Compositions comprising serum albumin and p53 peptides fusion proteins
View Patent ↗The present invention relates to compositions useful in inhibiting Bcl-XL or MCL-1 and disrupting p53-MDM2 and p53-MDMX interactions, and methods of using those compositions for treating a subject for conditions responsive to increasing p53 mediated activity or promoting p53 independent apoptosis, such as treating cancer. In some aspects, the compositions of this invention relate to fusion polypeptides comprising a human serum polypeptide and a p53-peptide, which can be, in some aspects, a p53 derived peptide and/or a p53 activating peptide.
1. A fusion polypeptide comprising a human serum albumin and a p53-peptide, further comprising one or more anticancer agent, wherein the one or more anticancer agent is bound to the human serum albumin via covalent interactions, or is chemically conjugated to a natural ligand of the human serum albumin, wherein the natural ligand is bound to the human serum albumin.
2. The fusion polypeptide of claim 1 , wherein the p53-peptide is chemically linked to the human serum albumin or a fragment thereof.
3. The fusion polypeptide of claim 2 , wherein the p53-peptide is covalently cross-linked to the human serum albumin or a fragment thereof via carboxyl groups, amino groups, amine-reactive groups, sulfhydryl-reactive groups, aldehyde-reactive groups, hydroxyl (nonaqueous)-reactive groups or a combination thereof.
4. The fusion polypeptide of claim 1 , wherein the p53-peptide is a p53-derived peptide or a p53-activating peptide.
5. The fusion polypeptide of claim 1 , wherein the fusion polypeptide is a chemically cross-linked conjugate comprising:
(a) a p53-derived peptide and a human serum albumin polypeptide, or
(b) a p53-activating peptide and a human serum albumin polypeptide.
6. The fusion polypeptide of claim 5 , wherein one or more anticancer agent is selected from the group consisting of 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, abiraterone acetate, afatinib, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide, anagrelide, anastrozole, anhydrovinblastine, arsenic trioxide, asparaginase, auristatin, azacitidine, azathioprine, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, BMS 184476, bortezomib, busulfan, cachectin, capecitabine, carboplatin, carmustine, cemadotin, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, denileukin diftitox, decitabine, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide, docetaxel, dexamethasone, doxifluridine, doxorubicin, epirubicin, epoetin alpha, epothilone, erlotinib, estramustine, etinostat, etoposide, everolimus, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, folate linked alkaloids, gefitinib, gemcitabine, gemtuzumab ozogamicin, GM-CT-01, goserelin, hexamethylmelamine, hydroxyureas, ibritumomab, idarubicin, ifosfamide, imatinib, interferon alpha, interferon beta, irinotecan, ixabepilone, lapatinib, leucovorin, leuprolide, lenalidomide, letrozole, lomustine, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nelarabine, nilotinib, nilutamide, octreotide, ofatumumab, oprelvekin, oxaliplatin, paclitaxel, panitumumab, pemetrexed, pentostatin, polysaccharide galectin inhibitors, procarbazine, raloxifene, retinoic acids, rituximab, romiplostim, sargramostim, sorafenib, streptozocin, sunitinib, tamoxifen, temsirolimus, temozolamide, teniposide, thalidomide, thioguanine, thiotepa, tioguanine, topotecan, toremifene, tositumomab, trametinib, trastuzumab, tretinoin, valrubicin, vegf inhibitors and traps, vinblastine, vincristine, vindesine, vinorelbine, vintafolide, vorinostat, and a combination thereof.
7. A fusion polypeptide comprising a human serum albumin and a p53-peptide, further comprising one or more anticancer agent, wherein the anticancer agent is covalently bound to the human serum albumin polypeptide.
8. The fusion polypeptide of claim 1 , wherein the one or more anticancer agent is chemically conjugated to a natural ligand of the human serum albumin.
9. The fusion polypeptide of claim 8 , wherein the natural ligand of the human serum albumin is a fatty acid, an amino acid, a nutrient, a vitamin, a metabolite, an hormone, or a drug.
10. The fusion polypeptide of claim 9 , wherein the natural ligand of human serum albumin is a fatty acid.
11. A pharmaceutical composition comprising a fusion polypeptide of claim 1 .
12. The pharmaceutical composition of claim 11 , further comprising a pharmaceutically acceptable excipient, wherein the fusion polypeptide is lyophilized.
13. The pharmaceutical composition of claim 11 , further comprising a pharmaceutically acceptable excipient.
14. The pharmaceutical composition of claim 13 , where the pharmaceutically acceptable excipient is selected from the group consisting of a solvent, solubilizer, stabilizer, buffer, pH adjuster, tonicity modifier, bulking agent, filler, binder, viscosity enhancer, viscosity reducer, emulsifier, surfactant, chelating agent, disintegrant, glidant, lubricant and adjuvant.
15. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated as a lyophilisate, powder, injection, solution, suspension, emulsion, powder, granule, capsule, tablet, pellet, dragee, semi-solid, suppositorie, ointment, cream, lotion, inhalant, cataplasm, gel, tape, eye drop, syrup, or an aerosol.
16. A fusion polypeptide comprising a human serum albumin and a p53-peptide, wherein the p53-peptide is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO:7.
17. A fusion polypeptide comprising a serum albumin, or a fragment thereof retaining its cell transport and/or ligand binding properties, and a p53-peptide further comprising a small molecule drug, wherein the small molecule drug is bound to the serum albumin via covalent interactions, or is chemically conjugated to a natural ligand of the serum albumin, wherein the natural ligand is bound to the serum albumin.
18. The fusion polypeptide of claim 17 , wherein the serum albumin is an animal serum albumin.
19. The fusion polypeptide of claim 17 , wherein the serum albumin is selected from an avian, bovine, canine, cervine , equine, ichthyic, feline, ovine, piscine and porcine albumin.
20. The fusion polypeptide of claim 17 , wherein the serum albumin is a recombinant protein.
21. The fusion polypeptide of claim 17 , wherein the small molecule drug is an extremely hydrophobic drug.
22. The fusion polypeptide of claim 17 , wherein the anticancer agent is bound to a ligand of the serum albumin.
23. The fusion polypeptide of claim 22 , wherein the ligand of the serum albumin is selected from the group consisting of a fatty acid, an amino acid, a nutrient, a vitamin, a metabolite, an hormone and a drug.