Toxin peptide therapeutic agents

• US 7,833,979 B2
• Filed: 04/17/2006
• Issued: 11/16/2010
• Est. Priority Date: 04/22/2005
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: McDonough, Stefan I., Nguyen, Hung Q., Miranda, Leslie P., McGivern, Joseph G., Sullivan, John K., Walker, Kenneth W., Hu, Shaw-Fen Sylvia, Gegg, Colin V.
• Primary Examiner(s): Desai; Anand U
• Application Number:
  US11/406,454
• Publication Number:
  US 20070071764A1
• Time in Patent Office: 1,674 Days
• Field of Search: None
• US Class Current: 514/9.7
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/43504 from invertebrates
• 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 2319/55 containing a fusion with a toxin, e.g. diphteria toxin

Abstract

Disclosed is a composition of matter of the formula
(X¹)_a—(F¹)_d—(X²)_b—(F²)_e—(X³)_c  (I)
and multimers thereof, in which F¹ and F² are half-life extending moieties, 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; L is an optional linker; and a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1. Linkage to the half-life extending moiety or moieties increases the in vivo half-life of the toxin peptide, which otherwise would be quickly degraded. A pharmaceutical composition comprises the composition and a pharmaceutically acceptable carrier. Also disclosed are a DNA encoding the inventive composition of matter, an expression vector comprising the DNA, and a host cell comprising the expression vector. Methods of treating an autoimmune disorder, such as, but not limited to, multiple sclerosis, type 1 diabetes, psoriasis, inflammatory bowel disease, contact-mediated dermatitis, rheumatoid arthritis, psoriatic arthritis, asthma, allergy, restinosis, systemic sclerosis, fibrosis, scleroderma, glomerulonephritis, Sjogren syndrome, inflammatory bone resorption, transplant rejection, graft-versus-host disease, and lupus 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

or multimers thereof, wherein;

F¹ and F² are half-life extending moieties, 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)₉-, and f and g are each independently 0 or 1;

P is a ShK peptide analog of no more than about 80 amino acid residues in length, comprising the amino acid sequence of SEQ ID NO;

914, SEQ ID NO;

915, SEQ ID NO;

916, or SEQ ID NO;

917, and comprising at least two intrapeptide disulfide bonds;

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;

or a physiologically acceptable salt thereof.

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)_g-F²-(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 is 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 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.

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

12. The composition of matter of claim 11, wherein the human IgG. Fc domain comprises a human IgG1 Fc domain.

13. The composition of matter of claim 11, wherein the human IgG Fc domain comprises a human IgG2 Fc domain.

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

15. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a sequence selected from the group consisting of 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).

16. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a human serum albumin protein domain.

17. The composition of matter of claim 1, wherein F or F², or both, comprises a transthyretin protein domain.

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

19. The composition of matter of claim 18, wherein the biologically suitable polymer is polyethylene glycol (PEG) of molecular mass about 1,000 Da to about 100,000 Da.

20. The composition of matter of claim 19, wherein the PEG is selected from the group consisting of 5 kD and 20 kD PEG.

21. The composition of matter of any of claim 5, 6, 8, or 9, wherein F¹ is an human IgG Fc domain or HSA, and F² is PEG.

22. The composition of matter of any of claim 5, 6, 7 or 9, wherein F² is an human IgG Fc domain or HSA and F¹ is PEG.

23. The composition of matter of claim 1, further comprising one or more PEG moieties conjugated to a non-PEG F¹ or non-PEG F², or to P, or to any combination of any of these.

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

26. A pharmaceutical composition, comprising the composition of claim 1 or claim 25;

and a pharmaceutically acceptable carrier.

27. The composition of matter of claim 1, wherein any f or any g is 1, and L is a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:

79, 84, and 637 through 656.

28. The composition of matter of claim 1 or claim 25, comprising a ShK peptide analog that comprises the amino acid sequence of SEQ ID NO:

914.

29. The composition of matter of claim 1 or claim 25, comprising a ShK peptide analog that comprises the amino acid sequence of SEQ ID NO:

915.

30. The composition of matter of claim 1 or claim 25, comprising a ShK peptide analog that comprises the amino acid sequence of SEQ ID NO:

916.

31. The composition of matter of claim 1 or claim 25, comprising a ShK peptide analog that comprises the amino acid sequence of SEQ ID NO:

917.

25. A composition of matter, comprising a ShK peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

914 through 917 as set forth in Table 2, or a physiologically acceptable salt thereof.