Claims
- 1. A thioester-terminated reactive polymer, comprising a water soluble and non-peptidic polymer backbone having at least one terminus bonded to the structure:
- 2. The reactive polymer of claim 1, wherein each X is H or C1-C6 alkyl.
- 3. The reactive polymer of claim 2, wherein each X is H or methyl.
- 4. The reactive polymer of claim 1, wherein Y is O or S.
- 5. The reactive polymer of claim 1, wherein Q has the formula —S—R1, wherein R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle.
- 6. The reactive polymer of claim 5, wherein R1 is selected from the group consisting of phenol, nitrophenol, benzoic acid, pyridine, pyridinecarboxylic acid, and nitropyridine.
- 7. The reactive polymer of claim 5, wherein R1 is substituted or unsubstituted pyridine.
- 8. The reactive polymer of claim 1, wherein a is 1 and Z is selected from the group consisting of —O—, —S—, —NHCO—, —CONH—, —O2C—, —NHCO2—, and —O2CNH—.
- 9. The reactive polymer of claim 1, wherein the polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), polyacrylate, polyacrylamides, polysaccharides, and copolymers, terpolymers, and mixtures thereof.
- 10. The reactive polymer of claim 1, wherein said water soluble and non-peptidic polymer backbone is selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), and copolymers of ethylene glycol and propylene glycol.
- 11. The reactive polymer of claim 1, wherein said polymer backbone is poly(ethylene glycol) having a number average molecular weight of about 100 Da to about 100,000 Da.
- 12. The reactive polymer of claim 1, wherein m is 1 to about 4.
- 13. The reactive polymer of claim 1, having the structure:
- 14. The reactive polymer of claim 13, wherein R is selected from the group consisting of alkoxy, alkyl, benzyl, aryl, aryloxy, hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, tresylate and —(Z)a—(CXH)m—CO—S—R1.
- 15. The reactive polymer of claim 13, wherein POLY is poly(ethylene glycol).
- 16. The reactive polymer of claim 1, having the structure:
- 17. The reactive polymer of claim 16, wherein POLY is poly(ethylene glycol).
- 18. The reactive polymer of claim 16, wherein R′ is a residue of a molecule selected from the group consisting of polyols, polyamines, and molecules having a combination of alcohol and amine groups.
- 19. The reactive polymer of claim 16, wherein R′ is a residue of a molecule selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, and lysine.
- 20. A polymer conjugate of a polypeptide having a cysteine or histidine residue at the N-terminus, said polymer conjugate comprising a water soluble and non-peptidic polymer backbone having at least one terminus bonded to the structure:
- 21. The polymer conjugate of claim 20, wherein the polymer backbone is poly(ethylene glycol).
- 22. The polymer conjugate of claim 20, wherein POLYPEPTIDE is selected from the group consisting of proteins, protein-ligands, enzymes, cytokines, hematopoietins, growth factors, hormones, antigens, antibodies, antibody fragments, receptors, and protein fragments.
- 23. The polymer conjugate of claim 20, wherein POLYPEPTIDE is an interferon molecule.
- 24. A method of conjugating a polymer derivative to a polypeptide having a cysteine or histidine residue at the N-terminus, said method comprising:
providing a polypeptide having a cysteine or histidine residue at the N-terminus; providing a thioester-terminated polymer, the polymer comprising a water soluble and non-peptidic polymer backbone having at least one terminus bonded to the structure: 27wherein:
L is the point of bonding to the polymer backbone; Z is a linker; m is from 0 to about 12; Y is a heteroatom; each X is independently selected from H and alkyl; a is 0 or 1; and Q is a sulfur-containing leaving group; reacting the thioester-terminated polymer with the polypeptide to form a conjugate having the structure: 28wherein
POLYPEPTIDE is the polypeptide molecule, and W is —CH2SH or 29
- 25. The method of claim 24, wherein the polymer backbone is poly(ethylene glycol).
- 26. The method of claim 24, wherein POLYPEPTIDE is selected from the group consisting of protein ligands, enzymes, cytokines, hematopoietins, growth factors, hormones, antigens, antibodies, antibody fragments, receptors, and protein fragments.
- 27. A polymer conjugate of a polypeptide having a cysteine molecule at the N-terminus, said polymer conjugate comprising two water soluble and non-peptidic polymer backbones attached at the N-terminus, the conjugate having the structure:
- 28. The polymer conjugate of claim 27, wherein L′ is selected from the group consisting of
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. application Ser. No. 09/973,318, filed Oct. 9, 2001, which is incorporated by reference herein in its entirety.
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
09973318 |
Oct 2001 |
US |
Child |
10269028 |
Oct 2002 |
US |