POLYMER CONJUGATES OF THYMOSIN ALPHA 1 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 residue of a thymosin alpha 1 moiety covalently attached, either directly or through a spacer moiety of one or more atoms, to a water-soluble, non-peptidic polymer.
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 . The conjugate of claim 1 , wherein the thymosin alpha 1 moiety is recombinantly prepared.
5 . The conjugate of claim 1 , wherein the thymosin alpha 1 moiety is prepared by chemical synthesis.
6 . The conjugate of claim 1 , wherein the polymer is selected from the group consisting of poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(acryloylmorpholine).
7 . The conjugate of claim 6 , wherein the polymer is a poly(alkylene oxide).
8 . The conjugate of claim 7 , 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 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 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 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 thymosin alpha 1 moiety.
14 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at a carboxy-terminal amino acid of the thymosin alpha 1 moiety.
15 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at an internal cysteine amino acid of the thymosin alpha 1 moiety.
16 . The conjugate of claim 1 , wherein the water-soluble, non-peptidic polymer is conjugated at an epsilon amino group of an internal lysine amino acid of the thymosin alpha 1 moiety.
17 .- 19 . (canceled)
20 . The conjugate of claim 1 having the following structure:
wherein n is an integer having a value within the range of from 2 to 4000 and TA1 is a residue of an amine-containing thymosin alpha 1 peptide.
21 . The conjugate of claim 1 having the following structure:
wherein n is an integer having a value within the range of from 2 to 4000 and TA1 is a residue of an amine-containing thymosin alpha 1 peptide.
22 . The conjugate of claim 1 having the following structure:
wherein n is an integer having a value within the range of from 2 to 4000 and TA1 is a residue of an amine-containing thymosin alpha 1 peptide.
23 . The conjugate of claim 1 having the following structure:
wherein each n is an integer having a value within the range of from 2 to 4000 and TA1 is a residue of an amine-containing thymosin alpha 1 peptide.
24 . The conjugate having the following structure:
wherein each “mPEG” represents a methoxy polyethylene glycol polymer having a weight average molecular weight of from 1,000 Daltons to 50,000 Daltons and TA1 is a residue of an amine-containing thymosin alpha 1 peptide.
25 . The conjugate of claim 1 , wherein the thymosin alpha 1 residue is covalently attached through a spacer moiety of one or more atoms.
26 . The conjugate of claim 25 , wherein the spacer moiety includes an amine linkage.
27 . The conjugate of claim 25 , wherein the spacer moiety includes an amide linkage.
28 . The conjugate of claim 25 , wherein the spacer moiety includes a disulfide linkage.
29 . The compound of claim 1 , wherein the thymosin alpha 1 residue is covalently attached via a stable linkage.
30 . The compound of claim 1 , wherein
the thymosin alpha 1 residue is covalently attached via a releasable linkage.
31 . A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable excipient.
32 . A method for making a conjugate of claim 1 comprising contacting, under conjugation conditions, a thymosin alpha 1 moiety with a polymeric reagent bearing a functional group.
33 . A method of treatment comprising administering a compound of claim 1 to a subject in need thereof.