Water-soluble non-antigenic polymer linkable to biologically active material

• US 6,113,906 A
• Filed: 12/29/1998
• Issued: 09/05/2000
• Est. Priority Date: 10/27/1993
• Status: Expired due to Term

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Greenwald, Richard B., Martinez, Anthony J.
• Primary Examiner(s): Sellers, Robert E.
• Application Number:
  US09/222,463
• Time in Patent Office: 616 Days
• Field of Search: 424/178.1, 424/179.1, 525/54.1, 525/403, 525/408, 530/406, 530/410, 560/182, 514/449, 549/510, 549/433
• US Class Current: 424/194.1
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07K 17/08 the carrier being a synthetic polymer
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08G 65/338 with inorganic and organic compounds
• CPC Class Codes: C12N 11/089 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Abstract

Branched, substantially non-antigenic polymers are disclosed. Conjugates prepared with the polymers and biologically active molecules such as proteins and peptides demonstrate extended circulating life in vivo. Substantially fewer sites on the biologically active material are used as attachment sites. Methods of forming the polymer, conjugating the polymers with biologically active moieties and methods of using the conjugates are also disclosed.

Claims

1. A substantially non-antigenic polymer of the formula:

##STR33##

17. The substantially non-antigenic polymer of claim 1, wherein the molecular weight of said polymer is less than about 80,000 Daltons.

2. A substantially non-antigenic polymer of the formula:

wherein (A) is a functional group capable of bonding with a biologically active nucleophile, or a spacer moiety capable of being functionalized to react with a biologically active nucleophile.

3. A substantially non-antigenic polymer of the formula:

##STR34## wherein (A) is a functional group of a biologically active material capable of reacting with an amino group.

4. A substantially non-antigenic polymer conjugate of the formula:

##STR35## wherein (A'"'"') is a linkage moiety.

18. The substantially non-antigenic polymer conjugate of claim 4, wherein the molecular weight of the polymer portion thereof is less than about 80,000 Daltons.

5. A branched substantially non-antigenic polymer of the formula:

space="preserve" listing-type="equation">(R).sub.n L-A

wherein;

(R) is a monomethyl polyethylene glycol;

(n) is 2;

(A) is a functional group capable bonding with a biologically active nucleophile, or a spacer moiety capable of being functionalized to react with a biologically active nucleophile ##STR36## wherein each (R) is linked to (L) by a urethane linkage.

6. A polymeric conjugate of the formula:

space="preserve" listing-type="equation">[(R).sub.n L-A.sup.1 ].sub.z -(nucleophile)

wherein;

(R) is a monomethyl polyethylene glycol;

(n) is 2;

##STR37## wherein each (R) is linked to (L) by a urethane linkage, (A'"'"') represents a linkage between (L) and the biologically active nucleophile;

(z) is an integer ≦

1; and

(nucleophile) is a biologically active nucleophile.

7. The polymeric conjugate of claim 6, wherein the (nucleophile) is α

-interferon and (z) is one.

8. A substantially non-antigenic polymer conjugate of the formula:

##STR38##

9. The conjugate of claim 8, wherein said protein is an interferon.

10. The polymer conjugate of claim 9, wherein said interferon is an α

-interferon.

19. The substantially non-antigenic polymer conjugate of claim 8, wherein the molecular weight of the polymer portion thereof is less than about 80,000 Daltons.

11. A substantially non-antigenic polymer conjugate of the formula:

wherein each (R) is a water-soluble substantially non-antigenic polymer containing a C_1-4 terminal group, each (R) is linked to each NH via a urethane bond and the polymer portion thereof has a molecular weight of less than about 80,000 Daltons.

12. The conjugate of claim 11, wherein said protein is an interferon.

13. The polymer conjugate of claim 12, wherein said interferon is an α

-interferon.

14. The conjugate of claim 11, wherein each (R) is a polyalkylene oxide.

15. The conjugate of claim 14, wherein said polyalkylene oxide is polyethylene glycol.

16. The conjugate of claim 15, wherein said polyalkylene oxide is monomethoxypolyethylene glycol.

20. The substantially non-antigenic polymer conjugate of claim 11, wherein the molecular weight of the polymer portion thereof is less than about 80,000 Daltons.