US5919455A
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US
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Non-antigenic branched polymer conjugates
Assignee: Viskase Holdings Inc
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Filing: 1997-03-20
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Granted: 1999-07-06
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Expires: 2017-03-20
Abstract
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.
Inventors
- 👤 Richard B. Greenwald
- 👤 Anthony J. Martinez
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 11:25
CPC Classifications
C; C07; C07K; C07K17/00; C07K17/02; C07K17/08; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/59; A61K47/60; A61P; A61P1/00; A61P13/00; A61P15/00; A61P15/08; A61P15/16; A61P15/18; A61P25/00; A61P25/04; A61P25/22; A61P25/28; A61P29/00; A61P31/00; A61P31/04; A61P35/00; A61P9/00; A61P9/08; C08; C08G; C08G65/00; C08G65/02; C08G65/32; C08G65/329; C08G65/331; C08G65/332; C08G65/3322; C08G65/333; C08G65/33396; C08G65/337; C08G65/338; C12; C12N; C12N11/00; C12N11/02; C12N11/08; C12N11/089
Claims Analysis
Total Claims: 47
Claim 1
Independent Claim
92 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 2
Dependent Claim
92 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 3
Dependent Claim
14 words
The polymer of claim 1, wherein at least one (R) is a straight-chained polymer.
Claim 4
Dependent Claim
14 words
The polymer of claim 1, wherein at least one (R) is a poly(alkylene oxide).
Claim 5
Dependent Claim
30 words
The polymer of claim 3, wherein said poly(alkylene oxide) is selected from the group consisting of poly(ethylene glycol) homopolymers, alkyl-capped poly(ethylene oxides), and copolymers of block copolymers of poly(alkylene oxides).
Claim 6
Dependent Claim
21 words
The polymer of claim 4, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.
Claim 7
Dependent Claim
20 words
The polymer of claim 5, wherein said poly(alkylene oxide) has a number average molecular weight between 2,000 and about 42,000.
Claim 8
Dependent Claim
20 words
The polymer of claim 6, wherein said poly(alkylene oxide) has a number average molecular weight between 5,000 and about 20,000.
Claim 9
Dependent Claim
12 words
The polymer of claim 1, wherein each (R) is a poly(ethylene glycol).
Claim 10
Dependent Claim
9 words
The polymer of claim 1, wherein (m) is zero.
Claim 11
Dependent Claim
15 words
The polymer of claim 1, wherein said C 1 -C 4 terminal group is methoxy.
Claim 12
Dependent Claim
9 words
The polymer of claim 1, wherein (n) is two.
Claim 13
Dependent Claim
100 words
The polymer of claim 1 comprising a structure selected form the group consisting of: ##STR34## 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 2 ; where Q is H. C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; (p) is a positive integer; and R 2 is a spacer moiety selected form the group consisting of: --CO--NH--(CH.sub.2 --).sub.d --, --CO--NH--(CH.sub.2 --CH.sub.2 O--).sub.d --, ##STR35## where (d) is an integer between about 1 and about 18 inclusive.
Claim 14
Dependent Claim
14 words
The polymer of claim 1, further comprising a spacer moiety proximal to said (L).
Claim 15
Dependent Claim
21 words
The polymer of claim 1, wherein at least one (R) further comprises a functional group capable of covalently bonding with nucleophiles.
Claim 16
Independent Claim
123 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 17
Independent Claim
123 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 18
Dependent Claim
17 words
A polymer conjugate prepared by reacting the branched substantially non-antigenic polymer of claim 1 with a nucleophile.
Claim 19
Dependent Claim
14 words
The conjugate of claim 16, wherein at least one (R) is a poly(alkylene oxide).
Claim 20
Dependent Claim
21 words
The conjugate of claim 17, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.
Claim 21
Dependent Claim
12 words
The conjugate of claim 16, wherein each (R) is a poly(ethylene glycol).
Claim 22
Dependent Claim
17 words
The conjugate of claim 16, wherein said nucleophile is selected from consisting of proteins, peptide and polypeptides.
Claim 23
Dependent Claim
43 words
The conjugate of claim 16, wherein said nucleophile is a member of the group consisting of anti-neoplastics, anti-infectives, anti-anxiety agents, anti-gastrointestinal agents, central nervous system-activating agents, analgesics, fertility, contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, cardiovascular agents, vasodilating agents and vasconstricting agents.
