Albumin Fusion Proteins

• US 20080146503A1
• Filed: 07/02/2007
• Published: 06/19/2008
• Est. Priority Date: 12/21/2001
• Status: Active Grant

• Current Assignee: Delta Biotechnology Limited, Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Delta Biotechnology Limited, Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Inventors: Turner, Andrew J., Rosen, Craig A., Haseltine, William A., Ruben, Steven M., Ballance, David J.
• Granted Patent: US 7,799,759 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 39/21 Retroviridae, e.g. equine infectious anemia virus
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 : for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/10 : for petit-mal
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 : for electrolyte homeostasis
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/40 : Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/005 : from viruses
• CPC Class Codes: C07K 14/435 : from animals; from humans
• CPC Class Codes: C07K 14/4713 : Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
• CPC Class Codes: C07K 14/4723 : Cationic antimicrobial peptides, e.g. defensins
• CPC Class Codes: C07K 14/475 : Growth factors; Growth regulators
• CPC Class Codes: C07K 14/50 : Fibroblast growth factor [FGF]
• CPC Class Codes: C07K 14/505 : Erythropoietin [EPO]
• CPC Class Codes: C07K 14/51 : Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: C07K 14/521 : Chemokines
• CPC Class Codes: C07K 14/525 : Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 14/535 : Granulocyte CSF; Granulocyte-macrophage CSF
• CPC Class Codes: C07K 14/54 : Interleukins [IL]
• CPC Class Codes: C07K 14/5406 : IL-4
• CPC Class Codes: C07K 14/55 : IL-2
• CPC Class Codes: C07K 14/555 : Interferons [IFN]
• CPC Class Codes: C07K 14/56 : IFN-alpha
• CPC Class Codes: C07K 14/565 : IFN-beta
• CPC Class Codes: C07K 14/575 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/57563 : Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/5759 : Products of obesity genes, e.g. leptin, obese (OB), tub, fat
• CPC Class Codes: C07K 14/585 : Calcitonins
• CPC Class Codes: C07K 14/59 : Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: C07K 14/60 : Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: C07K 14/605 : Glucagons
• CPC Class Codes: C07K 14/61 : Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: C07K 14/62 : Insulins
• CPC Class Codes: C07K 14/635 : Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: C07K 14/65 : Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
• CPC Class Codes: C07K 14/655 : Somatostatins
• CPC Class Codes: C07K 14/665 : derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
• CPC Class Codes: C07K 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/7151 : for tumor necrosis factor [TNF], for lymphotoxin [LT]
• CPC Class Codes: C07K 14/765 : Serum albumin, e.g. HSA
• CPC Class Codes: C07K 14/82 : Translation products from oncogenes
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/26 : against hormones ; against hormone releasing or inhibiting factors
• CPC Class Codes: C07K 2317/10 : characterized by their source of isolation or production
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/20 : containing a tag with affinity for a non-protein ligand
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/31 : fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C12N 15/62 : DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 2501/335 : Glucagon; Glucagon-like peptide [GLP]; Exendin
• CPC Class Codes: C12N 2740/16111 : concerning HIV env
• CPC Class Codes: C12N 2740/16122 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2740/16134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/16171 : Demonstrated in vivo effect
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: C12N 9/0006 : acting on CH-OH groups as donors (1.1)
• CPC Class Codes: C12N 9/0008 : acting on the aldehyde or oxo group of donors (1.2)
• CPC Class Codes: C12Y 101/01105 : Retinol dehydrogenase (1.1.1.105)
• CPC Class Codes: C12Y 102/01 : with NAD+ or NADP+ as acceptor (1.2.1)
• CPC Class Codes: C12Y 207/01095 : Kanamycin kinase (2.7.1.95), i.e. neomycin-kanamycin phosphotransferase

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.

Claims

1-23. -23. (canceled)

24. An albumin fusion protein comprising a member selected from:

(a) a Therapeutic protein;

X and albumin comprising the amino acid sequence of SEQ ID NO;

1038;

(b) a Therapeutic protein;

X and a fragment or a variant of the amino acid sequence of SEQ ID NO;

1038, wherein said fragment or variant has albumin activity;

(c) a Therapeutic protein;

X and a fragment or a variant of the amino acid sequence of SEQ ID NO;

1038, wherein said fragment or variant has albumin activity, and further wherein said albumin activity is the ability to prolong the shelf life of the Therapeutic protein;

X compared to the shelf-life of the Therapeutic protein;

X in an unfused state;

(d) a Therapeutic protein;

X and a fragment or a variant of the amino acid sequence of SEQ ID NO;

1038, wherein said fragment or variant has albumin activity, and further wherein the fragment or variant comprises the amino acid sequence of amino acids 1-387 of SEQ ID NO;

1038;

(e) a fragment or variant of a Therapeutic protein;

X and albumin comprising the amino acid sequence of SEQ ID NO;

1038, wherein said fragment or variant has a biological activity of the Therapeutic protein;

X;

(f) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein;

X, or fragment or variant thereof, is fused to the N-terminus of albumin, or the N-terminus of the fragment or variant of albumin;

(g) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein;

X, or fragment or variant thereof, is fused to the C-terminus of albumin, or the C-terminus of the fragment or variant of albumin;

(h) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein;

X, or fragment or variant thereof, is fused to the N-terminus and C-terminus of albumin, or the N-terminus and the C-terminus of the fragment or variant of albumin;

