Polymer conjugates of GLP-1
View Patent ↗Conjugates of a GLP-I moiety may be covalently attached to one or more water-soluble polymers. For instance, a GLP-I polymer conjugate may include a GLP-I moiety releasably attached at its N-terminus to a water-soluble polymer. The GLP-I polymer conjugate may include a GLP-I moiety covalently attached to a water-soluble polymer, wherein the GLP-I moiety possesses an N-methyl substituent. The GLP-I polymer conjugate may include a GLP-I moiety covalently attached at a polymer attachment site to a water-soluble polymer, wherein the GLP-I moiety is glycosylated at a site separate from the polymer attachment site.
1. A GLP-1 polymer conjugate comprising a GLP-1 moiety attached at its N-terminus to a water-soluble polymer, wherein the conjugate is formed by contacting the GLP-1 moiety with a polymeric reagent of the following structure:
where:
POLY 1 is a first water-soluble polymer;
POLY 2 is a second water-soluble polymer;
X 1 is a first spacer moiety;
X 2 is a second spacer moiety;
H α is an ionizable hydrogen atom;
R 1 is H or an organic radical;
R 2 is H or an organic radical; and
(FG) is a functional group capable of reacting with an amino group of the GLP-1 moiety to form a degradable carbamate linkage.
2. The GLP-1 polymer conjugate of claim 1 , wherein each of the first water-soluble polymer and second water-soluble polymer is independently selected from poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers and terpolymers thereof.
3. The GLP-1 polymer conjugate of claim 2 , wherein each of the first water-soluble polymer and second water-soluble polymer is a polyethylene glycol.
4. The GLP-1 polymer conjugate of claim 3 , further comprising at least one additional polyethylene glycol attached via a degradable carbamate linkage to a number of sites on the GLP-1 moiety selected from one and two.
5. The GLP-1 polymer conjugate of claim 4 , wherein the at least one additional polyethylene glycol is attached via a degradable carbamate linkage to one or more sites corresponding to Lys26 and Lys34 of the GLP-1 moiety of SEQ ID NO: 1.
6. The GLP-1 polymer conjugate of claim 3 , wherein the polyethylene glycol is attached via a degradable carbamate linkage to a single site of the GLP-1 moiety.
7. The GLP-1 polymer conjugate of claim 1 , wherein each of the first water-soluble polymer and the second water-soluble polymer independently has a molecular weight ranging from about 500 daltons to about 80,000 daltons.
8. The GLP-1 polymer conjugate of claim 7 , wherein each of the first water-soluble polymer and the second water-soluble polymer independently has a molecular weight ranging from about 1000 daltons to about 40,000 daltons.
9. The GLP-1 conjugate of claim 1 , wherein each of R 1 and R 2 is H.