US2009068139A1PendingUtilityA1
LOOP PEPTIDE AND TGF alpha FOR STIMULATING STEM CELL PROLIFERATION AND MIGRATION
Individually held — no corporate assignee on recordPriority: Apr 26, 1999Filed: Oct 31, 2007Published: Mar 12, 2009
Est. expiryApr 26, 2019(expired)· nominal 20-yr term from priority
A61P 43/00A61P 7/00A61P 37/00A61P 3/10A61P 39/02A61P 9/10A61P 27/02A61P 31/22A61P 25/00A61P 31/18A61P 29/00A61P 25/14A61P 25/28A61P 25/16A61P 25/18A61P 31/04A61P 35/00A61P 31/12A61P 25/32A61P 27/06A61P 1/04A61K 48/00C07K 14/495A61P 1/00A61P 1/14A61K 38/00A61P 1/02A61P 21/00A61P 19/00Y02A50/30
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Claims
Abstract
There is disclosed a novel genus of small peptides, smaller than human TGFα, identified as having TGFα biological activity and therefore being useful as pharmacologic agents. It is further disclosed that both TGFα and the genus of small peptides disclosed herein have therapeutic activity to stimulate hematopoiesis, e.g., in patients undergoing cytotoxic cancer chemotherapy, and also act as cytoprotective agents to protect patients undergoing cancer cytotoxic therapy from gastrointestinal (GI) side effects, such as mucositis, and otherwise to support the barrier function of the GI tract, such as when it is harmed by cytotoxic therapy.
Claims
exact text as granted — not AI-modified1 . A transforming growth factor-α (TGFα) mimetic peptide pharmaceutical formulation for oral administration, comprising:
(a) a polypeptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
wherein Cys at position 11 in SEQ ID NO:4 comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity; and
(b) a pharmaceutically acceptable carrier for oral administration.
2 . A method for treating or preventing gastrointestinal tract mucositis, comprising:
administering a transforming growth factor-α (TGFα) mimetic peptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
wherein Cys at position 11 in SEQ ID NO:4 comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity, and thereby treating or preventing the gastrointestinal tract mucositis.
3 . The method of claim 2 wherein the TGFα mimetic peptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally.
4 . A method for stimulating repair of gastrointestinal tract mucosal epithelium, comprising:
administering a transforming growth factor-α (TGFα) mimetic peptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
wherein Cys at position 11 in SEQ ID NO:4 comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity, and thereby stimulating repair of gastrointestinal tract mucosal epithelium.
5 . The method of claim 4 wherein the TGFα mimetic peptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally.
6 . The method of claim 4 wherein stimulating repair of gastrointestinal tract mucosal epithelium comprises increasing in number intestinal epithelial goblet cells to a level higher than is found in normal intestine.
7 . A method for treating or preventing an inflammatory reaction, comprising:
administering a transforming growth factor-α (TGFα) mimetic peptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4 wherein Cys at position 11 in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity, and thereby treating or preventing the inflammatory reaction.
8 . The method of claim 7 wherein the inflammatory reaction results from an autoimmune disease.
9 . The method of claim 8 wherein the autoimmune disease is selected from type II diabetes, rheumatoid arthritis, lupus erythematosus, multiple sclerosis and Crohn's disease.
10 . The method of claim 7 wherein the transforming growth factor-α (TGFα) mimetic peptide prevents mast cell degranulation.
11 . The method of claim 7 wherein the inflammatory reaction results from inflammatory bowel disease, colitis or Crohn's disease.
12 . The method of claim 7 wherein the TGFα mimetic peptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally.
13 . A method for enhancing or augmenting hematopoiesis, comprising:
administering a transforming growth factor-α (TGFα) mimetic peptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4 wherein Cys at position 11 in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity, and thereby enhancing or augmenting hematopoiesis.
14 . The method of claim 13 wherein the TGFα mimetic peptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally.
15 . The method of claim 13 further comprising administering a hematopoietic growth factor agent that is selected from the group consisting of erythropoietin, thrombopoietin, G-CSF, GM-CSF and stem cell factor (SCF).
