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WO1999046376A1 - Recepteur de la superfamille des recepteurs du facteur de necrose tumorale issu du poumon humain - Google Patents

Recepteur de la superfamille des recepteurs du facteur de necrose tumorale issu du poumon humain Download PDF

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Publication number
WO1999046376A1
WO1999046376A1 PCT/EP1999/001252 EP9901252W WO9946376A1 WO 1999046376 A1 WO1999046376 A1 WO 1999046376A1 EP 9901252 W EP9901252 W EP 9901252W WO 9946376 A1 WO9946376 A1 WO 9946376A1
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WIPO (PCT)
Prior art keywords
nucleic acid
protein
acid sequence
proteins
sequence
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Application number
PCT/EP1999/001252
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German (de)
English (en)
Inventor
Burkhard Kröger
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU29300/99A priority Critical patent/AU2930099A/en
Publication of WO1999046376A1 publication Critical patent/WO1999046376A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to new proteins from the superfamily of TNF receptors, especially from the human lung, their genes and their use. Furthermore, the invention relates to antibodies that specifically bind the new proteins. 0
  • the invention also relates to methods for identifying antagonists and / or agonists of these proteins of the invention, and a method for testing substances which are ligands of the proteins, and a method for qualitative and quantitative detection of proteins 5.
  • the invention further relates to a method for the qualitative and quantitative detection of the nucleic acids which code for the proteins according to the invention.
  • the TNF receptor family represents a super family integral
  • Membrane proteins that are involved in the signal transduction of a variety of cells In addition to the TNF receptors p55 and p75, this also includes other proteins such as CD27, OX40, and the Fas antigen (Armitage, RJ, Curr. Opin. Immunol. 6 (3) 1994: 5 407 ff.).
  • the receptors of this superfamily are characterized by four amino terminal, extracellular cysteine-rich, TNFR-like domains with strong conservation of the cystine bridges. There are 0 no homology of the intracellular portions of the TNF receptor superfamily members p55, p75, osteoprotegerin and the new receptor sequence described, suggesting a different signal transduction.
  • the representatives of this family are membrane-bound receptor forms.
  • the extracellular components / domains of the receptors can be released, as in the case of the TNF receptors (see: Lantz, M. et al. J. Clin. Invest. 86, 1990: 1396 ff.).
  • representatives of this family do not have a membrane anchor domain at all, but rather are released directly as "soluble", secreted receptors (Si onet, WS et al. Cell 89, 1997: 309ff.).
  • the TNF receptor family represents a super family integral
  • Membrane proteins which are involved in signal transduction in a variety of cells as described above. Due to the Due to the diverse physiological importance of the members of the TNF receptor superfamily, the task was to look for other members of this family and to make them available for the development of new drug targets or new drugs.
  • the essential biological property of the proteins according to the invention includes, for example, the four amino-terminal, extracellular, cysteine-rich TNFR-like domains with strong conservation of the cystine bridges. This property enables the special biological effects of the proteins.
  • the proteins according to the invention also have no homology within the typical intracellular sections of the TNF receptor superfamily members, such as to the proteins p55, p75.
  • the protein of the invention has no significant homology in the C-terminal region following the cysteine-rich region to the only soluble receptor of this family described so far, the osteoprotegerin.
  • the isolated protein and its functional variants can advantageously be isolated from the human lung, the heart and / or the kidney.
  • Another essential biological property can be seen in the ligand binding, in particular in the form of soluble receptors for these ligands.
  • proteins which still have the ligand binding activity and which can be produced by targeted changes based on the amino acid sequence shown in SEQ ID NO: 2.
  • certain amino acids can be replaced by those with similar physicochemical properties (space filling, basicity, hydrophobicity, etc.).
  • arginine residues are exchanged for lysine residues, valine residues for isoleucine residues or aspartic acid residues for glutamic acid residues.
  • one or more amino acids can also be interchanged, added or removed in their order, or several of these measures can be combined with one another.
  • the opposite way 3 of the SEQ ID NO: 2 modified proteins have at least 60%, preferably at least 75%, very particularly preferably at least 85% homology to SEQ ID NO: 2, calculated according to the algorithm by Pearson and Lipman, Proc. Natl. Acad. Sei (USA) 85, No. 8, 5 1988: 2444-2448.
  • the invention further relates to nucleic acid sequences which code for the abovementioned proteins, in particular those with the primary structure shown in SEQ ID NO: 1.
  • the nucleic acid sequences according to the invention also include allelic variants which, as described above for the amino acid sequences, can be obtained from the sequence shown in SEQ ID NO: 1 by deletion, inversion, insertion or substitution, the biological properties or the biolo - 5 genetic activity is retained.
