Toxin peptide therapeutic agents
Disclosed is a composition of matter of the formula (X 1 ) a —(F 1 ) d —(X 2 ) b —(F 2 ) e —(X 3 ) c (I) and multimers thereof, in which F 1 and F 2 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; X 1 , X 2 , and X 3 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.
1. A composition of matter of the formula
(X 1 )a—(F 1 )d—(X 2 )b—(F 2 )e—(X 3 )c
or multimers thereof, wherein:
F 1 and F 2 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;
X 1 , X 2 , and X 3 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 -F 1 .
3. The composition of matter of claim 1 of the formula F 1 -(L) f -P.
4. The composition of matter of claim 1 of the formula P-(L) g -F 1 -(L) f -P.
5. The composition of matter of claim 1 of the formula F 1 -(L) f -P-(L) g -F 2 .
6. The composition of matter of claim 1 of the formula F 1 -(L) f -P-(L) g -F 2 -(L) f -P.
7. The composition of matter of claim 1 of the formula F 1 -F 2 -(L) f -P
8. The composition of matter of claim 1 of the formula P-(L) g -F 1 -F 2 .
9. The composition of matter of claim 1 of the formula P-(L) g -F 1 -F 2 -(L) f -P.
10. The composition of matter of claim 1 , wherein F 1 or F 2 , 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 F 1 or F 2 , 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 F 1 and F 2 are different half-life extending moieties.
15. The composition of matter of claim 1 , wherein F 1 or F 2 , 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 , 11 A-C, 12 A-C, and 12 E-F).
16. The composition of matter of claim 1 , wherein F 1 or F 2 , or both, comprises a human serum albumin protein domain.
17. The composition of matter of claim 1 , wherein F or F 2 , or both, comprises a transthyretin protein domain.
18. The composition of matter of claim 1 , wherein F 1 or F 2 , 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 F 1 is an human IgG Fc domain or HSA, and F 2 is PEG.
22. The composition of matter of any of claim 5 , 6 , 7 or 9 , wherein F 2 is an human IgG Fc domain or HSA and F 1 is PEG.
23. The composition of matter of claim 1 , further comprising one or more PEG moieties conjugated to a non-PEG F 1 or non-PEG F 2 , 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.
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.
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.