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Claims for Patent: 5,919,455

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Claims for Patent: 5,919,455

Title: Non-antigenic branched polymer conjugates
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.
Inventor(s): Greenwald; Richard B. (Somerset, NJ), Martinez; Anthony J. (Hamilton Square, NJ)
Assignee: Enzon, Inc. (Piscataway, NJ)
Application Number:08/821,055
Patent Claims: 1. A branched substantially non-antigenic polymer comprising the formula:

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.

2. The polymer of claim 1, wherein at least one (R) is a straight-chained polymer.

3. The polymer of claim 1, wherein at least one (R) is a poly(alkylene oxide).

4. 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).

5. The polymer of claim 4, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.

6. The polymer of claim 5, wherein said poly(alkylene oxide) has a number average molecular weight between 2,000 and about 42,000.

7. The polymer of claim 6, wherein said poly(alkylene oxide) has a number average molecular weight between 5,000 and about 20,000.

8. The polymer of claim 1, wherein each (R) is a poly(ethylene glycol).

9. The polymer of claim 1, wherein (m) is zero.

10. The polymer of claim 1, wherein said C.sub.1 -C.sub.4 terminal group is methoxy.

11. The polymer of claim 1, wherein (n) is two.

12. 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.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

R.sub.2 is a spacer moiety selected form the group consisting of:

13. The polymer of claim 1, further comprising a spacer moiety proximal to said (L).

14. The polymer of claim 1, wherein at least one (R) further comprises a functional group capable of covalently bonding with nucleophiles.

15. 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:

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.

16. A polymer conjugate prepared by reacting the branched substantially non-antigenic polymer of claim 1 with a nucleophile.

17. The conjugate of claim 16, wherein at least one (R) is a poly(alkylene oxide).

18. The conjugate of claim 17, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.

19. The conjugate of claim 16, wherein each (R) is a poly(ethylene glycol).

20. The conjugate of claim 16, wherein said nucleophile is selected from consisting of proteins, peptide and polypeptides.

21. 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.

22. 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.

23. 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.

24. A branched substantially non-antigenic polymer comprising the formula:

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.

25. The polymer of claim 24, wherein at least one (R) is a poly(alkylene oxide).

26. The polymer of claim 24, wherein said poly(alkylene oxide) has a number average molecular weight between about 200 and about 80,000.

27. The polymer of claim 26, wherein said poly(alkylene oxide) has a number average molecular weight between 2,000 and about 42,000.

28. The polymer of claim 27, wherein said poly(alkylene oxide) has a number average molecular weight of about 5,000 to about 20,000.

29. The polymer of claim 24, wherein each (R) is a poly(ethylene glycol).

30. The polymer of claim 24, wherein said C.sub.1 -C.sub.4 terminal group is methoxy.

31. The polymer of claim 24, wherein (n) is two.

32. 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.sub.2 is a spacer moiety selected form the group consisting of: polymers, --CO--NH--(CH.sub.2 --).sub.d X.sub.2, --CO--NH--(CH.sub.2 --CH.sub.2 --O--).sub.d X.sub.2, ##STR39## where (d) is an integer between 1 and 18 inclusive and (X.sub.2) is H, OH, NH.sub.2 or COOH.

33. 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:

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.

34. 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:

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:

35. The method of claim 34, wherein said alkyl haloacetate is a tertiary alkyl haloacetate.

36. The method of claim 34, wherein said non-antigenic polymer is polyethylene glycol.

37. The method of claim 35, wherein said tertiary alkyl haloacetate comprises the formula: ##STR42## wherein: X.sub.3 is chlorine, bromine or iodine; and

R.sub.10-12 are independently selected from the group consisting of C.sub.1-8 alkyls, or C.sub.1-8 branched alkyls and aryls.

38. The method of claim 37, wherein said tertiary alkyl haloacetate is a tertiary butyl haloacetate.

39. 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:

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.

40. 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:

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.
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