinsulin polypeptide-acyl oligomer conjugate comprising the following structure: to provide the insulin-acyl oligomer conjugate comprising the following structure: 115. The method of claim 114, wherein the leader peptide is devoid of lysine residues. 116. The method of claim 114, wherein the enzymatically cleaving of the C-peptide and the leader peptide from the proinsulin polypeptide-acyl oligomer conjugate comprises: (a) contacting the proinsulin polypeptide-oligomer conjugate with a first enzyme under conditions sufficient to provide a (Arg 31)-insulin-oligomer conjugate; and (b) contacting the (Arg31)-insulin polypeptide-oligomer conjugate with a second enzyme under conditions sufficient to provide the insulin polypeptide-oligomer conjugate. 117. The method of claim 116, wherein the first enzyme is trypsin. 118. The method of claim 116, wherein the second enzyme is carboxy peptidase B. 119. A method of synthesizing a proinsulin polypeptide-oligomer conjugate comprising contacting a proinsulin polypeptide with an oligomer comprising a hydrophilic moiety and a lipophilic moiety under conditions sufficient to provide the proinsulin polypeptide-oligomer conjugate. 120. A method of synthesizing a C-peptide polypeptide-oligomer conjugate comprising: (a) contacting a pro-C-peptide polypeptide comprising a C-peptide polypeptide coupled to one or more non-insulin polypeptides by peptide bond(s) that are cleavable to yield the C-peptide polypeptide with an oligomer under conditions sufficient to couple the oligomer to the C-peptide polypeptide portion of the pro-C-peptide polypeptide and provide a pro-C-peptide polypeptide-oligomer conjugate; and (b) cleaving the one or more non-insulin polypeptides from the pro-C-peptide polypeptide-oligomer conjugate to provide the C-peptide polypeptide-oligomer conjugate. 121. The method of claim 120, wherein the C-peptide polypeptide is C-peptide. 122. The method of claim 120, wherein the pro-C-peptide polypeptide is a proinsulin polypeptide. 123. The method of claim 120, wherein the pro-C-peptide polypeptide is proinsulin. 124. The method of claim 1, wherein the proinsulin polypeptide is B-chain-Mg-A-chain. 125. The method of claim 1, wherein the proinsulin polypeptide is His-Gly-Arg-B-chain-Arg-A-chain. 126. The method of claim 1, wherein the proinsulin polypeptide is His-Gly-Mg-B-chain-Mg-Mg-A-chain. 127. The method of claim 1, wherein the proinsulin polypeptide is Leader peptide-Arg-B-chain-Arg-Pro-Arg-A-chain. 128. The method of claim 1, wherein the proinsulin polypeptide is Leader peptide-Arg-B-chain-Arg-Pro-Arg-A-chain. 129. The method of claim 1, wherein the proinsulin polypeptide is B-chain-Arg-Arg-A-chain. 130. The method of claim 1, wherein the oligomer comprises a C2 to C18 aryl group. 131. The method of claim 1, wherein the proinsulin polypeptide-oligomer conjugate comprises a LysB29 palmitoyl. 132. The method of claim 1, wherein the oligomer is a LysB29 C2to C18 aryl group.
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Greenwald Richard B. ; Gilbert Carl W., .alpha.-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same.
Belagaje Rama M. (Indianapolis IN) DiMarchi Richard D. (Carmel IN) Heath ; Jr. William F. (Indianapolis IN) Long Harlan B. (Carmel IN), A-C-B proinsulin, method of manufacturing and using same, and intermediates in insulin production.
Kitao Kazuhiko (Kyoto JPX) Nishimura Ken-ichi (Kyoto JPX), Adjuvant for promoting absorption of pharmacologically active substances through the rectum.
Speaker Tully J. (Philadelphia PA) Speaker Tycho J. (Philadelphia PA) Collett John H. (Sale GB2), Adjuvant-enhanced sustained release composition and method for making.
Ekwuribe Nnochiri ; Ramaswamy Muthukumar ; Rajagopalan Jayanthi Sethuraman, Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same.
Vanlerberghe Guy (Commune de Villevaude FRX) Handjani Rose-Marie (Paris FRX), Aqueous dispersions of lipid spheres and compositions containing the same.