  • nucleic acid sequences also include functional equivalents of the genes such as eukaryotic homologs, for example from evertebrates such as caenorhabditis or Drosophila or 0 vertebrates, advantageously from mammals such as mice, rats or monkeys, preferably from vertebrates which are capable of the biological activity of the gene or Gene product to take over.
  • eukaryotic homologs for example from evertebrates such as caenorhabditis or Drosophila or 0 vertebrates, advantageously from mammals such as mice, rats or monkeys, preferably from vertebrates which are capable of the biological activity of the gene or Gene product to take over.
  • nucleic acid sequences according to the invention also include shortened sequences, single-stranded DNA or RNA of the coding and non-coding DNA sequence, which have the biological properties.
  • the nucleic acid sequences also include derivatives such as promoter variants.
  • the promoters that precede the specified nucleotide sequences can be changed by one or more nucleotide exchanges, by inversions, by insertion (s) and / or deletion (s), but without the functionality or effectiveness of the promoters being impaired.
  • the effectiveness of the promoters can be increased by changing their sequence, or completely replaced by more effective promoters, including organisms of other species.
  • Derivatives are also to be understood as variants whose nucleotide sequence has been changed in the range from -1 to -1000 before the start codon in such a way that gene expression and / or protein expression is increased. 4
  • the present cDNA of the nucleic acid sequence can be introduced and expressed in vectors in suitable systems in a manner known to those skilled in the art.
  • the nucleic acid sequences according to the invention, their allele variants, their functional equivalents or derivatives are advantageously introduced and expressed as a recombinant nucleic acid construct in a suitable system.
  • Common cloning and transfection methods known to the person skilled in the art are advantageously used to bring the nucleic acids mentioned into expression in various expression systems. These systems are described, for example, in Current Protocols in Molecular Biology, ed. F. Ausubel et al. Wiley InterScience, New York 1997.
  • the nucleic acid sequence according to the invention is usually functionally linked to genetic regulatory elements such as transcription and translation signals. Depending on the desired application, this linkage can lead to an increase or decrease in gene expression. With the recombinant nucleic acid constructs produced in this way, host organisms are then transformed. In addition to these new regulatory sequences, the natural regulation of these sequences may still be present before the actual structural genes and may have been genetically modified so that the natural regulation has been switched off and the expression of the genes increased.
  • the gene construct can, however, also have a simpler structure, ie no additional regulation signals are inserted in front of the sequences and the natural promoter with its regulation is not removed. Instead, the natural regulatory sequence is mutated so that regulation no longer takes place and gene expression is increased. Additional advantageous regulatory elements can also be inserted at the 3 'end of the nucleic acid sequences.
  • the nucleic acid sequences can be contained in one or more copies in the gene construct.
  • Advantageous regulatory sequences for the method according to the invention are, for example, in promoters such as cos, tac, trp, tet, trp-tet, lpp, lac, lpp-lac, laclq, T7, T5, T3 , gal, trc, ara, SP6, 1-PR or contained in the 1-PL promoter, which are advantageously used in gram-negative bacteria.
  • promoters such as cos, tac, trp, tet, trp-tet, lpp, lac, lpp-lac, laclq, T7, T5, T3 , gal, trc, ara, SP6, 1-PR or contained in the 1-PL promoter, which are advantageously used in gram-negative bacteria.
  • Further advantageous regulatory sequences are, for example, in the gram-positive promoters amy and SP02, in the yeast promoters ADC1, MFa, AC, P-60, CYC1, GAPDH or in the plant promoters CaMV / 35S, SSU, OCS, lib4, usp, STLS1, B33 , nos or contained in the ubiquitin or phaseolin promoter. 5
  • regulatory sequences are intended to enable the targeted expression of the nucleic acid sequences and the protein expression. Depending on the host organism, this can mean, for example, that the gene is only expressed or overexpressed after induction, or that it is expressed and / or overexpressed immediately.
  • the regulatory sequences or factors can preferably have a positive influence on the expression and thereby increase it.
  • the regulatory elements can advantageously be strengthened at the transcription level by using strong transcription signals such as promoters and / or "enhancers".
  • an increase in translation is also possible, for example, by improving the stability of the mRNA.
  • Enhancers are understood to mean, for example, DNA sequences which bring about increased expression via an improved interaction between RNA polymerase and DNA.
  • a preferred embodiment is the linkage of the nucleic acid sequence according to the invention to a promoter, the promoter coming 5 'up stream. Further regulation signals such as terminators, polyadenylation signals, enhancers can be used in the nucleic acid construct.
  • the recombinant nucleic acid construct or gene construct is advantageously inserted into a host-specific vector, which enables optimal expression of the genes in the host.
  • Vectors are well known to those skilled in the art and can be found, for example, in the book Cloning Vectors (Eds. Pouwels P.H. et al. Elsevier, Amsterdam-New York-Oxford, 1985, ISBN 0 444 904018).
