POLYMER CONJUGATES OF THERAPEUTIC PEPTIDES
The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the peptide not attached to the water-soluble oligomer.
1 . A conjugate comprising a therapeutic peptide moiety covalently attached, either directly or through a spacer moiety of one or more atoms, to a water-soluble, non-peptidic polymer; wherein:
the therapeutic peptide is Human Opioid Growth Factor (SEQ. ID. NO. 283); and
the water-soluble, non-peptidic polymer is a poly(alkylene oxide).
2 . A conjugate of claim 1 , wherein the polymer is a linear polymer.
3 . A conjugate of claim 1 , wherein the polymer is a branched polymer.
4 - 7 . (canceled)
8 . The conjugate of claim 1 , wherein the poly(alkylene oxide) is a poly(ethylene glycol).
9 . The conjugate of claim 8 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy.
10 . The conjugate of claim 8 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 500 Daltons to about 100,000 Daltons.
11 . The conjugate of claim 10 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 2000 Daltons to about 50,000 Daltons.
12 . The conjugate of claim 11 , wherein the poly(ethylene glycol) has a weight-average molecular weight in a range of from about 5000 Daltons to about 40,000 Daltons.
13 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at an amino-terminal amino acid of the therapeutic peptide moiety.
14 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at a carboxy-terminal amino acid of the therapeutic peptide moiety.
15 . (canceled)
16 . (canceled)
17 . The conjugate of claim 8 , wherein the conjugate is formed by reacting a polymeric reagent with the therapeutic peptide, wherein the polymeric reagent has the following structure:
wherein, (n) is independently an integer having a value of from about 2 to about 4000.
18 . (canceled)
19 . The conjugate of claim 8 , wherein the conjugate is formed by reacting a polymeric reagent with the therapeutic peptide, wherein the polymeric reagent has the following structure:
wherein, (n) is independently an integer having a value of from about 2 to about 4000.
20 . The conjugate of claim 1 , wherein the therapeutic peptide residue is covalently attached through a spacer moiety of one or more atoms.
21 . The conjugate of claim 20 , wherein the spacer moiety includes an amine linkage.
22 . The conjugate of claim 20 , wherein the spacer moiety includes an amide linkage.
23 . (canceled)
24 . The conjugate of claim 1 , wherein the therapeutic peptide residue is covalently attached via a stable linkage.
25 . The conjugate of claim 1 , wherein the therapeutic peptide residue is covalently attached via a releasable linkage.
26 . (canceled)
27 . (canceled)
28 . A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable excipient.
29 . (canceled)
30 . A method of treatment comprising administering a conjugate of claim 1 to a subject in need thereof.
31 . The conjugate of claim 1 , wherein the conjugate is formed by reacting an mPEG-epoxide with the therapeutic peptide.
32 . The conjugate of claim 31 , wherein the mPEG-epoxide has a molecular weight of about 5 kD.