(i) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), which comprises a first Therapeutic protein;

X, or fragment or variant thereof, and a second Therapeutic protein;

X, or fragment or variant thereof, wherein said first Therapeutic protein;

X, or fragment or variant thereof, is different from said second Therapeutic protein;

X, or fragment or variant thereof;

j) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (i), wherein the Therapeutic protein;

X, or fragment or variant thereof, is separated from the albumin or the fragment or variant of albumin by a linker;

(k) a Therapeutic protein;

X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (j), wherein the albumin fusion protein has the following formula;

R1-L-R2;

R2-L-R1;

or R1-L-R2-L-R1,

and further wherein R1 is Therapeutic protein;

X, or fragment or variant thereof, L is a peptide linker, and R2 is albumin comprising the amino acid sequence of SEQ ID NO;

1038 or a fragment or variant of albumin;

(l) a Therapeutic protein;

X, or fragment or variant thereof, inserted into an albumin, or fragment or variant thereof, comprising the amino acid sequence of SEQ ID NO;

1038 or fragment or variant thereof;

(m) a Therapeutic protein;

X, or fragment or variant thereof, inserted into an albumin, or fragment or variant thereof, comprising an amino acid sequence selected from the group consisting of;

(i) amino acids 54 to 61 of SEQ ID NO;

1038;

(ii) amino acids 76 to 89 of SEQ ID NO;

1038;

(iii) amino acids 92 to 100 of SEQ ID NO;

1038;

(iv) amino acids 170 to 176 of SEQ ID NO;

1038;

(v) amino acids 247 to 252 of SEQ ID NO;

1038;

(vi) amino acids 266 to 277 of SEQ ID NO;

1038;

(vii) amino acids 280 to 288 of SEQ ID NO;

1038;

(viii) amino acids 362 to 368 of SEQ ID NO;

1038;

(ix) amino acids 439 to 447 of SEQ ID NO;

1038;

(x) amino acids 462 to 475 of SEQ ID NO;

1038;

(xi) amino acids 478 to 486 of SEQ ID NO;

1038; and

(xii) amino acids 560 to 566 of SEQ ID NO;

1038;

(n) two or more tandemly oriented Therapeutic protein;

X polypeptides, or fragments or variants thereof, fused to the N-terminus of an albumin comprising the amino acid sequence of SEQ ID NO;

1038 or fragment or variant thereof; and

(o) two or more tandemly oriented Therapeutic protein;

X polypeptides, or fragments or variants thereof, fused to the C-terminus of an albumin comprising the amino acid sequence of SEQ ID NO;

1038 or fragment or variant thereof.

25. The albumin fusion protein of claim 24, wherein the shelf-life of the albumin fusion protein is greater than the shelf-life of the Therapeutic protein:

X, or fragment or variant thereof, in an unfused state.

26. The albumin fusion protein of claim 24, wherein the in vitro biological activity of the Therapeutic protein:

X, or fragment or variant thereof, fused to albumin, or fragment or variant thereof, is greater than the in vitro biological activity of the Therapeutic protein;

X, or fragment or variant thereof, in an unfused state.

27. The albumin fusion protein of claim 24, wherein the in vivo biological activity of the Therapeutic protein:

X, or fragment or variant thereof, fused to albumin, or fragment or variant thereof, is greater than the in vivo biological activity of the Therapeutic protein;

X, or fragment or variant thereof, in an unfused state.

28. The albumin fusion protein of claim 24, which is non-glycosylated.

29. The albumin fusion protein of claim 24, which is expressed in yeast.

30. The albumin fusion protein of claim 29, wherein the yeast is glycosylation deficient.

31. The albumin fusion protein of claim 29 wherein the yeast is glycosylation and protease deficient.

32. The albumin fusion protein of claim 24, which is expressed by a mammalian cell.

33. The albumin fusion protein of claim 24, wherein the albumin fusion protein is expressed by a mammalian cell in culture.

34. The albumin fusion protein of claim 24, wherein the albumin fusion protein further comprises a secretion leader sequence.

35. A composition comprising the albumin fusion protein of claim 24 and a pharmaceutically acceptable carrier.

36. A kit comprising the composition of claim 35.

37. A method of treating a disease or disorder in a patient, comprising the step of administering the albumin fusion protein of claim 24.

38. The method of claim 37, wherein the disease or disorder comprises indication:

Y.

39. A method of treating a patient with a disease or disorder that is modulated by Therapeutic protein:

X, or fragment or variant thereof, comprising the step of administering an effective amount of the albumin fusion protein of claim 24.

40. The method of claim 39, wherein the disease or disorder is indication:

Y.

42. A nucleic acid molecule comprising a polynucleotide sequence encoding the albumin fusion protein of claim 24.

43. A vector comprising the nucleic acid molecule of claim 42.

44. A host cell comprising the nucleic acid molecule of claim 42.

41. A method of extending the shelf life of

Therapeutic protein:

X, or fragment or variant thereof, comprising the step of fusing the

Therapeutic protein;

X, or fragment or variant thereof, to albumin, or fragment or variant thereof, sufficient to extend the shelf-life of the Therapeutic protein;

X, or fragment or variant thereof, compared to the shelf-life of the Therapeutic protein;

X, or fragment or variant thereof, in an unfused state.