Combinations Of Albumin-Based Drug Delivery Systems

Abstract

The present invention relates to a composition comprising at least two different albumin-based drug delivery systems, as well as to a pharmaceutical composition comprising said composition.

What is claimed is: 
     
         1 . A method of treating a disease comprising:
 administering an effective amount of a pharmaceutical composition comprising a combination of at least two different albumin-based drug delivery systems, wherein at least one of said at least two different albumin-based drug delivery systems is selected from albumin-binding prodrugs, albumin drug conjugates, albumin peptide conjugates, albumin fusion proteins, albumin-binding peptide conjugates, albumin drug nanoparticles, and albumin-based antibody constructs and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable adjuvant and/or diluent,   wherein the disease is selected from the group consisting of cancer, autoimmune disease, acute or chronic inflammatory diseases, or diseases caused by viruses and/or microorganisms.   
     
     
         2 . The method of  claim 1 , wherein at least one of said at least two different albumin-based drug delivery systems is an albumin-binding prodrug comprising an albumin-binding group, a drug, and a linker that can be cleaved hydrolytically, reductively, enzymatically, or in a pH-dependent manner. 
     
     
         3 . The method of  claim 1 , wherein at least two of said at least two different albumin-based drug delivery systems are albumin-binding prodrugs, each comprising an albumin-binding group, a drug, and a linker that can be cleaved hydrolytically, reductively, enzymatically, or in a pH-dependent manner. 
     
     
         4 . The method of  claim 1 , wherein at least one of said at least two different albumin-based drug delivery systems is an albumin-binding prodrug comprising an albumin-binding group, a drug, and a linker that can be cleaved hydrolytically, reductively, enzymatically, or in a pH-dependent manner, and wherein at least one of said two different albumin-based drug delivery systems is an albumin-drug nanoparticle. 
     
     
         5 . The method of  claim 1 , wherein the drug contained in each of the albumin-based drug delivery systems is independently selected from the group consisting of a cytostatic agent, a cytokine, an immunosuppressant, an antirheumatic, an antiphlogistic, an antibiotic, an analgesic, a virostatic, an antimycotic agent, a transcription factor inhibitor, a cell cycle modulator, an MDR modulator, a proteasome or protease inhibitor, an apoptosis modulator, an enzyme inhibitor, an angiogenesis inhibitor, a hormone or hormone derivative, an antibody or a fragment thereof, a therapeutically or diagnostically active peptide, a radioactive substance, a light emitting substance, or a light absorbing substance. 
     
     
         6 . The method of  claim 1 , wherein the drug contained in each of the albumin-based drug delivery systems is a cytostatic agent independently selected from the group consisting of N-nitrosoureas; the anthracyclines doxorubicin, 2-pyrrollinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, mitoxantrone and ametantrone, and any derivatives thereof; the alkylating agents chlorambucil, bendamustine, melphalan, and oxazaphosphorines, and any derivatives thereof; the antimetabolites 5-fluorouracil, 2′-deoxy-5-fluoridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, and thioguanine, and any derivatives thereof; the folic acid antagonists methotrexate, raltitrexed, pemetrexed, and plevitrexed, and any derivatives thereof; the taxanes paclitaxel and docetaxel, and any derivatives thereof; the camptothecins topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin and camptothecin, and any derivatives thereof; the Vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine, and any derivatives thereof; calicheamicins and and derivatives thereof; maytansinoids and any derivatives thereof; auristatins and any derivatives thereof; epothilones and any derivatives thereof; bleomycin, dactinomycin, plicamycin, miromycin C and cis-configured platinum(II) complexes, and any derivatives thereof. 
     
     
         7 . The method of  claim 2 , wherein one or more of the albumin-binding group(s) bind in situ to cysteine-34 of albumin. 
     
     
         8 . The method of  claim 2 , wherein one or more of the albumin-binding group(s) are independently selected from the group consisting of a maleinimide group, a halogenacetamide group, a halogenacetate group, a pyridylthio group, a vinyl-carbonyl group, an aziridin group, a thiol group, a disulfide group, a substituted or unsubstituted acetylene group, or an N-hydroxysuccinimide ester group. 
     
