Methods of using conjugated toxin peptide therapeutic agents
First Claim
1. A method of mitigating a relapse of a symptom of multiple sclerosis, comprising administering to a patient, who has been diagnosed with multiple sclerosis, an effective amount of 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 immunonlobulin light chain and heavy chain an immunoglobulin Fc 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; 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, such that the symptom of multiple sclerosis is mitigated.
1 Assignment
0 Petitions
Accused Products
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.
-
Citations
12 Claims
-
1. A method of mitigating a relapse of a symptom of multiple sclerosis, comprising administering to a patient, who has been diagnosed with multiple sclerosis, an effective amount of a composition of matter of the formula
(X1)a—- (F1)d—
(X2)b—
(F2)e—
(X3)cand 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 immunonlobulin light chain and heavy chain an immunoglobulin Fc 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; 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, such that the symptom of multiple sclerosis is mitigated. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
(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.
- (F1)d—
-
9. The method of claim 1 or claim 2, wherein the OSK1 peptide analog of the composition of matter 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.
-
-
10. The method of claim 1 or claim 2, wherein the OSK1 peptide analog of the composition of matter 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.
-
-
11. The method of claim 1 or claim 2, wherein the OSK1 peptide analog of the composition of matter is covalently linked at its N-terminal to a moiety selected from acyl, aryl, fatty acid, or polyethylene glycol.
-
12. The method of claim 1 or claim 2, wherein the OSK1 peptide analog of the composition of matter is covalently linked at its N-terminal to a polyethylene glycol.
-
2. A method of treating an autoimmune disorder, comprising administering to a patient who has been diagnosed with an autoimmune disorder selected from multiple sclerosis, type 1 diabetes, psoriasis, inflammatory bowel disease (IBD), 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, a therapeutically effective amount of a composition of matter of the formula
(X1)a—- (F1)d—
(X2)b—
(F2)e—
(X3)cand 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 Fc 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; 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, whereby at least one symptom of the disorder is alleviated in the patient.
- (F1)d—
Specification