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Claims for Patent: 4,179,337

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Claims for Patent: 4,179,337

Title: Non-immunogenic polypeptides
Abstract:Polypeptides such as enzymes and insulin are coupled to polyethylene glycol or polypropropylene glycol having a molecular weight of 500 to 20,000 daltons to provide a physiologically active non-immunogenic water soluble polypeptide composition. The polyethylene glycol or polypropylene glycol protect the polypeptide from loss of activity and the composition can be injected into the mammalian circulatory system with substantially no immunogenic response.
Inventor(s): Davis; Frank F. (East Brunswick, NJ), Van Es; Theodorus (Piscataway, NJ), Palczuk; Nicholas C. (Bound Brook, NJ)
Assignee:
Application Number:05/819,831
Patent Claims: 1. A physiologically active, substantially non-immunogenic water soluble polypeptide composition comprising, a physiologically active polypeptide coupled with a coupling agent to

at least one substantially linear polymer having a molecular weight of between about 500 to about 20,000 daltons selected from the group consisting of polyethylene glycol and polypropropylene glycol

wherein the polymer is unsubstituted or substituted by alkoxy or alkyl groups, said alkoxy or alkyl group possessing less than 5 carbon atoms.

2. The polypeptide composition of claim 1 wherein the polypeptide is selected from the group consisting of insulin, ACTH, glucagon, somatostatin, somatotropin, thymosin, parathyroid hormone, pigmentary hormones, somatomedin, etythropoietin, luteinizing hormone, chorionic gonadotropin, hypothalmic releasing factors, antidiuretic hormones, thyroid stimulating hormone and prolactin.

3. The polypeptide composition of claim 2 wherein the polypeptide is insulin.

4. The polypeptide composition of claim 1 wherein the polymer has a molecular weight of between about 750 and 2,000 daltons.

5. The polypeptide composition of claim 4 which comprises between 10 and 100 polymer moieties per molecule of insulin.

6. The polypeptide composition of claim 1 wherein the polymer is polyethylene glycol.

7. The polypeptide composition of claim 4 wherein the polypeptide is insulin.

8. The polypeptide composition of claim 6 wherein the polypeptide is insulin.

9. The polypeptide composition of claim 1 wherein the group between the polypeptide and the polymer has the formula selected from the group consisting of ##STR14## wherein the bond designated--.multidot. of each group is attached to the polypeptide provided that in the case where the group is ##STR15## portion is part of the polypeptide carboxy group.

10. The polypeptide composition of claim 9 wherein the polypeptide is insulin.

11. The polypeptide composition of claim 10 wherein the group is ##STR16##

12. The polypeptide composition of claim 11 wherein the polymer is polyethylene glycol.

13. A substantially non-immunogenic insulin-containing composition comprising the insulin composition of claim 3 and a pharmaceutically acceptable injectable carrier.

14. A process of preparing a physiologically active, substantially non-immunogenic water soluble polypeptide composition from a polypeptide; originally having physiological activity and immunogenicity which comprises the steps of:

(a) reacting at least one terminal carbon atom bearing a hydroxy group, of a substantially straight chain polymer selected from the group consisting of polyethylene glycol and polypropylene glycol having a molecular weight of from about 500 to about 20,000 daltons said polymer being unsubstituted or substituted by alkoxy or alkyl groups, said alkoxy or alkyl groups having less than 5 carbon atoms with a coupling agent to provide an activated polymer containing a reactive terminal group, and;

(b) reacting a physiologically active immunogenic poly peptide with from 10 to 100 moles of said activated polymer per mole of poly peptide by coupling said polypeptide to the reactive terminal group of the polymer to provide said water soluble polypeptide composition.

15. A process of claim 14 wherein the coupling agent is cyanuric chloride.

16. A process of claim 15 wherein the polypeptide is insulin.

17. A physiologically active substantially non-immunogenic water soluble enzyme composition comprising a physiologically active enzyme coupled with a coupling agent to

at least one substantially linear polymer selected from the group consisting of polyethylene glycol and polypropylene glycol having molecular weight of between 500 and 20,000 daltons

wherein the polymer moiety is unsubstituted or substituted by alkoxy or alkyl groups, said alkoxy or alkyl group possessing less than 5 carbon atoms.

18. The enzyme composition of claim 17 wherein the polymer has a molecular weight of between about 500 and about 5,000 daltons.

19. The enzyme composition of claim 17 which comprises between 10 and 100 polymer moieties per molecule of enzyme.

20. The enzyme composition of claim 17 wherein the polymer is polyethylene glycol.

21. The enzyme composition of claim 17 wherein the enzyme is selected from the group consisting of oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases.

22. The enzyme composition of claim 17 wherein the group between the enzyme and the polymer has the formula selected from the group consisting of ##STR17## wherein the bonds designated--.multidot. of each group is attached to the enzyme provided that in the case where the group is ##STR18## portion is part of the polypeptide carboxy group.

23. A process of preparing a physiologically active, substantially non-immunogenic water soluble enzyme composition from an enzyme originally having physiological activity and immunogenicity which comprises the steps of:

(a) reacting at least one terminal carbon atom bearing a hydroxy group, of a substantially straight chain polymer selected from the group consisting of polyethylene glycol and polypropylene glycol having a molecular weight of from about 500 to about 20,000 daltons said polymer being unsubstituted or substituted by alkoxy or alkyl groups, said alkoxy or alkyl groups having less than 5 carbon atoms with a coupling agent to provide an activated polymer containing a reactive terminal group, and

(b) reacting a physiologically active immunogenic enzyme with from 10 to 100 moles of said activated polymer per mole of enzyme by coupling the enzyme to the reactive terminal group of said polymer to provide said water soluble enzyme composition.

24. The process of claim 23 wherein the enzyme is selected from the group consisting of oxidoreductases, transrerases, hydrolases, lysases, isomerases, and ligases.

25. A process of claim 24 wherein the coupling moiety is cyanuric chloride.

26. A process of claim 24 wherein the polymer is polyethylene glycol.

27. A process of claim 26 wherein the coupling moiety is cyanuric chloride.
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