EP1144634A2 - Nouvelles proteines complexantes - Google Patents

Nouvelles proteines complexantes

Info

Publication number
EP1144634A2
EP1144634A2 EP00906186A EP00906186A EP1144634A2 EP 1144634 A2 EP1144634 A2 EP 1144634A2 EP 00906186 A EP00906186 A EP 00906186A EP 00906186 A EP00906186 A EP 00906186A EP 1144634 A2 EP1144634 A2 EP 1144634A2
Authority
EP
European Patent Office
Prior art keywords
component
proteins
jun
protein
receptor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00906186A
Other languages
German (de)
English (en)
Inventor
Valerie Jerome
Hans-Harald Sedlacek
Rolf Müller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Publication of EP1144634A2 publication Critical patent/EP1144634A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1055—Protein x Protein interaction, e.g. two hybrid selection
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/09—Fusion polypeptide containing a localisation/targetting motif containing a nuclear localisation signal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/71—Fusion polypeptide containing domain for protein-protein interaction containing domain for transcriptional activaation, e.g. VP16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/80—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor
    • C07K2319/81—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor containing a Zn-finger domain for DNA binding

Definitions

  • these proteins can be assigned to the following groups:
  • the mutations in the binding domains of the same or different proteins therefore have the purpose of preventing the ability to complex between an unmutated monomer and a mutant monomer of a pair of identical or different proteins or peptides that would complex in the unmutated state.
  • the mutations give such a pair of mutant proteins the ability to bind to one another with high specificity.
  • the mutations thus occur in pairs, one mutation being present in component b) and the other in component c) in such a way that a molecular interaction between the respective amino acids of such a pair is possible.
  • Such cells can be used to produce the protein according to the invention or can be administered to an organism itself for the purpose of prophylaxis or therapy.
  • Such nucleic acid constructs, inserted into a vector can, however, also be administered directly to an organism for the purpose of prophylaxis or therapy.
  • VZV varicella zoster virus
  • HHV-6 Herpes virus 6
  • the ligands include antibodies or antibody fragments directed against the virus antigens expressed on the cell membrane of virus-infected cells.
  • Retinoids e.g. "Retinoic acid” in acute promyelocytic leukemia.
  • cytostatic or cytotoxic antibodies include those directed against membrane structures of endothelial cells, as described, for example, by Burrows et al. (Pharmac. Ther. 64, 155 (1994)), Hughes et al., (Cancer Res. 49, 6214 (1989)) and Maruyama et al., (PNAS USA 87, 5744 (1990)). In particular, these include antibodies against the VEGF receptors.
  • MCP-2 - RANTES
  • Effectors Enzymes for the activation of precursors of cytostatics, for example for enzymes which cleave inactive pre-substances (prodrugs) into active cytostatics (drugs).
  • Oxidase in particular human lysyloxidase or human acidic D-aminooxidase
  • NGF Nerve growth factor
  • BDNF Brain-derived neurotrophic factor
  • Target structures proteins of the blood coagulation system such as
  • a component a) When used as a multifunctional ligand, a component a) must be selected which is directed against a cellular target structure. Examples of ligands (component a) specific for cellular target structures have already been listed in section 3).
  • the effector (component d) should be selected so that it binds to a viral vector or to a non-viral vector.
  • Such effectors are for example:
  • the murine monoclonal antibodies are preferably used in humanized form. Humanization takes place in the method described by Winter et al. (Nature 349, 293 (1991)) and Hoogenboom et al. (Rev. Tr. Transfus. Hemobiol. 36, 19 (1993)). Antibody fragments and recombinant Fv fragments are produced in accordance with the prior art and as already described.
  • These carriers include cationic polymers, peptides, proteins, polyamines or cationic lipids such as cationic lipids and phospholipids. Examples of antibodies against such carriers are
  • component d) is the receptor for the coat protein of the virus harboring the transgene.
