Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity
First Claim
1. A method for synthesizing conjugates of one or more synthetic water-soluble polymers with a cytokine, a chemokine, a growth factor or a polypeptide hormone, or an antagonist thereof, that preserves more of the receptor-binding potency of said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof, than is preserved when such polymers are randomly coupled, comprising:
- (a) selecting a cytokine, chemokine, growth factor or polypeptide hormone in which the amino-terminal amino acid is located remotely from one or more receptor-binding domains of said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof; and
(b) coupling said one or more polymers selectively to said amino-terminal amino acid.
2 Assignments
0 Petitions
Accused Products
Abstract
Methods are provided for the synthesis of polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and receptor-binding antagonists thereof, which conjugates retain unusually high receptor-binding activity. Preparation of polymer conjugates according to the methods of the present invention diminishes or avoids steric inhibition of receptor-ligand interactions that commonly results from the attachment of polymers to receptor-binding regions of cytokines, chemokines, growth factors and polypeptide hormones, as well as to agonistic and antagonistic analogs thereof. The invention also provides conjugates and compositions produced by such methods. The conjugates of the present invention retain a higher level of receptor-binding activity than those produced by traditional polymer coupling methods that are not targeted to avoid receptor-binding domains of cytokines, chemokines, growth factors and polypeptide hormones. The conjugates of the present invention also exhibit an extended half-life in vivo and in vitro compared to unconjugated cytokines, chemokines, growth factors and polypeptide hormones. The present invention also provides kits comprising such conjugates and/or compositions, and methods of use of such conjugates and compositions in a variety of diagnostic, prophylactic, therapeutic and bioprocessing applications.
-
Citations
164 Claims
-
1. A method for synthesizing conjugates of one or more synthetic water-soluble polymers with a cytokine, a chemokine, a growth factor or a polypeptide hormone, or an antagonist thereof, that preserves more of the receptor-binding potency of said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof, than is preserved when such polymers are randomly coupled, comprising:
-
(a) selecting a cytokine, chemokine, growth factor or polypeptide hormone in which the amino-terminal amino acid is located remotely from one or more receptor-binding domains of said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof; and
(b) coupling said one or more polymers selectively to said amino-terminal amino acid. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 73)
-
- 38. A conjugate comprising a cytokine, a chemokine, a growth factor or a polypeptide hormone, or antagonist thereof, coupled to one or more synthetic water-soluble polymers, wherein said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof, is selected for its membership in the group of receptor-binding proteins and polypeptides in which the amino-terminal amino acid is located remotely from one or more receptor-binding domains and wherein said one or more polymers is/are coupled to said amino-terminal amino acid.
-
77. A method for synthesizing conjugates of one or more synthetic water-soluble polymers with a cytokine, a chemokine, a growth factor or a polypeptide hormone, or antagonist thereof, that preserves more of the receptor-binding potency of said cytokine, chemokine, growth factor or polymers are randomly coupled, comprising:
-
(a) selecting a cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof, in which a naturally occurring or genetically engineered glycosylation site is located remotely from one or more receptor-binding domains of said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof; and
(b) coupling said one or more polymers selectively to said glycosylation site or to a carbohydrate moiety attached thereto. - View Dependent Claims (78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 140, 141, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164)
-
- 109. A conjugate comprising a cytokine, a growth factor, a chemokine or a polypeptide hormone, or antagonist thereof, coupled to one or more synthetic water-soluble polymers, wherein said cytokine, chemokine, growth factor or polypeptide hormone, or antagonist thereof, is selected for its membership in the group of receptor-binding proteins and polypeptides in which a glycosylation site is located remotely from one or more receptor-binding domains and wherein said one or more polymers is/are coupled at or near one or more glycosylation sites or to a carbohydrate moiety attached thereto.
Specification