Veronese Francesco (Padua ITX) Sartore Luciana (Padua ITX) Orsolini Piero (Martigny CHX) Deghenghi Romano (S.-Cergue CHX), Biologically active drug polymer derivatives and method for preparing same.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Biologically inert, biocompatible-polymer conjugates.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Collagen-polymer conjugates.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Collagen-polymer conjugates.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Collagen-polymer conjugates.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Collagen-polymer conjugates containing an ether linkage.
Mill Patrick James (Beaconfield EN) Cresswell Michael Alan (High Wycombe EN) Feinberg Joseph George (London EN), Conjugates of acid polysaccharides and complex organic substances.
Saifer Mark (Berkeley CA) Somack Ralph (Oakland CA) Williams L. David (Fremont CA), Conjugates of superoxide dismutage coupled to high molecular weight polyalkylene glycols.
Ekwuribe Nnochiri N. (Southfield MI), Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and m.
Ekwuribe Nnochiri N. (Southfield MI), Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and m.
Huper Fritz (Wuppertal DT) Rauenbusch Erich (Wuppertal DT) Schmidt-Kastner Gunter (Wuppertal DT) Bomer Bruno (Leverkusen DT) Bartl Herbert (Odenthal-Hahnenberg DT), Crosslinked copolymers of ab
상세보기
Greenwald Richard B. (Somerset NJ) Martinez Anthony J. (Hamilton Square NJ), Cyclic imide thione activated polyalkylene oxides.
Shorr Robert G. L. (Edison NJ) Cho Myung-Ok P. (Highland Park NJ) Nho Kwang (Somerset NJ), Fractionation of polyalkylene oxide-conjugated hemoglobin solutions.
Buckley Douglas I. (215 Brookward Rd. Woodside CA 94062) Habener Joel F. (217 Plymouth Rd. Newton Highlands MA 02161) Mallory Joanne B. (199 Acalanes ; Apt. 3 Sunnyvale CA 94086) Mojsov Svetlana (504, GLP-1 analogs useful for diabetes treatment.
Kahne Daniel Evan (Princeton NJ) Kahne Suzanne Walker (Princeton NJ), Glycosylated steroid derivatives for transport across biological membranes and process for making and using same.
Woodle Martin C. (Menlo Park CA) Martin Francis J. (San Francisco CA) Yau-Young Annie (Los Altos CA) Redemann Carl T. (Walnut Creek CA), Liposomes with enhanced circulation time.
Phillips Christopher P. (Brandamore PA) Snow Robert A. (West Chester PA), Lyophilized polyethylene oxide modified protein and polypeptide complexes with cyclodextrin.
Sutton Peter M. (Manderley GB2) Atkinson Anthony (Twingley GB2) Lloyd Graham (East Gomeldon GB2), Method and composition for the treatment and prevention of viral infections.
Brownlee Michael (Watertown MA) Cerami Anthony (Flanders NJ), Method and system for the controlled release of biologically active substances to a body fluid.
Brownlee Michael (Watertown MA) Cerami Anthony (Flanders NJ), Method and system for the controlled release of biologically active substances to a body fluid.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Method of preparing collagen-polymer conjugates.
Ekwuribe, Nnochiri N.; Price, Christopher H.; Ansari, Aslam M.; Odenbaugh, Amy L., Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same.
Ekwuribe, Nnochiri N.; Price, Christopher H.; Ansari, Aslam M.; Radhakrishnan, Balasingam; Odenbaugh, Amy L., Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same.
Harris J. Milton ; Veronese Francesco Maria,ITX ; Caliceti Paolo,ITX ; Schiavon Oddone,ITX, Multiarmed, monofunctional, polymer for coupling to molecules and surfaces.
Davis Frank F. (19 Farmingdale Rd. East Brunswick NJ 08816) Van Es Theodorus (313 Overbrook Rd. Piscataway NJ 08854) Palczuk Nicholas C. (45 W. Franklin St. Bound Brook NJ 08805), Non-immunogenic polypeptides.
Rhee Woonza (Palo Alto CA) Wallace Donald G. (Menlo Park CA) Michaels Alan S. (Boston MA) Burns ; Jr. Ramon A. (Fremont CA) Fries Louis (Los Altos CA) DeLustro Frank (Belmont CA) Bentz Hanne (Newark , Polymer conjugates ophthalmic devices comprising collagen-polymer conjugates.