  • vectors are also understood to mean all other vectors known to the person skilled in the art, such as phages, viruses such as SV40, CMV, baculovirus, adenovirus, transposons, IS elements, phasmids, cosmids, linear or circular DNA. These vectors can be replicated autonomously in the host organism or can be replicated chromosomally.
  • all organisms which express the nucleic acids according to the invention, their allele variants, their functional equivalents or derivatives are suitable as host organisms 6 or the recombinant nucleic acid construct.
  • Host organisms are, for example, bacteria, fungi, yeasts, plant or animal cells.
  • Preferred organisms are bacteria such as Escherichia coli, Streptomyces, Bacillus or Pseudomonas, eukaryotic microorganisms such as Saccharomyces cerevisiae, Aspergillus, higher eukaryotic cells from animals or plants, for example Sf9 or CHO cells.
  • the gene product can also be used in transgenic organisms such as transgenic animals e.g. Mice, sheep or transgenic plants can be expressed.
  • transgenic organisms can also be so-called knock-out animals or plants.
  • plasmids such as plasmids, viruses or phages such as, for example, plasmids with the RNA polymerase / promoter system, which form phages 1, Mu or other tempered phages or transposons and / or further advantageous regulatory sequences
  • expression systems is preferably understood to mean, for example, the combination of mammalian cells such as CHO cells and vectors such as pcDNA3neo vector which are suitable for mammalian cells.
  • the present invention is a cDNA encoding a new member of the TNF receptor superfamily. Sequence comparisons with the amino acid sequence of the present receptor show similarities with the human osteoprotegerin (GenBank acc. No. U94332) and the human TNFRII p75 (GenBank acc. No. U52165). In both cases, the similarity is limited to the C-terminal half of the proteins, which essentially corresponds to the cysteine-rich domain, ie the ligand-binding domain.
  • the identity between SEQ ID NO: 2 (AS 34-193) and the human osteoprotegerin (AS 26-185) is 43%; the identity between SEQ ID NO: 2 (AS 3-134) and the human TNFRII (p75) (AS 8-139) was 27%. (FastA program, Pearson and Lipman, Proc. Natl. Acad. Sei (USA) 85, 2444-2448).
  • the polypeptide encoded by the present cDNA can be identified without a doubt as a member of the TNF receptor superfamily.
  • the extracellular, cysteine-rich domain known for the members of the TNF receptor superfamily is also found in the new receptor encoded by the nucleic acid sequence according to the invention.
  • the new receptor described does not have the membrane anchor domain known, for example, in the case of the TNF receptor II (p75, Goodwin, RG, Mol.Cell.Biol. Vol.11 No.6, 1991: 3020ff.), So that it can be assumed that the polypeptide according to the invention is a so-called "soluble" receptor that is secreted by the producing cell.
  • the gene product can also advantageously be used in transgenic animals, e.g. Mice, sheep or transgenic plants can be expressed. It is also possible to program cell-free translation systems with the RNA derived from the nucleic acid.
  • the gene product can also be expressed in the form of therapeutically or diagnostically suitable fragments.
  • vector systems or oligonucleotides can advantageously be used which extend the cDNA by certain nucleotide sequences and thus code for modified polypeptides which serve for easier purification.
  • anchors there are, for example, so-called “tags” in the literature e.g. Known hexa-histidine anchors or epitopes that can be recognized as antigens of various antibodies (described, for example, in Harlow, E. and Lane, D., 1988, Antibodies: A Laboratory Manual. Cold Spring Harbor (NY) Press) .
  • anchors can be used to attach the proteins to a solid support such as a polymeric matrix, which can be filled, for example, in a chromatography column, or to a microtiter plate or to another support.
  • these anchors can also be used to recognize the proteins.
  • customary markers such as fluorescent dyes, enzyme markers which form a detectable reaction product after reaction with a substrate, or a radioactive marker can be used alone or in combination with the anchors to derivatize the proteins.
  • synthetic peptides can be generated that are used individually or in combination as antigens for the production of antibodies. It is also possible to use the polypeptide or fragments thereof to generate antibodies. 8th
  • Antibodies mean both polyclonal, monoclonal, human or humanized antibodies or fragments thereof, single chain antibodies or synthetic antibodies.
  • the present cDNA also offers the prerequisite for cloning the genomic sequence of this new receptor gene. This also includes the associated regulatory or promoter sequence, which is accessible, for example, by sequencing the 5 'upstream region of the present cDNA.
  • Sequence information of the cDNA is also the basis for the production of antisense molecules or ribozymes. This genomic DNA can also be used to produce the gene constructs described above.
  • nucleotide sequence or parts thereof Another possibility of using the nucleotide sequence or parts thereof is the generation of transgenic animals.
  • Transgenic overexpression or genetic knockout of the sequence information in suitable animal models can provide valuable additional information about the (patho-) physiology of the new receptor.
  • the described receptor protein according to claim 1
  • several methods of substitution can be used.
  • the protein can be applied, naturally or recombinantly, directly or by suitable measures in the form of its coding nucleic acid (DNA or RNA).
  • Any vectors for example both viral and non-viral vehicles, can be used for this purpose.