16 . (canceled)
17 . A method for treating a neurological deficit that is caused by at least one of (i) a degenerative disease, (ii) a traumatic or neurotoxic injury, (iii) ischemia, (iv) a developmental disorder, (v) a disorder affecting vision caused by loss or failure of retinal cells, (vi) a spinal cord injury, (vii) a demyelinating autoimmune disorder, and (viii) an infectious or inflammatory disease, said method comprising:
administering a transforming growth factor-α (TGFα) mimetic peptide that comprises (i) a first amino acid sequence as set forth in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
wherein Cys at position 11 in SEQ ID NO:4 comprises a C terminus, and (ii) added to the C terminus of (i), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences, wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and wherein the TGFα mimetic peptide exhibits TGFα biological activity, and thereby treating the neurological deficit.
18 . The method of claim 17 wherein the TGFα mimetic peptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally.
19 . The method of claim 17 wherein:
(i) the degenerative disease is selected from the group consisting of Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD), Pick's disease, progressive supranuclear palsy, striatonigral degeneration, cortico-basal degeneration, olivopontocerebellar atrophy, Leigh's disease, infantile necrotizing encephalomyelopathy, Hunter's disease, mucopolysaccharidosis, Krabbe's disease, Pelizaeus-Merzbacher disease, amaurotic (familial) idiocy, Kuf's disease, Spielmayer-Vogt disease, Tay Sachs disease, Batten disease, Jansky-Bielschowsky disease, Reye's disease, cerebral ataxia, chronic alcoholism, beriberi, Hallervorden-Spatz syndrome, and cerebellar degeneration, (ii) the traumatic or neurotoxic injury is selected from the group consisting of a gunshot wound, a blunt force injury, a penetration injury, an injury caused by a surgical procedure, poisoning, shaken baby syndrome, an adverse reaction to a medication, a drug overdose, and post-traumatic encephalopathy, (iii) the ischemia results from at least one of stroke, anoxia, hypoxia, partial drowning, myoclonus, severe smoke inhalation, a dystonia and acquired hydrocephalus, (iv) the developmental disorder is selected from the group consisting of schizophrenia, mental retardation, cerebral palsy, congenital hydrocephalus, autism, Downs Syndrome, LHRH/hypothalamic disorder, and spina bifida, (v) the disorder affecting vision caused by loss or failure of retinal cells is selected from the group consisting of diabetic retinopathy, retinal detachment, glaucoma, traumatic injury to the retina, retinal vascular occlusion, macular degeneration, and optic nerve atrophy, (vi) the spinal cord injury is selected from the group consisting of post-polio syndrome, amyotrophic lateral sclerosis, traumatic spinal cord injury, surgical spinal cord injury, and a paralytic disease, (vii) the demyelinating autoimmune disorder is multiple sclerosis, and (viii) the infectious or inflammatory disease is selected from the group consisting of Creutzfeldt-Jacob disease, a slow virus infectious CNS disease, AIDS encephalopathy, post-encephalitic Parkinsonism, viral encephalitis and bacterial meningitis.
20 . A transforming growth factor-α (TGFα) mimetic peptide, comprising:
(a) a first amino acid sequence as set forth in SEQ ID NO:4:
[SEQ ID NO: 4]
X 1a -Cys-His-Ser-X 1b -X 2 -X 1a -X 1b -X 1a -X 3 -Cys
wherein Cys at position 11 in SEQ ID NO:4 comprises a C terminus; and
(b) added to the C terminus of (a), a second amino acid sequence as set forth in SEQ ID NO:5:
-X 4 -His-X 1c -X 4 -X 5 -X 6 -X 1c
[SEQ ID NO: 5]
to obtain a TGFα mimetic peptide of 18 amino acids that comprises a combination of said first and second amino acid sequences,
wherein X 1a , X 1b and X 1c are independently Val, Gly or Ala, wherein X 2 is Tyr or Phe, wherein X 3 is Arg or Lys, wherein X 4 is Glu or Asp, wherein X 5 is Leu or Ile, wherein X 6 is Asp, Leu or Glu, wherein if X 6 is Leu then at least one of (i) X 1b is not Gly, (ii) X 1c is not Ala, (iii) X 2 is not Tyr, and (iv) X 3 is not Arg,
wherein the C terminus Cys at position 11 in SEQ ID NO:4 forms a disulfide bond with Cys at position 2 in SEQ ID NO:4, and
wherein the TGFα mimetic peptide exhibits TGFα biological activity.
21 . The method of any one of claims 2 , 4 and 13 wherein the step of administering takes place following or during cytotoxic or immune-suppressing therapy.
22 . The method of claim 21 wherein the cytotoxic or immune-suppressing therapy comprises administering cisplatinum.Join the waitlist — get patent alerts
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