Saposin-A derived peptides and uses thereof
Disclosed herein are polypeptides and fusion polypeptides that have anti-angiogenic activity that can be used to inhibit tumor growth and tumor metastasis. The polypeptide consists of 9 or less consecutive amino acid residues (e.g., 8, 7, 6, 5, or 4) comprising the active core amino acid sequence DWLP, or an amino acid substitution variant thereof. Specific amino acid substitutions are disclosed herein. In some embodiments, the peptide consists essentially of 4-6 mers identified as exhibiting the activity of prosaposin A. Also disclosed herein are therapeutic compositions comprising the polypeptides and fusion polypeptides, and their use in the treatment, prevention, and inhibition of angiogenesis-related diseases and disorders such as cancer and cancer metastasis.
1. An isolated peptide consisting of the amino acid sequence DWLP (SEQ ID NO: 5), wherein the peptide is acylated, carboxyamidated, pegylated, or conjugated to a polymer that enhances serum half-life of the peptide.
2. A chimeric peptide comprising at least a first portion and at least a second portion, wherein the first portion is the peptide of claim 1 and wherein the second portion is a non-Psap polypeptide.
3. The chimeric peptide of claim 2 , wherein the second portion comprises an amino acid sequence or a polymer that enhances the serum half-life of said first portion.
4. The chimeric peptide of claim 3 , wherein the second portion comprises an antibody Fc domain.
5. The chimeric peptide of claim 2 , wherein the second portion comprises an antibody.
6. A composition comprising the peptide of claim 1 or a chimeric peptide of any one of claims 2 - 5 , and a pharmaceutically acceptable carrier.
7. A method of inhibiting angiogenesis in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 6 .
8. The method of claim 7 , wherein the subject in need thereof has an angiogenesis dependent disease or disorder.
9. The method of claim 7 , wherein the subject has cancer.
10. A method of stimulating expression of Tsp-1 in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 1 .
11. The method of claim 10 , wherein the subject in need thereof has an angiogenesis dependent disease or disorder.
12. The method of claim 10 , wherein the subject has cancer.
13. A method of inhibiting growth and/or metastasis of cancer in a subject diagnosed with cancer, the method comprising administering to the subject a therapeutically effective amount of a composition of claim 1 .
14. The method of claim 8 , wherein the angiogenesis dependent disease or disorder is selected from a group consisting of cancer, psoriasis, age-related macular degeneration, thyroid hyperplasia, preeclampsia, rheumatoid arthritis and osteoarthritis, inflammatory bowel disease (IBD), Alzheimer's disease, obesity, pleural effusion, atherosclerosis, endometriosis, diabetic/other retinopathies, neovascular glaucoma, age-related macular degeneration, hemangiomas, and corneal neovascularization.