  • Another way is through the stimulation of the endogenous, body's own gene by suitable means. Turn-over or inactivation e.g. can be blocked by receptor kinases. Finally, agonists of this protein or receptor can be used.
  • inhibitors can be used. This inhibition can be achieved both by antisense molecules or ribozymes, or antibodies and oligonucleotides, and by low molecular weight compounds.
  • the receptor can also be blocked by antagonists.
  • the cDNA, the genomic DNA, the promoter, and the polypeptide, as well as partial fragments thereof can be used in recombinant or non-recombinant form for the development of a test system.
  • This test system is suitable for the activity of the promoter or of the protein in the presence of a test substance 9 to measure.
  • These are preferably simple measurement methods (colorimetric, luminometric, fluorimetric, immunological or radioactive type) which advantageously allow the rapid measurement of a large number of test substances in a so-called high-throughput screening.
  • the test systems described allow the binding or agonization or antagonization of test substances to be described in relation to the new receptor.
  • the determination of the amount, activity and distribution of the receptor or its underlying mRNA in the human body can serve for diagnosis, predisposition and monitoring for certain diseases.
  • the sequence of the cDNA and the genomic sequence can be used to make statements about the genetic causes and predispositions of certain diseases.
  • both DNA / RNA samples and unnatural DNA / RNA samples as well as antibodies of various types can be used.
  • the nucleotide sequence described or parts thereof in the form of suitable samples are used to detect point mutations or deletions / insertions.
  • the protein described can be used to determine and isolate its natural ligands.
  • the protein described can be used to determine and isolate artificial or synthetic ligands.
  • the recombinantly produced or purified natural protein can be derivatized in such a way that it bears modifications which allow it to be linked to carrier materials. Proteins bound in this way can be incubated with protein extracts or peptide libraries or other sources of ligands. Specifically bound peptides, proteins or low-molecular, non-proteinogenic substances can be isolated and characterized in this way.
  • the protein extracts used can advantageously originate from the lungs, heart, kidney or body fluids such as lymph, cerebrospinal fluid, blood or urine.
  • the ligands described above can be isolated by a method of testing substances for their ability to act as ligands for the protein according to claim 1, comprising the steps of: 10 a) recombinant expression of the protein according to claim 1, wherein the protein is provided with an anchor or marker which enables attachment to a support or the recognition or attachment to a support and the recognition of the protein,
  • the protein extracts (c) advantageously come from the lungs, heart or kidney.
  • the nucleic acid sequence according to the invention and the protein encoded by it can be used for the development of reagents, agonists and antagonists, for the diagnosis and therapy of chronic and acute diseases which are preferably associated with the expression of the protein sequence according to the invention with the increased or decreased expression of the sequence .
  • the developed reagents, agonists and / or antagonists can then be used for the production of pharmaceutical preparations for the treatment or diagnosis of diseases.
  • the invention further provides a method for the qualitative and quantitative detection of a nucleic acid according to claim 2 in a biological sample, which comprises the following steps:
  • the invention further comprises a method for the qualitative and quantitative detection of a protein according to claim 1 in a biological sample, which comprises the following steps:
  • Bio samples such as pieces of tissue, serum or blood taken from healthy subjects can serve as the standard.
  • the present cDNA sequence was found in the sequence analysis of cDNA clones from a human lung cDNA library. The sequence of this clone is described in SEQ ID N0: 1.
  • the expression of the new receptor was examined in 50 different human tissues by means of RNA dot blot analysis.
  • a blot from Clontech (# 7770-1) was hybridized with a receptor sample.
  • the sample was prepared by in vitro transcription of the corresponding cDNA in the presence of digoxigenin-labeled nucleotides. After stringent washing, the transcript was mainly found in the lungs, heart and kidneys.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
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  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne de nouvelles protéines de la superfamille des récepteurs du facteur de nécrose tumorale, issus notamment du poumon humain, les gènes et l'utilisation de ce récepteur. L'invention concerne également des anticorps fixant spécifiquement ces nouvelles protéines. Elle concerne aussi des méthodes pour identifier des antagonistes et/ou des agonistes de ces protéines, un procédé pour tester des substances qui sont des ligands desdites protéines, un procédé pour la détection qualitative et quantitative de ces protéines, ainsi qu'un procédé pour la détection qualitative et quantitative des acides nucléiques codant pour ces dernières.
PCT/EP1999/001252 1998-03-09 1999-02-26 Recepteur de la superfamille des recepteurs du facteur de necrose tumorale issu du poumon humain WO1999046376A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29300/99A AU2930099A (en) 1998-03-09 1999-02-26 Receptor from the superfamily of tnt-receptors from the human lung