Nitecki Danute E. (Berkeley CA) Katre Nandini (El Cerrito CA) Goodson Robert J. (Albany CA) Aldwin Lois (San Mateo CA), Preparation of a polymer/interleukin-2 conjugate.
Baker Jeffrey Clayton (Indianapolis IN) Moser Brian A. (Indianapolis IN) Shrader Warren E. (Indianapolis IN), Preparation of an acylated protein powder.
Baker Jeffrey C. (Indianapolis IN) Carter Nancy D. (Indianapolis IN) Frank Bruce H. (Indianapolis IN), Preparation of stable zinc insulin analog crystals.
Appelgren Curt H. (Kungsbacka SEX) Eskilsson Eva C. (Mlnlycke SEX) Uvdal Jonas P. (Gothenburg SEX), Process for preparing rapidly disintegrating granulates.
Maitra Amarnath,INX ; Ghosh Prashant Kumar,INX ; De Tapas K.,INX ; Sahoo Sanjeeb Kumar,INX, Process for the preparation of highly monodispersed polymeric hydrophilic nanoparticles.
Frank Bruce H. (Indianapolis IN) Prouty Walker E. (Indianapolis IN) Heiney Richard E. (Greenwood IN) Walden Mark R. (Indianapolis IN), Process for transforming a human insulin precursor to human insulin.
Backstrom Kjell Goran Erik,SEX ; Dahlback Carl Magnus Olof,SEX ; Edman Peter,SEX ; Johansson Ann Charlotte Birgit,SEX, Processes for preparing compositions for inhalation.
Eckenhoff James B. (Los Altos CA) Cortese Richard (Los Gatos CA) Landrau Felix A. (Milpitas CA), Rate controlled dispenser for administering beneficial agent.
Baker Jeffrey C. (Indianapolis IN) Hanquier Jose M. (Martinsville IN) Shrader Warren E. (Indianapolis IN), Reducing gelation of a fatty acid-acylated protein.
Baker Jeffrey C. (Indianapolis IN) Chen Victor J. (Indianapolis IN) Hanquier Jose M. (Martinsville IN) Kriauciunas Aidas (Indianapolis IN) Moser Brian A. (Indianapolis IN) Shuman Robert T. (Greenwood, Selective acylation of epsilon-amino groups.
Backstrom Kjell Goran Erik,SEX ; Dahlback Carl Magnus Olof,SEX ; Edman Peter,SEX ; Johansson Ann Charlotte Birgit,SEX, Systemic administration of a therapeutic preparation.
Bckstrm Kjell G. E. (Lund SEX) Dahlbck Carl M. O. (Lund SEX) Edman Peter (Bjrred SEX) Johansson Ann C. B. (Lund SEX), Systemic administration of a therapeutic preparation.
Backstrom Kjell Goran Erik (Lund SEX) Dahlback Carl Magnus Olof (Lund SEX) Edman Peter (Bjarred SEX) Johansson Ann Charlotte Birgit (Lund SEX), Therapeutic preparation for inhalation.
Backstrom Kjell Goran Erik,SEX ; Dahlback Carl Magnus Olof,SEX ; Edman Peter,SEX ; Johansson Ann Charlotte Birgit,SEX, Therapeutic preparation for inhalation.
Backstrom Kjell Goran Erik,SEX ; Dahlback Carl Magnus Olof,SEX ; Edman Peter,SEX ; Johansson Ann Charlotte Birgit,SEX, Therapeutic preparation for inhalation.
Backstrom Kjell Goran Erik,SEX ; Dahlback Carl Magnus Olof,SEX ; Edman Peter,SEX ; Johansson Ann Charlotte Birgit,SEX, Therapeutic preparation for inhalation.
Bckstrm Kjell G. E. (Lund SEX) Dahlbck Carl M. O. (Lund SEX) Edman Peter (Bjrred SEX) Johansson Ann C. B. (Lund SEX), Therapeutic preparation for inhalation.
Longenecker John P. (Mountain View CA) Ennis Richard (Fremont CA) Baldwin Patricia A. (Hayward CA) Lee William A. (Los Altos CA), Transmembrane formulations for drug administration.
Radhakrishnan,Balasingam; Soltero,Richard; Ekwuribe,Nnochiri N., Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same.
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