Conjugated toxin peptide therapeutic agents

• US 7,820,623 B2
• Filed: 10/25/2007
• Issued: 10/26/2010
• Est. Priority Date: 10/25/2006
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Nguyen, Hung Q., Adler, Beverly S., Miranda, Leslie P., McGivern, Joseph G., Khare, Taruna Arora, Sullivan, John K., Martin, Francis H., Walker, Kenneth W., Gegg, Colin V. Jr., Hu, Shaw-Fen Sylvia
• Primary Examiner(s): Cordero Garcia; Marcela M
• Application Number:
  US11/978,076
• Publication Number:
  US 20090291885A1
• Time in Patent Office: 1,097 Days
• Field of Search: None
• US Class Current: 514/17.4
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/43522 from scorpions
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/31 fusions, other than Fc, for prolonged plasma life, e.g. albumin

Abstract

Disclosed is a composition of matter comprising an OSK1 peptide analog, and in some embodiments, a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises the composition and a pharmaceutically acceptable carrier. Also disclosed are DNAs encoding the inventive composition of matter, an expression vector comprising the DNA, and host cells comprising the expression vector. Methods of treating an autoimmune disorder and of preventing or mitigating a relapse of a symptom of multiple sclerosis are also disclosed.

Claims

1. A composition of matter of the formula

(X¹)_a—

(F¹)_d—

(X²)_b—

(F²)_e—

(X³)_c

and multimers thereof, wherein;

F¹ and F² are half-life extending moieties, wherein F¹ or F², or both is a polyethylene glycol, a copolymer of ethylene glycol, a polypropylene glycol, a copolymer of propylene glycol, a carboxymethylcellulose, a polyvinyl pyrrolidone, a poly-1,3-dioxolane , a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid, a dextran n-vinyl pyrrolidone, a poly n-vinyl pyrrolidone, a propylene glycol homopolymer, a propylene oxide polymer, an ethylene oxide polymer, a polyoxyethylated polyol, a polyvinyl alcohol, a linear or branched glycosylated chain, a polyacetal, a long chain fatty acid, a long chain hydrophobic aliphatic group, an immunoglobulin light chain and heavy chain, an immunoglobulin F_c domain or portion thereof, a CH2 domain of Fc, an Fc domain loop, an albumin, an albumin-binding protein, a transthyretin, a thyroxine-binding globulin, or a ligand that has an affinity for a long half-life serum protein, said ligand being selected from the group consisting of peptide ligands and small molecule ligands;

or a combination of any of these members; and

d and e are each independently 0 or 1, provided that at least one of d and e is 1;

X¹, X², and X³ are each independently -(L)_f-P-(L)_g, and f and g are each independently 0 or 1;

P is a toxin peptide of no more than about 80 amino acid residues in length, comprising at least two intrapeptide disulfide bonds, and at least one P is an OSK1 peptide analog comprising the amino acid sequence of SEQ ID NO;

4916;

L is a linker; and

a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1.

2. The composition of matter of claim 1 of the formula P-(L)_g-F¹.

3. The composition of matter of claim 1 of the formula F¹-(L)_f-P.

4. The composition of matter of claim 1 of the formula P-(L)_g-F¹-(L) _f-P.

5. The composition of matter of claim 1 of the formula F¹-(L)_f-P-(L) _g-F².

6. The composition of matter of claim 1 of the formula F¹-(L)_f-P-(L)_gF ²-(L)_f-P.

7. The composition of matter of claim 1 of the formula F¹-F²-(L)_f-P.

8. The composition of matter of claim 1 of the formula P-(L)_g-F¹-F².

9. The composition of matter of claim 1 of the formula P-(L)_g-F¹-F²-(L) _f-P.

10. The composition of matter of claim 1 wherein F¹ or F², or both, comprises a human IgG Fc domain or a portion thereof.

11. The composition of matter of claim 1, wherein F¹ and F² are different half-life extending moieties.

12. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a sequence selected from SEQ ID NOS:

2, 4, 70, 71, 72, 74, 75, 76, 1340 through 1342, and 1359 through 1363 as set forth in FIGS. 3, 4, 11A-C, 12A-C, and 12E-F.

13. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a biologically suitable polymer or copolymer.