Claim 24
Dependent Claim
25 words
The conjugate of claim 21, wherein said antineoplastic agent is selected from the group consisting of taxol, taxanes, taxotere, taxoid molecules, camptothecan, anthracyclines and methotrexates.
Claim 25
Dependent Claim
26 words
A method of treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of the branched polymer conjugate of claim 16.
Claim 26
Dependent Claim
131 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 27
Dependent Claim
131 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 1-8 branched alkyl, aryl, or aralkyl; and (p) is a positive integer.
Claim 28
Dependent Claim
14 words
The polymer of claim 24, wherein at least one (R) is a poly(alkylene oxide).
Claim 29
Dependent Claim
21 words
The polymer of claim 24, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.
Claim 30
Dependent Claim
20 words
The polymer of claim 26, wherein said poly(alkylene oxide) has a number average molecular weight between 2,000 and about 42,000.
Claim 31
Dependent Claim
21 words
The polymer of claim 27, wherein said poly(alkylene oxide) has a number average molecular weight of about 5,000 to about 20,000.
Claim 32
Dependent Claim
12 words
The polymer of claim 24, wherein each (R) is a poly(ethylene glycol).
Claim 33
Dependent Claim
15 words
The polymer of claim 24, wherein said C 1 -C 4 terminal group is methoxy.
Claim 34
Dependent Claim
9 words
The polymer of claim 24, wherein (n) is two.
Claim 35
Dependent Claim
89 words
The polymer of claim 24 comprising a structure selected form the group consisting of: ##STR38## wherein: (a) is an integer of from about 1 to about 5; (m) is 0 or 1; (p) is a positive integer; and R 2 is a spacer moiety selected form the group consisting of: polymers, --CO--NH--(CH 2 --) d X 2 , --CO--NH--(CH 2 --CH 2 --O--) d X 2 , ##STR39## where (d) is an integer between 1 and 18 inclusive and (X 2 ) is H, OH, NH 2 or COOH.
Claim 36
Independent Claim
138 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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.
Claim 37
Independent Claim
138 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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.
Claim 38
Independent Claim
172 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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).
Claim 39
Independent Claim
172 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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).
Claim 40
Dependent Claim
14 words
The method of claim 34, wherein said alkyl haloacetate is a tertiary alkyl haloacetate.
Claim 41
Dependent Claim
12 words
The method of claim 34, wherein said non-antigenic polymer is polyethylene glycol.
Claim 42
Dependent Claim
43 words
The method of claim 35, wherein said tertiary alkyl haloacetate comprises the formula: ##STR42## wherein: X 3 is chlorine, bromine or iodine; and R 10-12 are independently selected from the group consisting of C 1-8 alkyls, or C 1-8 branched alkyls and aryls.
Claim 43
Dependent Claim
15 words
The method of claim 37, wherein said tertiary alkyl haloacetate is a tertiary butyl haloacetate.
Claim 44
Independent Claim
140 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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.
Claim 45
Independent Claim
140 words
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 1 -C 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 2 ; where Q is H, C 1-8 alkyl, C 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.
Claim 46
Independent Claim
127 words
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 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 2 ; where Q is H, C 1-8 alkyl, C 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.
Claim 47
Independent Claim
127 words
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 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 2 ; where Q is H, C 1-8 alkyl, C 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.
References Cited (Backward Citations)
US4179337A
Cited
US4101380A
Cited
US4275000A
Cited
US5217564A
Cited
US4766106A
Cited
US4680338A
Cited
US4889916A
Cited
EP0236987A2
Cited
US5229490A
Cited
US4846548A
Cited
US4904582A
Cited
US5093531A
Cited
US5214131A
Cited
US5091176A
Cited
US5122614A
Cited
US5324844A
Cited
WO1991002763A1
Cited
US5091542A
Cited
US5183660A
Cited
US5545698A
Cited
US5252714A
Cited
EP0510356A1
Cited
US5281698A
Cited
EP0539167A2
Cited
WO1993024476A1
Cited
US5514379A
Cited
US5298643A
Cited
US5349001A
Cited
US5321095A
Cited
US5543158A
Cited
US5643575A
Cited
US5681567A
Cited
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