MODIFIED CAVEOLIN-1 PEPTIDE FORMULATIONS AND METHODS OF MANUFACTURING AND USE THEREOF
Provided herein are modified caveolin-1 (Cav-1) peptide and pharmaceutical formulations and methods of using the peptide or formulations for treating a subject in need thereof. In particular, provided herein are modified Cav-1 peptide formulations and methods of using the formulations for treating various diseases, such as fibrosis, by providing extended release of the peptide over a desired time period.
1 . A formulation, comprising:
a) a polypeptide comprising an amino acid sequence having a core sequence of FTTFTVT; and
b) a sucrose acetate isobutyrate (SAIB).
2 . The formulation of claim 1 , further comprising a first solvent.
3 . The formulation of claim 2 , wherein the first solvent is selected from N-methylpyrrolidone (NMP), anhydrous ethanol, or ethyl acetate.
4 . The formulation of any one of claims 1-3 , wherein the SAIB is present in the first solvent in about 50% w/w to about 95% w/w.
5 . The formulation of any one of claims 1-4 , wherein the SAIB is present in the first solvent in about 70% w/w to about 90% w/w.
6 . The formulation of any one of claims 1-5 , wherein the SAIB is present in the first solvent in about 80% w/w.
7 . The formulation of any one of claims 1-6 , wherein the first solvent is NP or ethyl acetate.
8 . The formulation of any one of claims 1-7 , wherein the polypeptide is micronized.
9 . The formulation of any one of claims 1-8 , wherein the polypeptide has a mean particle size in the range of about 0.5 μm to about 100 μm.
10 . The formulation of any one of claims 1-9 , wherein the polypeptide has a mean particle size in the range of about 1 μm to about 5 μm.
11 . The formulation of any one of claims 1-10 , wherein the formulation is in the form of an emulsion, a solution, microspheres, nanoparticles, nanospheres, implants, or gels.
12 . The formulation of any one of claims 1-10 , wherein the formulation is a suspension.
13 . The formulation of any one of claims 1-12 further comprising a second solvent.
14 . The formulation of claim 13 , wherein the second solvent is sterile water, phosphate-buffered saline (PBS), or any pharmaceutically acceptable carrier.
15 . The formulation of any one of claims 1-14 , wherein the formulation comprises the polypeptide and the SAB at a weight ratio of about 1:50 to about 1:1.
16 . The formulation of claim 15 , wherein the weight ratio is about 1:30 to about 1:1.
17 . The formulation of any one of claims 1-16 , wherein the formulation releases at least about 1% to about 30% of the polypeptide by four hours under physiological conditions.
18 . The formulation of any one of claims 1-16 , wherein the formulation releases at least about 5% to about 25% of the polypeptide by four hours under physiological conditions.
19 . The formulation of any one of claims 1-18 , wherein the polypeptide comprises ASFTTFTVTK.
20 . The formulation of any one of claims 1-19 , wherein the polypeptide comprises:
a) at least one amino acid added to the N-terminus;
b) at least one amino acid added to the C-terminus; or
c) at least one amino acid added to the N-terminus and the C-terminus.
21 . The formulation of any one of claims 1-20 , wherein the polypeptide consists of 20 or less amino acids.
22 . The formulation of any one of claims 1-21 , wherein the addition made within 5 amino acids of each terminus has an amino acid sequence that is less than 80% identical to a contiguous amino acid sequence of SEQ ID NO:1.
23 . The formulation of claim 22 , wherein the addition made within 5 amino acids of each terminus has an amino acid sequence that is less than 60% identical to a contiguous amino acid sequence of SEQ ID NO: 1.
24 . The formulation of claim 22 , wherein the addition made within 5 amino acids of each terminus has an amino acid sequence that is less than 40% identical to a contiguous amino acid sequence of SEQ ID NO: 1.
25 . The formulation of claim 22 , wherein the addition made within 5 amino acids of each terminus has an amino acid sequence that is less than 20% identical to a contiguous amino acid sequence of SEQ ID NO: 1.
26 . The formulation of any one of claims 1-25 , wherein the peptide sequence comprises:
a) the polypeptide comprises L-amino acids;
b) the polypeptide comprises D-amino acids; or
c) the polypeptide comprises both L- and D-amino acids.
27 . The formulation of any one of claims 1-26 , wherein:
a) the polypeptide comprises at least one non-standard amino acid; or
b) the polypeptide comprises two non-standard amino acids.
