WO2005059543A1 - Diagnostics et therapeutique pour maladies associees au recepteur h963 couple a la proteine g - Google Patents

Diagnostics et therapeutique pour maladies associees au recepteur h963 couple a la proteine g Download PDF

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Publication number
WO2005059543A1
WO2005059543A1 PCT/EP2004/013553 EP2004013553W WO2005059543A1 WO 2005059543 A1 WO2005059543 A1 WO 2005059543A1 EP 2004013553 W EP2004013553 W EP 2004013553W WO 2005059543 A1 WO2005059543 A1 WO 2005059543A1
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disorders
diseases
polypeptide
hormone
cancer
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PCT/EP2004/013553
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English (en)
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Stefan Golz
Ulf Brüggemeier
Andreas Geerts
Holger Summer
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Bayer Healthcare Ag
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Publication of WO2005059543A1 publication Critical patent/WO2005059543A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH

Definitions

  • the nucleotide sequence of H963 is accessible in public databases by the accession number NM_013308 and is given in SEQ ID NO:l.
  • the amino acid sequence of H963 is depicted in SEQ ID NO:2.
  • H963 is published in WO200146454, WO9926973, WO9807859, EP837128, WO9833908 and US5723315.
  • Fig. 1 shows the nucleotide sequence of a H963 receptor polynucleotide (SEQ ID NO: 1).
  • Chimeric molecules may be constructed by introducing all or part of the nucleotide sequence of this invention into a vector containing additional nucleic acid sequence which might be expected to change any one or several of the following H963 characteristics: cellular location, distribution, ligand-binding affinities, interchain affinities, degradation/turnover rate, signaling, etc.
  • examples of the uses for hybridization probes include: histochemical uses such as identifying tissues that express H963; measuring mRNA levels, for instance to identify a sample's tissue type or to identify cells that express abnormal levels of H963; and detecting polymorphisms of H963.
  • the labeled probe is selected so that its sequence is substantially complementary to a segment of the test locus or a reference locus. As indicated above, the nucleic acid site to which the probe binds should be located between the primer binding sites for the upstream and downstream amplification primers.
  • PCR-based methods can be used to extend nucleic acid sequences encoding human H963, for example to detect upstream sequences of H963 gene such as promoters and regulatory elements.
  • restriction-site PCR uses universal primers to retrieve unknown sequence adjacent to a known locus. Genomic DNA is first amplified in the presence of a primer to a linker sequence and a primer specific to the known region. The amplified sequences are then subjected to a second round of PCR with the same linker primer and another specific primer internal to the first one. Products of each round of PCR are transcribed with an appropriate RNA polymerase and sequenced using reverse transcriptase.
  • Randomly-primed libraries are preferable, in that they will contain more sequences which contain the 5' regions of genes. Use of a randomly primed library may be especially preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries can be useful for extension of sequence into 5' non-transcribed regulatory regions.
  • a number of viral-based expression systems can be used to express H963 in mammalian host cells.
  • sequences encoding H963 can be ligated into an adenovirus transcription/translation complex comprising the late promoter and tripartite leader sequence. Insertion in a non-essential El or E3 region of the viral genome can be used to obtain a viable virus which is capable of expressing H963 in infected host cells [Engelhard, 1994)].
  • transcription enhancers such as the Rous sarcoma virus (RSV) enhancer, can be used to increase expression in mammalian host cells.
  • RSV Rous sarcoma virus
  • HACs Human artificial chromosomes
  • HACs also can be used to deliver larger fragments of DNA than can be contained and expressed in a plasmid.
  • HACs of 6M to 10M are constructed and delivered to cells via conventional delivery methods (e.g., liposomes, polycationic amino polymers, or vesicles).
  • Specific initiation signals also can be used to achieve more efficient translation of sequences encoding H963. Such signals include the ATG initiation codon and adjacent sequences. In cases where sequences encoding H963, its initiation codon, and upstream sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed.
  • exogenous translational control signals including the ATG initiation codon
  • the initiation codon should be in the correct reading frame to ensure translation of the entire insert.
  • Exogenous translational elements and initiation codons can be of various origins, both natural and synthetic.
  • cells can be allowed to grow for 1-2 days in an enriched medium before they are switched to a selective medium.
  • the purpose of the selectable marker is to confer resistance to selection, and its presence allows growth and recovery of cells which successfully express the introduced H963 sequences.
  • Resistant clones of stably transformed cells can be proliferated using tissue culture techniques appropriate to the cell type. Any number of selection systems can be used to recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase [Logan, (1984)] and adenine phosphoribosyltransferase [Wigler, (1977)] genes which can be employed in tk ⁇ or aprf cells, respectively.
