WO2002057435A2 - Bifunctional fusion proteins with glucocerebrosidase activity - Google Patents
Bifunctional fusion proteins with glucocerebrosidase activity Download PDFInfo
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- WO2002057435A2 WO2002057435A2 PCT/EP2001/015328 EP0115328W WO02057435A2 WO 2002057435 A2 WO2002057435 A2 WO 2002057435A2 EP 0115328 W EP0115328 W EP 0115328W WO 02057435 A2 WO02057435 A2 WO 02057435A2
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- gcr
- fusion protein
- molecule
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010089669 glutathione conjugate reductase Proteins 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- JYPCXBJRLBHWME-UHFFFAOYSA-N glycyl-L-prolyl-L-arginine Natural products NCC(=O)N1CCCC1C(=O)NC(CCCN=C(N)N)C(O)=O JYPCXBJRLBHWME-UHFFFAOYSA-N 0.000 description 1
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010025801 glycyl-prolyl-arginine Proteins 0.000 description 1
- 108010043293 glycyl-prolyl-glycyl-glycine Proteins 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
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- MXHCPCSDRGLRER-UHFFFAOYSA-N pentaglycine Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O MXHCPCSDRGLRER-UHFFFAOYSA-N 0.000 description 1
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- 239000003208 petroleum Substances 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
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- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
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- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- GCR fusion proteins By selective altering of the amino acid sequences of the Ig moiety, GCR fusion proteins with improved properties, e.g. enhanced stability, can be obtained. Furthermore, fusion proteins can be provided, wherein shortened versions of GCR and the Ig chain are used.
- the present invention relates also to pharmaceutical compositions and therapeutic methods and systems comprising such GCR fusion proteins and methods of treating Gaucher's disease or another disease caused by glycolipid storage disorders, such as Fabry's and Tay-Sachs disease, comprising administering to a subject afflicted with this disease, a pharmaceutical composition comprising a therapeutic amount of recombinantly produced GCR fusion protein in a pharmaceutically acceptable carrier.
- the dose of the enzyme to treat these diseases is about 60 units per kilogram body weight every two weeks, that means that the average costs per year for the treatment of a 70 kg patient are about US$ 380.000,- for the enzyme alone. This is due to the short intracellular half-life of exogenous acid ⁇ -glucosidase.
- Preferred truncated forms are for example those which consist of about one third to one half of the amino acid sequence of the natural GCR enzyme truncated from the carboxy terminal site of the enzyme.
- Those truncated proteins may be derived from the full length protein by cleaving off the desired chain with a suitable reagent such as a restriction enzyme or the like.
- GCR m is an GCR according to this invention which is mutated but not truncated in its amino acid sequence.
- the number of mutations is not limited but is restricted to the loss of the biological activity of the molecule. In a preferred embodiment the degree of mutation is between 5 and 30 per cent, in a especially preferred embodiment between 5 and 20 per cent of the amino acid residues.
- Variants with increased GCR biological activity can be generated by procedures described known in the art.
- L has the meaning of a series of peptides such as. e.g., glycine and/or serine.
- the peptide linker is a mixed series of glycine and serine peptides about 5 - 25, preferably 10 - 20 residues in length.
- proteolytically cleavable linkers especially linkers which are cleavable by lysosomal proteases like cathepsins.
- the Ig moiety is specific for a cell bearing an Fc receptor.
- a preferred fragment of an Ig molecule to be linked to GCR is the Fc region.
- the Fc region of an immunoglobulin is the amino acid sequence for the carboxyl-terminal portion of an immunoglobulin heavy chain constant region. The Fc regions are particularly important in determining the biological functions of the immunoglobulin and these biological functions are termed effector functions.
- the heavy chains of the immunoglobulin subclasses comprise four or five domains: IgM and IgE have five heavy chain domains, and IgA, IgD and IgG have four heavy chain domains.
- Fc portion means the carboxyl-terminal portion of an immunoglobulin heavy chain constant region, or an analog or portion thereof. That is, e.g., an immunoglobulin Fc region of Ig, preferably IgG, which may comprise at least a portion of a hinge region, a CH2 domain, and a CH3 domain.
- IgG histidins located at the junction between the CH2 and CH3 domains (residues 310 and 433) of the IgG heavy chain contribute to the pH-dependent binding to the FcRn receptor (Raghavan, et al., Biochemistry 34(45): 14649-57 (1995)). Also lie 253 and His 435 and 436 (Kim et al., Eur. J. Immunol.