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19809978.9 1998-03-09
DE1998109978 DE19809978A1 (de) 1998-03-09 1998-03-09 Neuer Rezeptor aus der menschlichen Lunge

Publications (1)

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WO1999046376A1 true WO1999046376A1 (fr) 1999-09-16

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AU (1) AU2930099A (fr)
DE (1) DE19809978A1 (fr)
WO (1) WO1999046376A1 (fr)

Cited By (3)

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EP1159286A4 (fr) * 1999-03-04 2003-01-15 Human Genome Sciences Inc Recepteurs du facteur de necrose tumorale 6 alpha et 6 beta
US7186800B1 (en) 1997-01-14 2007-03-06 Human Genome Sciences, Inc. Tumor necrosis factor 6α and 6β
US7285267B2 (en) 1997-01-14 2007-10-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α & 6β

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JP4303883B2 (ja) 1997-09-18 2009-07-29 ジェネンテック・インコーポレーテッド ＤｃＲ３ポリペプチドというＴＮＦＲ相同体
US6627199B1 (en) 1999-07-09 2003-09-30 Amgen Inc Isolation, identification and characterization of tmst2, a novel member of the TNF-receptor supergene family
AU6517800A (en) 1999-08-04 2001-03-05 Amgen, Inc. Ntr3, a member of the tnf-receptor supergene family
MXPA02001264A (es) 1999-08-04 2002-07-22 Amgen Inc Fhm, nuevo miembro de la familia de supergenes de ligando de factor de necrosis tumoral.

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EP0861850A1 (fr) * 1997-02-04 1998-09-02 Smithkline Beecham Corporation Récepteurs TR4, liés à la nécrose tumorale
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7186800B1 (en) 1997-01-14 2007-03-06 Human Genome Sciences, Inc. Tumor necrosis factor 6α and 6β
US7285267B2 (en) 1997-01-14 2007-10-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α & 6β
US7534428B2 (en) 1997-01-14 2009-05-19 Human Genome Sciences, Inc. Antibodies to tumor necrosis factor receptors 6α and 6β
US7709218B2 (en) 1997-01-14 2010-05-04 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α and 6β
US8003386B1 (en) 1997-01-14 2011-08-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α and 6β
EP1159286A4 (fr) * 1999-03-04 2003-01-15 Human Genome Sciences Inc Recepteurs du facteur de necrose tumorale 6 alpha et 6 beta

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AU2930099A (en) 1999-09-27

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