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Publication Number
US-8334365-B2
Publication Date
2012-12-18
Expiration Date
Abstract
The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.
Core Innovation
The invention relates to therapeutic albumin fusion proteins in which a therapeutic protein polypeptide is genetically fused to human serum albumin. The fusion protein comprises a Butyrylcholinesterase (BChE) polypeptide fused to an albumin polypeptide, and the albumin fusion protein comprises amino acids 24-1137 of SEQ ID NO: 306. The disclosure also describes related fusion forms using albumin fragments or variants and can include additional binding moieties fused to albumin.
A central aspect described is that the albumin fusion protein includes albumin-related features for formation and secretion, including leader or signal peptides, with host processing such as signal peptide cleavage, folding, disulfide formation, and glycosylation or proteolysis. The fusion is presented alongside polynucleotides encoding the fusion protein, vectors, and host cells capable of expression. The document context also includes albumin mutations for improved yeast production, including protease-resistance or proteolytic cleavage resistance.
The disclosure frames the problem as improving therapeutic behavior compared with unfused proteins by extending therapeutic shelf life and increasing plasma stability. The described content also includes pharmaceutical compositions and kits and references therapeutic proteins associated with preferred indications.
Claims Coverage
The independent claim set is directed to one albumin fusion protein featuring a BChE-to-albumin fusion containing amino acids 24-1137 of SEQ ID NO: 306. The claim coverage includes refinements regarding glycosylation status, host type, secretion leader sequence, and production via nucleic acid encoding the fusion.
Butyrylcholinesterase-albumin fusion defined by SEQ ID NO: 306 region
An albumin fusion protein comprising a Butyrylcholinesterase (BChE) polypeptide fused to an albumin polypeptide, wherein said albumin fusion protein comprises amino acids 24-1137 of SEQ ID NO: 306.
Non-glycosylated albumin fusion protein
The albumin fusion protein is non-glycosylated.
Glycosylation-deficient yeast expression context
An albumin fusion protein produced or used with a yeast strain that is glycosylation-deficient.
Mammalian cell expression context
The albumin fusion protein is expressed by a mammalian cell.
Inclusion of a secretion leader sequence
The albumin fusion protein includes a secretion leader sequence.
Production by culturing a host cell with a nucleic acid encoding the fusion and recovering the expressed protein
A method for producing an albumin fusion protein by culturing an isolated host cell with a nucleic acid encoding the fusion protein to express it and then recovering the expressed protein.
Overall, the claims coverage centers on a BChE-to-albumin fusion containing amino acids 24-1137 of SEQ ID NO: 306, with further refinements for non-glycosylated forms, glycosylation-deficient yeast or mammalian-cell expression contexts, inclusion of a secretion leader sequence, and production via culturing a host cell carrying a nucleic acid encoding the fusion followed by recovery.
Stated Advantages
Extended plasma stability.
Extended shelf life.
Increasing plasma stability versus unfused proteins.
Enabling reduced dosing.
Improved storage and transport.
Documented Applications
Regenerating nerve and brain tissue and treating central and peripheral nervous system diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome.
Treating a wide range of gastrointestinal and liver/pancreatic/gallbladder/intestinal disorders.
Using the described binding activity and therapeutic protein portion, including albumin/HSA fusions, in binding-activity screening to identify agonists and antagonists that bind the therapeutic fusion portion.
Receptor identification and modulation via generation of agonists and antagonists for drug screening, using assay formats described in the document.
Pharmaceutical compositions.
Kits.
Recombinant expression and gene therapy targeting using polynucleotides and polypeptides.
In vivo imaging and labeling using radiolabels and other detectable moieties.
Diagnostic and therapeutic application categories for albumin fusion proteins and formulations, including pharmaceutical compositions, carriers, and kits.
Therapeutic use of albumin fusion proteins associated with preferred indications corresponding to the therapeutic proteins listed.
Treating diseases using the therapeutic protein portion corresponding to Table-1/Therapeutic Protein X entries, including endocrine, nervous, immune, respiratory, cardiovascular, digestive, reproductive systems and hematopoietic or blood-related disorders.
Immune-system disorders including immunodeficiencies and autoimmune disorders.
Infectious disease applications, including direct inhibition or enhanced immune response and vaccine adjuvant roles.
Hyperproliferative disorders and cancers, including gene-based approaches.
Anti-angiogenesis applications in ocular and tumor-site delivery concepts.
Regeneration, wound healing, and epithelial proliferation concepts.
Renal, cardiovascular, respiratory, neurological, endocrine, and gastrointestinal disorder applications.
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