- a typical signal peptide consists of three regions: a basic N-terminal region, a central hydrophobic region, and a more polar
- compositions comprising effective amounts of protein or derivative products of the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Enzymes And Modification Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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BR0116803-7A BR0116803A (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
CA002435037A CA2435037A1 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
KR10-2003-7009521A KR20030067755A (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
HU0401300A HUP0401300A3 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
MXPA03006294A MXPA03006294A (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity. |
PL01362394A PL362394A1 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
JP2002558488A JP2004525621A (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion protein having glucocerebrosidase activity |
US10/466,593 US20040043457A1 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
EP01989057A EP1392826A2 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
NO20033247A NO20033247D0 (en) | 2001-01-18 | 2003-07-17 | Bifunctional fusion proteins with glucocerebrosidase activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01101056.8 | 2001-01-18 | ||
EP01101056 | 2001-01-18 |
Publications (2)
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WO2002057435A2 true WO2002057435A2 (en) | 2002-07-25 |
WO2002057435A3 WO2002057435A3 (en) | 2003-12-24 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2001/015328 WO2002057435A2 (en) | 2001-01-18 | 2001-12-27 | Bifunctional fusion proteins with glucocerebrosidase activity |
Country Status (13)
Country | Link |
---|---|
US (1) | US20040043457A1 (en) |
EP (1) | EP1392826A2 (en) |
JP (1) | JP2004525621A (en) |
KR (1) | KR20030067755A (en) |
CN (1) | CN1630720A (en) |
BR (1) | BR0116803A (en) |
CA (1) | CA2435037A1 (en) |
HU (1) | HUP0401300A3 (en) |
MX (1) | MXPA03006294A (en) |
NO (1) | NO20033247D0 (en) |
PL (1) | PL362394A1 (en) |
WO (1) | WO2002057435A2 (en) |
ZA (1) | ZA200306333B (en) |
Cited By (10)
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WO2007012188A1 (en) * | 2005-07-27 | 2007-02-01 | Qinghua Wang | GLP/1/EXENDM 4 IgG Fc FUSION CONSTRUCTS FOR TREATMENT OF DIABETES |
EP2256134A1 (en) * | 2003-11-13 | 2010-12-01 | Hanmi Pharmaceutical Co., Ltd. | IgG Fc fragment for a drug carrier and method for the preparation thereof |
WO2011107991A1 (en) * | 2010-03-02 | 2011-09-09 | Protalix Ltd. | Glucocerebrosidase multimers and uses thereof |
US8110665B2 (en) | 2003-11-13 | 2012-02-07 | Hanmi Holdings Co., Ltd. | Pharmaceutical composition comprising an immunoglobulin FC region as a carrier |
US8742079B2 (en) | 2007-08-20 | 2014-06-03 | Protalix Ltd. | Saccharide-containing protein conjugates and uses thereof |
US9194011B2 (en) | 2009-11-17 | 2015-11-24 | Protalix Ltd. | Stabilized alpha-galactosidase and uses thereof |
US9732333B2 (en) | 2011-01-20 | 2017-08-15 | Protalix Ltd. | Nucleic acid construct for expression of alpha-galactosidase in plants and plant cells |
US10604576B2 (en) | 2016-06-20 | 2020-03-31 | Kymab Limited | Antibodies and immunocytokines |
US11753479B2 (en) | 2014-03-04 | 2023-09-12 | Kymab Limited | Nucleic acids encoding anti-OX40L antibodies |
US11779604B2 (en) | 2016-11-03 | 2023-10-10 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses and methods |
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Publication number | Priority date | Publication date | Assignee | Title |
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ATE267215T1 (en) | 1997-12-08 | 2004-06-15 | Lexigen Pharm Corp | HETERODIMARY FUSION PROTEINS FOR USE FOR TARGETED IMMUNTHERAPY AND GENERAL IMMUNE EXCITATION |
JP2002511432A (en) * | 1998-04-15 | 2002-04-16 | レキシジェン ファーマシューティカルズ コーポレイション | Enhancement of antibody-cytokine fusion protein-mediated immune response by co-administration of an angiogenesis inhibitor |
SK782002A3 (en) | 1999-07-21 | 2003-08-05 | Lexigen Pharm Corp | FC fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
HUP0202442A3 (en) * | 1999-08-09 | 2005-01-28 | Lexigen Pharmaceuticals Corp L | Multiple cytokine-antibody complexes |
US20050202538A1 (en) * | 1999-11-12 | 2005-09-15 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
ATE336514T1 (en) * | 2000-02-11 | 2006-09-15 | Merck Patent Gmbh | INCREASE THE CIRCULATION HALF-LIFE OF ANTIBODIES-BASED FUSION PROTEINS |
PT1294401E (en) * | 2000-06-29 | 2007-11-09 | Merck Patent Gmbh | Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents |
KR20090010127A (en) * | 2001-03-07 | 2009-01-28 | 메르크 파텐트 게엠베하 | Expression technology for proteins containing a hybrid isotype antibody moiety |
WO2002079415A2 (en) * | 2001-03-30 | 2002-10-10 | Lexigen Pharmaceuticals Corp. | Reducing the immunogenicity of fusion proteins |
DK1383785T3 (en) * | 2001-05-03 | 2011-05-23 | Merck Patent Gmbh | Recombinant tumor-specific antibody and its use |
ATE542137T1 (en) * | 2001-12-04 | 2012-02-15 | Merck Patent Gmbh | IMMUNOCYTOKINE WITH MODULATED SELECTIVITY |
WO2004055056A1 (en) * | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | Humanized antibody (h14.18) of the mouse 14.18 antibody binding to gd2 and its fusion with il-2 |
US20050069521A1 (en) * | 2003-08-28 | 2005-03-31 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of interleukin-2 proteins |
DE602004013372T2 (en) | 2003-12-30 | 2009-07-02 | Merck Patent Gmbh | IL-7 FUSION PROTEINS WITH ANTIBODY PORTIONS, THEIR PREPARATION AND THEIR USE |
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Also Published As
Publication number | Publication date |
---|---|
ZA200306333B (en) | 2004-11-17 |
HUP0401300A2 (en) | 2004-09-28 |
HUP0401300A3 (en) | 2005-06-28 |
JP2004525621A (en) | 2004-08-26 |
PL362394A1 (en) | 2004-11-02 |
EP1392826A2 (en) | 2004-03-03 |
MXPA03006294A (en) | 2003-09-16 |
KR20030067755A (en) | 2003-08-14 |
CA2435037A1 (en) | 2002-07-25 |
NO20033247L (en) | 2003-07-17 |
CN1630720A (en) | 2005-06-22 |
US20040043457A1 (en) | 2004-03-04 |
WO2002057435A3 (en) | 2003-12-24 |
NO20033247D0 (en) | 2003-07-17 |
BR0116803A (en) | 2004-02-17 |
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