Polymer conjugates of interferon-beta with enhanced biological potency
First Claim
1. A composition comprising a detergent and a non-glycosylated interferon-beta conjugate prepared by selectively coupling one or more synthetic water-soluble polymers to the amino-terminal amino acid of a non-glycosylated interferon-beta,wherein said one or more synthetic water-soluble polymers is selected from the group consisting of one or more polyethylene glycols and one or more polyethylene oxides,wherein said amino-terminal amino acid is located remotely from the receptor-binding domain(s) of said interferon-beta, andwherein said conjugate has increased in vitro biological potency as compared to said non-glycosylated interferon-beta that has not been coupled with one or more synthetic water-soluble polymers when assayed under the same conditions.
1 Assignment
0 Petitions
Accused Products
Abstract
Methods are provided for the synthesis of polymer conjugates of cytokines and receptor-binding antagonists thereof, especially a non-glycosylated interferon-beta, which conjugates retain unusually high biological potency. 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, 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 high level of biological potency compared to those produced by traditional polymer coupling methods that are not targeted to avoid receptor-binding domains of cytokines. In assays in vitro, the biological potency of the conjugates of non-glycosylated interferon-beta of the present invention is substantially higher than that of unconjugated interferon-beta and is similar to that of interferon-beta-1a that is glycosylated. The conjugates of the present invention also exhibit an extended half-life in vivo compared to the corresponding unconjugated cytokine. 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 and therapeutic applications, including treatment of multiple sclerosis.
-
Citations
38 Claims
-
1. A composition comprising a detergent and a non-glycosylated interferon-beta conjugate prepared by selectively coupling one or more synthetic water-soluble polymers to the amino-terminal amino acid of a non-glycosylated interferon-beta,
wherein said one or more synthetic water-soluble polymers is selected from the group consisting of one or more polyethylene glycols and one or more polyethylene oxides, wherein said amino-terminal amino acid is located remotely from the receptor-binding domain(s) of said interferon-beta, and wherein said conjugate has increased in vitro biological potency as compared to said non-glycosylated interferon-beta that has not been coupled with one or more synthetic water-soluble polymers when assayed under the same conditions.
-
3. A composition comprising a detergent and a conjugate that comprises a non-glycosylated interferon-beta selectively and covalently coupled at its amino-terminal amino acid to one or more synthetic water-soluble polymers,
wherein said one or more synthetic water-soluble polymers is selected from the group consisting of one or more polyethylene glycols and one or more polyethylene oxides, wherein said amino-terminal amino acid is located remotely from the receptor-binding domain(s) of said interferon-beta, and wherein the in vitro biological potency of said interferon-beta is increased compared to the same interferon-beta that has not been so coupled when assayed under the same conditions.
-
4. A composition comprising a detergent and a conjugate that comprises a non-glycosylated interferon-beta selectively and covalently coupled at its amino-terminal amino acid to one or more synthetic water-soluble polymers,
wherein said one or more synthetic water-soluble polymers is selected from the group consisting of one or more polyethylene glycols and one or more polyethylene oxides, wherein said amino-terminal amino acid is located remotely from the receptor-binding domain(s) of said interferon-beta, and wherein the in vitro biological potency of said conjugate of interferon-beta is increased compared to the same interferon-beta to which the same number of the same synthetic water-soluble polymers has been coupled randomly to solvent-accessible lysine residues when assayed under the same conditions.
Specification