  • viruses also have glycoproteins which are responsible both for virus attachment and subsequently for cell membrane fusion (Gaudin et al., J. Gen. Viro. 76, 1541 (1995)).
  • the invention further relates to multifunctional protein complexes which have a peptide sequence between component a) and b) or between component c) and d) which is cleavable for proteases.
  • the effector can be split off from the ligand (component a) or from the ligand and the mutated proteins [components a), b) and c)] and, for example, develop its effect in free form at the site of the enrichment of the multivalent protein complexes.
  • NLS nuclear localization signal
  • the cyclin A promoter regulates cell cycle-specific the transcription of the combined cDNAs for the activation domain of VP16 and the mutant leucine zipper of c-jun (activation subunit A) (FIG. 3)
  • the tyrosinase promoter restricts the transcription of the combined cDNAs for the Gal4 binding domain, the NLS of SV40 and the mutant leucine zipper of c-fos to melanoma cells (activation subunit B) (FIG. 3).
  • the individual components of the construct are linked and inserted into a plasmid (pGL3, Promega, Madison Wi USA) (FIG. 6) via suitable restriction sites which are carried out at the termini of the various elements via PCR amplification.
  • the linkage takes place with the aid of enzymes and DNA ligases which are known to the person skilled in the art and are specific for the restriction sites. These enzymes are commercially available.
  • Lung carcinoma xenografts were introduced into nude mice by subcutaneous injection of 2.10 7 H322 cells (H3 22, bronchoalveolar carcinomas, human ATCC No. CRL 5806).
  • Plasmid combination When the xenografts reached a size of 4 mm, they were co-injected intratumorally with the following plasmid combination in a carrier solution of 5% glucose, 0.01% Triton X100. Plasmid combination:
  • the pRL-SV40 vector was used as an internal control to standardize the results of the various xenografts.
  • MeWo (human melanoma) and H322 (bronchoalveolar lung carcinoma) cell lines were transfected with Lipofectin (Gibco BRL Inc.) and DOTAP (Boehringer Mannheim Inc.) as described by the manufacturer.
  • the cells were co-transfected with the following plasmids: pCDNA3 (Invitrogen Inc .; control): 1 ng CMV-luc + 1 ⁇ g Tyr-m-fos-CycA-VP16 + 1 ⁇ g pCDNA3
  • CMV-bax (Bax cDNA, cloned in pCDNA3): 1 ng CMV-luc + 1 ⁇ g Tyr-m-fos-CycA-VP16-m-jun + 1 ⁇ g CMV-bax
  • the luciferase values measured in the case of cotransfection with pCDNA3 and pBax (control plasmids which do not express Bax cDNA) were assumed to be 100% survival of the transfected cells.
  • the cells were collected 48 h after the transfection and the luciferase activity was measured.
  • the percentage of surviving transfected cells decreased in both cell types, to 9-10% for MeWo cells and to 32-36% for H322 cells.
  • the Tyr-m-fos-CycA-VP16, Tyr-m-fos-CycA-VP16-m-jun and the 10 x BS Gal4-SV40-luc transcription cassettes were determined by bacterial recombination as described by He et al. (1998), cloned in a human E1 / E3-deleted adenovirus (serotype 5).
  • the MeWo and H322 cells were either with for 6 hours

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)

Abstract

L'invention concerne un complexe à base de protéines spécifiquement complexantes n'intervenant pas de manière naturelle, qui contiennent les constituants suivants: a) au moins un ligand spécifique d'une structure cible; b) au moins une protéine contenant un domaine de dimérisation muté, ledit domaine de dimérisation muté ayant été dérivé par mutation d'un domaine de dimérisation intervenant de manière naturelle, ledit domaine de dimérisation muté peut entrer de manière spécifique en interaction avec le constituant b) et le constituant c) est lié de manière covalente au constituant d); et d) au moins un effecteur. L'invention concerne en outre l'utilisation et la préparation de ces complexes, ainsi que des produits de recombinaison d'acide nucléique codant pour les protéines mentionnées et leur utilisation.
EP00906186A 1999-01-12 2000-01-05 Nouvelles proteines complexantes Withdrawn EP1144634A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19900743A DE19900743A1 (de) 1999-01-12 1999-01-12 Neue komplexbildende Proteine
DE19900743 1999-01-12
PCT/EP2000/000029 WO2000042179A2 (fr) 1999-01-12 2000-01-05 Nouvelles proteines complexantes

