Non-antigenic branched polymer conjugates

• US 6,566,506 B2
• Filed: 04/07/2000
• Issued: 05/20/2003
• Est. Priority Date: 10/27/1993
• Status: Expired due to Fees

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Martinez, Anthony J., Greenwald, Richard B.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/545,066
• Publication Number:
  US 20020052443A1
• Time in Patent Office: 1,138 Days
• Field of Search: 424/94.3, 424/178.1, 424/179.1, 424/193.1, 424/194.1, 424/195.11, 435/188, 514/2, 514/8, 514/12, 514/21, 514/449, 525/54.1, 525/54.11, 525/4.3, 525/408, 525/409, 530/345, 530/391.1, 530/395, 530/402, 530/403, 530/405, 530/406, 530/408, 530/409, 530/410, 528/300, 528/302, 528/310, 528/322, 528/332, 528/361, 549/433, 549/510, 560/26, 560/158, 560/182, 564/159
• US Class Current: 530/391.1
• 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 branched polymer comprising the formula:

wherein (a) is from 1 to 5.

2. A method of preparing a branched substantially non-antigenic polymer, comprising providing a compound of the formula:

wherein;

(a) is an integer of from about 1 to about 5;

R₂ is a spacer moiety selected from the group consisting of;

—

CO—

NH—

(CH₂—

)_dX₄—

, —

CO—

NH—

(CH₂—

CH₂—

O—

)_dH,

wherein (d) is an integer between about 1 and about 18 inclusive; and

X₄ is selected from the group consisting of OH, NH₂, and COOH;

and converting the terminal group of R₂ into a functional group capable of bonding with a biologically active nucleophile.

3. The method of claim 2, wherein said functional group capable of bonding with a biologically active nucleophile is selected from the group consisting of carbonyl imidazole, aziactones, cyclic imide thiones, isocyanates, isothiocyanates, primary amines, hydrazines, acyl hydrazines, carbazates, semicarbazates, thiocarbazates and phenylglyoxals.

4. The method of claim 3, wherein said functional group capable of bonding with a biologically active nucleophile is a cyclic imide thione.

5. A polymer conjugate of the formula:

wherein (protein) is an antibody fragment.

6. The polymer conjugate of claim 5, wherein the molecular weight of said polymer is less than about 80,000 daltons.

7. The polymer conjugate of claim 5, wherein said polymer conjugate has a molecular weight of from about 200 to about 80,000 daltons.

8. The polymer conjugate of claim 5, wherein said polymer conjugate has a molecular weight of from about 2,000 to about 42,000 daltons.

9. The polymer conjugate of claim 5, wherein said polymer conjugate has a molecular weight of from about 5,000 to about 20,000 daltons.