Multi-armed, monofunctional, and hydrolytically stable derivatives of poly (ethylene glycol) and related polymers for modification of surfaces and molecules

• US 7,786,221 B2
• Filed: 09/18/2008
• Issued: 08/31/2010
• Est. Priority Date: 01/10/1995
• Status: Expired due to Fees

• Current Assignee: Nektar Therapeutics
• Original Assignee: Nektar Therapeutics
• Inventors: Schiavon, Oddone, Caliceti, Paola, Harris, J. Milton, Veronese, Francesco Maria
• Primary Examiner(s): Choi; Ling-Siu
• Assistant Examiner(s): Wright; Sonya
• Application Number:
  US12/284,357
• Publication Number:
  US 20090054590A1
• Time in Patent Office: 712 Days
• Field of Search: 528/425, 525/419, 514/424
• US Class Current: 525/419
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/48 Polymers modified by chemical after-treatment
• CPC Class Codes: C12N 9/96 Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/816 Attached to the carrier via a bridging agent

Abstract

Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure

wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms poly_a and poly_b, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure

where mPEG_a and mPEG_b have the structure CH₃O—(CH₂CH₂O)_nCH₂CH₂— wherein n may be the same or different for poly_a- and poly_b- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.

Claims

1. A monofunctional water-soluble polymer having the structure:

2. The monofunctional water soluble polymer of claim 1, having the structure:

3. The monofunctional water soluble polymer of claim 2, wherein R_z comprises an amide linkage.

4. The monofunctional water soluble polymer of claim 3, wherein R_z comprises an amide linkage covalently attached to an alkylene chain.

5. The monofunctional water soluble polymer of claim 1, wherein —

P—

CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.

6. The monofunctional water soluble polymer of claim 2, wherein —

P—

CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.

7. The monofunctional water soluble polymer of claim 4, wherein —

P—

CH(Q-)Z is formed from an alcohol having more than two hydroxyl groups.

8. The monofunctional water soluble polymer of claim 1, wherein P is an alkyl fragment joined to poly_a by an ether linkage.

9. The monofunctional water soluble polymer of claim 2, wherein P is an alkyl fragment joined to poly_a by an ether linkage.

10. The monofunctional water soluble polymer of claim 4, wherein P is an alkyl fragment joined to poly_a by an ether linkage.

11. The monofunctional water soluble polymer of claim 2, wherein the reactive site is selected from carboxyl and activated carboxyl.

12. The monofunctional water soluble polymer of claim 10, wherein the reactive site is selected from carboxyl and activated carboxyl.

13. The monofunctional water soluble polymer of claim 2, wherein the reactive site is selected from active esters, active carbonates, and maleimide.

14. The monofunctional water soluble polymer of claim 10, wherein the reactive site is selected from active esters, active carbonates, and maleimide.

15. The monofunctional water soluble polymer of claim 14, wherein the reactive site is selected from N-hydroxysuccinimidyl ester and maleimide.

16. The monofunctional water soluble polymer of claim 1 covalently attached via the single reactive site of Z to a biologically active molecule.

17. The monofunctional water soluble polymer of claim 16, wherein said biologically active molecule is a protein.

18. The monofunctional water soluble polymer of claim 10 covalently attached via the single reactive site of Z to a biologically active molecule.

19. A conjugate formed by reacting the monofunctional water soluble polymer of claim 1 with a biologically active molecule.

20. The monofunctional water soluble polymer of claim 1 wherein P and Q are the same.

21. The monofunctional water soluble polymer of claim 1 wherein P and Q are different.