Publications (1)

Publication Number Publication Date
EP1144634A2 true EP1144634A2 (fr) 2001-10-17

Family

ID=7893962

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00906186A Withdrawn EP1144634A2 (fr) 1999-01-12 2000-01-05 Nouvelles proteines complexantes

Country Status (12)

Country Link
US (2) US6495346B1 (fr)
EP (1) EP1144634A2 (fr)
JP (1) JP2002534121A (fr)
KR (1) KR20010089817A (fr)
CN (1) CN1340103A (fr)
AU (1) AU2796000A (fr)
CA (1) CA2359479A1 (fr)
DE (1) DE19900743A1 (fr)
HK (1) HK1042520A1 (fr)
MX (1) MXPA01006988A (fr)
WO (1) WO2000042179A2 (fr)
ZA (1) ZA200105427B (fr)

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US6346510B1 (en) * 1995-10-23 2002-02-12 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
KR100474114B1 (ko) * 2001-12-24 2005-03-08 대한민국 소 타일레리아병에 대한 면역원성이 증진된 융합단백질, 및 그의 제조방법 및 용도
US7906118B2 (en) * 2005-04-06 2011-03-15 Ibc Pharmaceuticals, Inc. Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology
WO2004015083A2 (fr) * 2002-08-08 2004-02-19 Insert Therapeutics, Inc. Compositions et utilisation de fractions de proteines liantes motrices
US8062891B2 (en) 2003-10-24 2011-11-22 Gencia Corporation Nonviral vectors for delivering polynucleotides to plants
CA2543257C (fr) 2003-10-24 2013-12-31 Gencia Corporation Procedes et compositions permettant de distribuer des polynucleotides
US8133733B2 (en) 2003-10-24 2012-03-13 Gencia Corporation Nonviral vectors for delivering polynucleotides to target tissues
US20090123468A1 (en) 2003-10-24 2009-05-14 Gencia Corporation Transducible polypeptides for modifying metabolism
US8507277B2 (en) 2003-10-24 2013-08-13 Gencia Corporation Nonviral vectors for delivering polynucleotides
US20060063930A1 (en) * 2004-08-20 2006-03-23 Agoston Gregory E Compositions and methods comprising proteinase activated receptor antagonists
ES2325344B1 (es) * 2004-11-02 2010-06-09 Univ Madrid Autonoma Inhibidores de angiogenesis multifuncionales y multivalentes.
JP5856059B2 (ja) * 2009-08-28 2016-02-09 ザ クリーブランド クリニック ファウンデーション 虚血組織を治療するためのｓｄｆ−１送達
EA020171B1 (ru) * 2009-11-09 2014-09-30 Илья Валерьевич ТИМОФЕЕВ Слитый белок, содержащий фактор роста фибробластов или его фрагмент и рецептор фактора роста фибробластов или его фрагмент, и применение белка для лечения или профилактики заболеваний или состояний, связанных с патологией сосудов
RU2486918C1 (ru) * 2011-10-25 2013-07-10 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Способ стимулирования восстановления периферической иннервации тканей с помощью векторных конструкций
RU2538621C2 (ru) * 2013-05-08 2015-01-10 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Способ стимулирования восстановления иннервации тканей после травм и ишемии с помощью векторной конструкции
CN113150086B (zh) * 2021-04-22 2022-10-11 成都欧林生物科技股份有限公司 幽门螺杆菌HefC重组蛋白及其应用

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Also Published As

Publication number Publication date
CA2359479A1 (fr) 2000-07-20
MXPA01006988A (es) 2002-04-24
HK1042520A1 (zh) 2002-08-16
US20030054409A1 (en) 2003-03-20
CN1340103A (zh) 2002-03-13
WO2000042179A3 (fr) 2000-11-16
ZA200105427B (en) 2002-07-16
DE19900743A1 (de) 2000-07-13
AU2796000A (en) 2000-08-01
WO2000042179A2 (fr) 2000-07-20
KR20010089817A (ko) 2001-10-08
US6495346B1 (en) 2002-12-17
JP2002534121A (ja) 2002-10-15

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