Therapeutic Peptides

• US 20080254020A1
• Filed: 07/08/2005
• Published: 10/16/2008
• Est. Priority Date: 07/08/2004
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Walker, Kenneth W., Sitney, Karen C., Kinstler, Olaf B.
• Granted Patent: US 8,143,380 B2
• Time in Patent Office: Days
• US Class Current: 424/130.1
• 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: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

The invention relates to compounds that exhibit improved bioefficacy in multidose administration. More specifically, the invention relates to polypeptides or peptides modified to include an antibody Fc region and one or more water soluble polymers.

Claims

1. A substantially homogenous compound comprising a structure set out in Formula I,

[(X¹)_a—

F¹—

(X²)_b]-(L¹)_c-WSP_d 

 

Formula I

wherein;

F¹ is a vehicle;

X¹ is selected from

P¹-(L²)_e—

P²-(L³)_f-P¹-(L²)_e

P³-(L⁴)_g-P²-(L³)_f-P¹—

-(L²)_e- and

P⁴ (L⁵)_h-P³-(L⁴)_g-P²-(L³)_f-P¹-(L²)_e-

X² is selected from;

-(L²)_e-P¹,

-(L²)_e-P¹-(L³)_f-P²,

-(L²)_e-P¹-(L³)_f-P²-(L⁴)_g-P³, and

-(L²)_e-P¹-(L³)_f-P²-(L⁴)_g-P³-(L⁵)_h-P⁴

wherein P¹, P², P³, and P⁴ are each independently sequences of pharmacologically active peptides;

L¹, L², L³, L⁴, and L⁵ are each independently linkers;

a, b, c, e, f, g, and h are each independently 0 or 1,

provided that at least one of a and b is 1;

d is at least 1; and

WSP is a water soluble polymer, the attachment of which is effected at any reactive moiety in F¹;

said compound having a property of improved bioefficacy when administered in a multidose regimen.

2. The compound of claim 1 which is a multimer.

3. The compound of claim 2 which is a dimer.

4. The compound of claim 1 comprising a structure set out in Formula II

[X¹—

F¹]-(L¹)_c-WSP_d 

 

Formula II

wherein F¹ is an Fc domain and is attached at the C-terminus of X¹, and one or more WSP is attached to the Fc domain, optionally through linker L¹;

5. The compound of claim 4 which is a multimer.

6. The compound of claim 5 which is a dimer.

7. The compound of claim 1 comprising a structure set out in Formula III

[F¹—

X²]-(L¹)_c-WSP_d 

 

Formula III

wherein F¹ is an Fc domain and is attached at the N-terminus of X², and one or more WSP is attached to the Fc domain, optionally through linker L¹;

8. The compound of claim 7 which is a multimer.

9. The compound of claim 8 which is a dimer.

10. The compound of claim 1 comprising a structure set out in Formula IV

[F¹-(L²)_e-P¹]-(L¹)_c-WSP_d 

 

Formula IV

wherein F¹ is an Fc domain and is attached at the N-terminus of -(L¹)_c-P¹ and one or more WSP is attached to the Fc domain, optionally through linker L¹.

11. The compound of claim 10 which is a multimer.

12. The compound of claim 11 which is a dimer.

13. The compound of claim 1 comprising a structure set out in Formula V

[F¹-(L²)_e-P¹-(L³)_f-P²]-(L¹)_c-WSP_d 

 

Formula V

wherein F¹ is an Fc domain and is attached at the N-terminus of -L²-P¹-L³-P² and one or more WSP is attached to the Fc domain, optionally through linker L¹.

14. The compound of claim 10 which is a multimer.

15. The compound of claim 11 which is a dimer.

16. The compound of claim 1 wherein P¹ and/or P² are independently selected from a peptide set out in any one of Tables 4 through 20.

17. The compound of claim 16 wherein P¹ and/or P² have the same amino acid sequence.

18. The compound of claim 1 wherein F¹ is an Fc domain.

19. The compound of claim 1 wherein WSP is PEG.

20. The compound of claim 1, wherein F¹ is an Fc domain and WSP is PEG.

21. The compound of claim 19 wherein PEG has a molecular weight of between about 2 kDa and 100 kDa.

22. The compound of claim 21 wherein said PEG has a molecular weight of between about 6 kDa and 25 kDa.

23. A composition comprising the compound of claim 19, wherein said composition comprises the PEGylated compound in an amount selected from the group consisting of:

at least 50% PEGylated compound, at least 75% PEGylated compound, at least 85% PEGylated compound, at least 90% PEGylated compound, at least 95% PEGylated compound.

28. A method of treating a disease or disorder comprising administering a composition comprising the compound of claim 1 in an amount effective to treat the disease or disorder.

29. The method of claim 28, wherein said amount is from 0.1-1000 μ

g/kg—

of body weight or from 0.1-150 μ

g/kg body weight.

30. A pharmaceutical composition comprising the compound of claim 1 in admixture with a pharmaceutically acceptable carrier thereof.

31. A polynucleotide that encodes a compound comprising the structure selected from the group consisting of:

(a) [(X¹)_a—

F¹—

(X²)_b]-(L¹)_c as defined in claim 1;

(b) [X¹—

F¹]-(L¹)_c as defined in claim 4;

(c) [F¹—

X²]-(L¹)_c as defined in claim 7;

(d) [F¹-(L²)_e-P¹]-(L¹)_c as defined in claim 10; and

(e) [F¹-(L²)_e-P¹-(L³)_f-P²]-(L¹)_c as defined in claim 13.

32. A vector that comprises the polynucleotide of claim 31.

33. A host cell that comprises the vector of claim 32.

34. A method of producing a compound of claim 1 comprising growing the host cell of claim 33 in a suitable nutrient medium.

35. The method of claim 34 further comprising isolating said compound from said cell or nutrient medium.

36. The method of claim 34 or 35 further comprising pegylating said compound.

24-27. -27. (canceled)