14. The composition of matter of claim 1, in which the toxin peptide is inserted into a human IgG1 Fc domain loop.

15. The composition of matter of claim 1, wherein the C-terminal carboxylic acid moiety of the OSK1 peptide analog is replaced with a moiety selected from

(A) —

COOR, where R is independently (C₁-C₈)alkyl, haloalkyl, aryl or heteroaryl;

(B) —

C(═

O)NRR, where R is independently hydrogen, (C₁-C₈)alkyl, haloalkyl, aryl or heteroaryl; and

(C) —

CH₂OR where R is hydrogen, (C₁-C₈) alkyl, aryl or heteroaryl.

16. The composition of matter of claim 1, wherein the OSK1 peptide analog is conjugated to a polyethylene glycol (PEG) via:

(a) 1, 2, 3 or 4 amino functionalized sites of the PEG;

(b) 1, 2, 3 or 4 thiol functionalized sites of the PEG;

(c) 1, 2, 3 or 4 maleimido functionalized sites of the PEG;

(d) 1, 2, 3 or 4 N-succinimidyl functionalized sites of the PEG;

(e) 1, 2, 3 or 4 carboxyl functionalized sites of the PEG;

or

(f) 1, 2, 3 or 4 p-nitrophenyloxycarbonyl functionalized sites of the PEG.

17. The composition of matter of claim 1, wherein the OSK1 peptide analog is conjugated to an acyl, aryl, fatty acid, or polyethylene glycol (PEG) via:

(a) 1, 2, 3 or 4 amino functionalized sites in the OSK1 peptide analog;

(b) 1, 2, 3 or 4 thiol functionalized sites in the OSK1 peptide analog;

(c) 1 or 2 ketone functionalized sites in the OSK1 peptide analog;

(d) 1 or 2 azido functionalized sites in the OSK1 peptide analog;

(e) 1 or 2 carboxyl functionalized sites in the OSK1 peptide analog;

(f) 1 or 2 aminooxy functionalized sites in the OSK1 peptide analog;

or

(g) 1 or 2 seleno functionalized sites in the OSK1 peptide analog.

18. The composition of matter of claim 1, wherein the OSK1 peptide analog is covalently linked at its N-terminal to a moiety selected from acyl, aryl, fatty acid, or polyethylene glycol.

19. The composition of matter of claim 1, wherein the OSK1 peptide analog is covalently linked at its N-terminal to a moiety selected from benzyl, dibenzyl, benzoyl, benzyloxycarbonyl, N,N-dimethylglycine, creatine, formyl, acetyl, propanoyl, butanyl, heptanyl, hexanoyl, octanoyl, nonanoyl, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid.

20. The composition of matter claim 1, further comprising, covalently bound to F1, F2, or to P, an additional agonistic peptide or an antagonistic peptide, in relation to the activity of the OSK1 peptide analog, or a targeting peptide.

21. A pharmaceutical composition, comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

22. A composition of matter of the formula

(X¹)_a—

(F¹)_d—

(X²)_b—

(F²)_e—

(X³)_c

and multimers thereof, wherein;

F¹ and F² are half-life extending moieties selected from an acyl, aryl, fatty acid, and polyethylene glycol (PEG), and d and e are each independently 0 or 1, provided that at least one of d and e is 1;

X¹, X², and X³ are each independently -(L)_f-P-(L)_g-, and f and g are each independently 0 or 1;

P is an OSK1 peptide analog of no more than about 80 amino acid residues in length, comprising at least two intrapeptide disulfide bonds, comprising the amino acid sequence of SEQ ID NO;

4916;

L is a linker;

a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1; and

the toxin peptide is conjugated to F¹ or F², or both, via;

(a) 1, 2, 3 or 4 amino functionalized sites in the toxin peptide;

(b) 1, 2, 3 or 4 thiol functionalized sites in the toxin peptide;

(c) 1 or 2 ketone functionalized sites in the toxin peptide;

(d) 1 or 2 azido functionalized sites in the toxin peptide;

(e) 1 or 2 carboxyl functionalized sites in the toxin peptide;

(f) 1 or 2 aminooxy functionalized sites in the toxin peptide;

or

(g) 1 or 2 seleno functionalized sites in the toxin peptide.

23. A pharmaceutical composition, comprising the composition of claim 22 and a pharmaceutically acceptable carrier.