28 . The formulation of claim 27 , wherein the non-standard amino acid is ornithine.
29 . The formulation of any one of claims 1-28 , wherein the polypeptide further comprises:
a) an N-terminal modification;
b) a C-terminal modification; or
c) an N- and C-terminal modification.
30 . The formulation of claim 29 , wherein:
the N-terminal modification is acylation; and/or
the C-terminal modification is amidation.
31 . The formulation of any one of claims 1-30 , wherein the polypeptide comprises the amino acid sequence of KASFTTFTVTKGS (SEQ ID NO: 4), KASFTTFTVTKGS-NH2 (SEQ ID NO: 5), aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6), aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 7), Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8), OASFTTFTVTOS (SEQ ID NO: 9), or OASFTTFTVTOS-NH2 (SEQ ID NO: 10).
32 . The formulation of any one of claims 1-31 , wherein the polypeptide consists of an amino acid sequence selected from KASFTTFTVTKGS (SEQ ID NO: 4), KASFTTFTVTKGS-NH2 (SEQ ID NO: 5), aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6), aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 7), Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8), OASFTTFTVTOS (SEQ ID NO: 9), or OASFTTFTVTOS-NH2 (SEQ ID NO: 10).
33 . The formulation of any one of claims 1-32 , wherein the polypeptide consists of an amino acid sequence of Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8).
34 . A method of treating a disease in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the formulation of any one of claims 1-33 .
35 . The method of claim 34 , wherein the disease is fibrosis.
36 . The method of claim 35 , wherein the fibrosis is interstitial lung disease, liver fibrosis, renal fibrosis, skin fibrosis, glomerulonephritis, systemic sclerosis, cardiac fibrosis, myocardial fibrosis, kidney fibrosis, hepatic cirrhosis, renal sclerosis, arteriosclerosis, macular degeneration, ocular scarring, cataracts, retinal and vitreal retinopathy, Grave's ophthalmopathy, neurofibromatosis, scleroderma, glioblastoma, keloids and hypertrophic scarring, peritoneal fibrotic disease, chronic obstructive pulmonary disease, post-operative fibroids, diabetic nephropathy, gynecological cancer, myeloproliferative syndrome, myeloid leukemia, myelodysplastic syndrome, inflammatory bowel disease, non-alcoholic fatty liver disease, fibrosarcoma, rheumatoid arthritis, non-alcoholic steatohepatitis, Alport syndrome, or chronic COVID syndrome.
37 . The method of claim 36 , wherein the interstitial lung disease is idiopathic pulmonary fibrosis, familial pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, conventional interstitial pneumonia, cryptogenic organizing pneumonia, or sarcoidosis.
38 . The method of claim 37 , wherein the interstitial lung disease is idiopathic pulmonary fibrosis.
39 . The method of claim 34 , wherein the disease is a kidney disease or disorder.
40 . The method of claim 39 , wherein the kidney disease or disorder is selected from the group consisting of chronic kidney disease, end-stage renal disease, glomerulonephritis, focal segmental glomerulosclerosis, kidney fibrosis, polycystic kidney disease, IgA nephropathy, lupus nephritis, nephrotic syndrome, Alport syndrome, amyloidosis, Goodpasture syndrome, granulomatosis with polyangiitis, or acute kidney injury.
41 . The method of claim 40 , wherein the kidney disease or disorder is kidney fibrosis.
42 . The method of claim 40 , wherein the kidney disease or disorder is Alport syndrome.
43 . The method of any one of claims 34-42 , wherein the administration is intraocular, intradermal, transdermal, intramuscular, or subcutaneous administration.
44 . The method of any one of claims 34-43 , wherein the subject is a human.
45 . The method of any one of claims 34-44 , wherein the formulation releases the polypeptide for at least 7 days following administration of a single dose.
46 . The method of any one of claims 34-44 , wherein the formulation releases the polypeptide for at least 21 days following administration of a single dose.
47 . The method of any one of claims 34-44 , wherein the formulation releases the polypeptide for at least 28 days following administration of a single dose.
48 . The method of any one of claims 34-47 , wherein the formulation is administered to the subject at a dose of about 0.01 mg/kg to about 250 mg/kg.
49 . The method of claim 48 , wherein the formulation is administered to the subject at a dose of about 0.05 mg/kg to about 50 mg/kg.