Back to results
US 5,919,455 AGranted
Non-antigenic branched polymer conjugates
AssigneeEnzon, Inc.
InventorsRichard B. Greenwald, Anthony J. Martinez
Life of this patent
Estimating the term…
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.
Claims40
A branched substantially non-antigenic polymer comprising the formula:
- (R).sub.n L--COOH (Ia)
- wherein (R) is a water soluble, substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- (L) is selected from the group consisting of ##STR33## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of:
- O, NQ, S, SO, SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- and
- (p) is a positive integer.
8 more elements
A method of forming a biologically active conjugate, comprising:
- contacting a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules with an activated branched non-antigenic polymer having a structure represented by:
- (R).sub.n L--COOH (Ia)
- wherein:
- (R) is a water-soluble substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- and
- (L) is selected from the group consisting of ##STR36## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of:
- O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- and
- (p) is a positive integer.
11 more elements
A branched substantially non-antigenic polymer comprising the formula:
- (R).sub.n L--A
- wherein (R) is a water soluble, substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- (A) is a functional group capable of bonding with a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules or a moiety capable of being functionalized to react with said nucleophile;
- and
- (L) is selected from the group consisting of ##STR37## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of:
- O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- and
- (p) is a positive integer.
10 more elements
A method of forming a biologically active conjugate, comprising:
- contacting a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules with an activated branched non-antigenic polymer having a structure represented by:
- (R).sub.n L--A (I)
- wherein:
- (R) is a water-soluble substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- (L) is selected from the group consisting of:
- ##STR40## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of:
- O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- (p) is a positive integer;
- and
- (A) is a functional group capable of forming a covalent bond with said biologically active nucleophile.
12 more elements
A method of preparing a branched non-antigenic polymer containing a reactive carboxylic acid group thereon, comprising:
- i) contacting a branched non-antigenic polymer having a structure represented by:
- (R).sub.n L--A (I)
- wherein (R) is a water-soluble substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- and
- (L) is selected form the group consisting of ##STR41## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- (p) is a positive integer;
- (A) is a functional group capable of forming a covalent bond with a nucleophile;
- with an alkyl haloacetate in the presence of a base to form a alkyl ester of a branched non-antigenic polymer;
- and
- ii) reacting said alkyl ester with an acid to form said branched non-antigenic polymer containing a reactive carboxylic acid thereon comprising the formula:
- (R).sub.n L--COOH (Ia).
13 more elements
A method of preparing an active carbonate of a branched non-antigenic polymer comprising the steps of:
- i) contacting a branched non-antigenic polymer having a structure represented by:
- (R).sub.n L--A (I)
- wherein (R) is a water-soluble substantially non-antigenic polymer containing a C.sub.1 -C.sub.4 terminal group;
- (n)=2 or 3;
- (L) is selected from the group consisting of:
- ##STR43## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- (p) is a positive integer;
- (A) is a functional group capable of forming a covalent bond with a nucleophile;
- with p-nitrophenyl chloroformate;
- and
- ii) reacting the p-nitrophenyl carbonate active ester of step i) with N-hydroxysuccinimide.
12 more elements
A method of preparing a succinimidyl carbonate active ester of a branched non-antigenic polymer comprising:
- contacting a branched non-antigenic polymer having a structure represented by:
- (R).sub.n L--A (I)
- wherein (R) is a water-soluble substantially non-antigenic polymer containing a C.sub.1-4 terminal group;
- (n)=2 or 3;
- (L) is selected from the group consisting of:
- ##STR44## wherein:
- (a) is an integer of from about 1 to about 5;
- (m) is 0 or 1;
- X is selected from the group consisting of O, NQ, S, SO, and SO.sub.2 ;
- where Q is H, C.sub.1-8 alkyl, C.sub.1-8 branched alkyl, aryl, or aralkyl;
- (p) is a positive integer;
- and
- (A) is a functional group capable of forming a covalent bond with a nucleophile with N-hydroxysuccinimide and a condensing agent.
10 more elements
Dependencies are inferred from the claim text.