     
         9 . The method of  claim 2 , wherein one or more of the albumin-binding group(s) are independently selected from phthalocyanines, coumarins, flavonoids, tetracyclines, naphthalenes, aryl- and heteroarylcarboxylic acids, lipids and fatty acids, cyclic or linear tetrapyrroles and organometallic compounds thereof, aromatic acid derivatives substituted with 2 to 5 halogen atoms (CI, Br or I), organic dyes, and the tryptophan and thyroxine analog compounds, and any derivatives thereof. 
     
     
         10 . The method of  claim 2 , wherein one or more of the cleavable linker(s) independently comprise a substituted or unsubstituted, branched-chain or straight-chain aliphatic alkyl group with 1 to 20 carbon atoms, which may comprise one or more oxygen or nitrogen atoms, and/or a substituted or unsubstituted aryl residue. 
     
     
         11 . The method of  claim 2 , wherein one or more of the cleavable linkers are enzymatically cleavable and comprise a peptide sequence selected from Arg, Arg-Arg, Phe-Arg, Phe-Cit, Ile-Pro, Lys, Lys-Lys, Arg-Lys, Ala-Leu-Ala-Leu (SEQ ID No: 1), Phe-Lys, Phe-Lys-Ala, Val-Cit, Val-Arg, Ala-Phe-Lys, D-Ala-Phe-Lys, Met, Met-Met, Phe-Met, Tyr-Met, Ala-Met, Ala-Phe-Met, Phe-Ala-Met, Ala-Tyr-Met, Phe-Tyr-Met, Ser-Ser-Tyr-Tyr-Ser-Arg (SEQ ID No: 2), Ser-Ser-Tyr-Tyr-Ser-Leu (SEQ ID No: 3), Arg-Ser-Ser-Tyr-Tyr-Ser-Leu (SEQ ID No: 4), Phe-Pro-Lys-Phe-Phe-Ser-Arg-Gln (SEQ ID No: 5), Lys-Pro-Ile-Glu-Phe-Nph-Arg-Leu (SEQ ID No: 6), Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln (SEQ ID No: 7), Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln (SEQ ID No: 8), Gly-Pro-Gln-Gly-Ile-Trp-Gly-Gln (SEQ ID No: 9), Gly-Phe-Leu-Gly (SEQ ID No: 10), or is a p-aminobenzyloxycarbonyl (PABC) linker or a N-methyl- or symmetric N,N-dimethylethylene linker, or wherein one or more of the cleavable linker(s) are cleaved upon reduction and comprise disulfide bonds, or wherein one or more of the cleavable linker(s) are acid-labile linkers and comprise an acid-labile bond selected from ester, acetal, ketal, imine, aconityl, hydrazone, carboxyl-hydrazone and sulfonylhydrazone bonds and bonds containing a trityl group. 
     
     
         12 . The method of  claim 1 , wherein the at least two different albumin-based drug delivery systems are each present in separate containers to be sequentially administered. 
     
     
         13 . The method of  claim 1 , wherein one of said at least two different albumin-based drug delivery systems is the 6-maleimidocaproyl(hydrazone) derivative of doxorubicin (DOXO-EMCH), and wherein one of the at least two different albumin-based drug delivery systems is selected from
 (i) an albumin-binding prodrug selected from the methotrexate derivative EMC-D-Ala-Phe-Lys-Lys(γ-MTX)-OH, wherein EMC=6-maleimidocaproic acid, (AW054),   (ii) an albumin-drug nanoparticle selected from nab-paclitaxel (ABI-007), Nab®-docetaxel (ABI-008) or nab-rapamycin (ABI-010),   (iii) an albumin-binding antibody construct selected from camelid anti-HSA trivalent nanobodies, and   (iv) an albumin fusion protein with interferons or interleukins selected from albinterferon alfa-2b or albuleukin.   
     
     
         14 . The method of  claim 13 , wherein one of said at least two different albumin-based drug delivery systems is the 6-maleimidocaproyl(hydrazone) derivative of doxorubicin (DOXO-EMCH), and wherein one of the at least two different albumin-based drug delivery systems is the methotrexate derivative EMC-D-Ala-Phe-Lys-Lys(γ-MTX)-OH, wherein EMC=6-maleimidocaproic acid, (AW054). 
     
     
         15 . The method of  claim 14 , wherein the disease to be treated is cancer.