  • marker gene expression suggests that a H963 polynucleotide is also present, its presence and expression may need to be confirmed. For example, if a sequence encoding H963 is inserted within a marker gene sequence, transformed cells containing sequences which encode H963 can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding H963 under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of H963 polynucleotide.
  • purification facilitating domains include, but are not limited to, metal chelating peptides such as histidine-tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized imrnunoglobulin, and the domain utilized in the FLAGS extension/affinity purification system (hnmunex Corp., Seattle, Wash.).
  • Antibody as used herein includes intact immunoglobulin molecules, as well as fragments thereof, such as Fab, F(ab') 2 , and Fv, which are capable of binding an epitope of H963. Typically, at least 6, 8, 10, or 12 contiguous amino acids are required to form an epitope. However, epitopes which involve non-contiguous amino acids may require more, e.g., at least 15, 25, or 50 amino acid.
  • Such adjuvants include, but are not limited to, Freund's adjuvant, mineral gels (e.g., aluminum hydroxide), and surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol).
  • mineral gels e.g., aluminum hydroxide
  • surface active substances e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol.
  • BCG Bacilli Calmette-Guerin
  • Corynebacterium parvum are especially useful.
  • Antibodies which specifically bind to H963 also can be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents.
  • Other types of antibodies can be constructed and used therapeutically in methods of the invention.
  • chimeric antibodies can be constructed as disclosed in WO 93/03151.
  • Modifications of H963 gene expression can be obtained by designing antisense oligonucleotides which will form duplexes to the control, 5', or regulatory regions of the H963 gene. Oligonucleotides derived from the transcription initiation site, e.g., between positions -10 and +10 from the start site, are preferred. Similarly, inhibition can be achieved using "triple helix" base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or chaperons. Therapeutic advances using triplex DNA have been described in the literature [Nicholls, (1993)]. An antisense oligonucleotide also can be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.
  • Antisense oligonucleotides which comprise, for example, 2, 3, 4, or 5 or more stretches of contiguous nucleotides which are precisely complementary to a H963 polynucleotide, each separated by a stretch of contiguous nucleotides which are not complementary to adjacent H963 nucleotides, can provide sufficient targeting specificity for H963 mRNA.
  • each stretch of complementary contiguous nucleotides is at least 4, 5, 6, 7, or 8 or more nucleotides in length.
  • the coding sequence of a H963 polynucleotide can be used to generate ribozymes which will specifically bind to mRNA transcribed from a H963 polynucleotide.
  • Methods of designing and constructing ribozymes which can cleave other RNA molecules in trans in a highly sequence specific manner have been developed and described in the art.
  • the cleavage activity of ribozymes can be targeted to specific RNAs by engineering a discrete "hybridization" region into the ribozyme.
  • the hybridization region contains a sequence complementary to the target RNA and thus specifically hybridizes with the target RNA.
  • Ribozymes can be introduced into cells as part of a DNA construct. Mechanical methods, such as microinjection, liposome-mediated transfection, electroporation, or calcium phosphate precipitation, can be used to introduce a ribozyme-containing DNA construct into cells in which it is desired to decrease H963 expression.
  • Determining the ability of the test compound to modulate the activity of H963 can be accomplished, for example, by determining the ability of H963 to bind to or interact with a target molecule.
  • the target molecule can be a molecule with which H963 binds or interacts with in nature, for example, a molecule on the surface of a cell which expresses H963, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule.
  • the target molecule can be a component of a signal transduction pathway which facilitates transduction of an extracellular signal (e.g., a signal generated by binding of a H963 ligand, through the cell membrane and into the cell.
  • the target H963 molecule can be, for example, a second intracellular protein which has catalytic activity or a protein which facilitates the association of downstream signaling molecules with H963. Determining the ability of H963 to bind to or interact with a target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of a polypeptide of the invention to bind to or interact with a target molecule can be accomplished by determining the activity of the target molecule.
  • non-ionic detergents such as n-
  • glutathione-S-transferase (GST) fusion proteins or glutathione-S-transferase fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical; St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the test compound or the test compound and either the non-adsorbed target protein or H963, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtitre plate wells are washed to remove any unbound components and complex formation is measured either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of binding or activity of H963 can be determined using standard techniques.
  • the test compound is preferably a small molecule which binds to and occupies the active site of H963 polypeptide, thereby making the ligand binding site inaccessible to substrate such that normal biological activity is prevented.
  • small molecules include, but are not limited to, small peptides or peptide-like molecules.
  • Potential ligands which bind to a polypeptide of the invention include, but are not limited to, the natural ligands of known H963 GPCRs and analogues or derivatives thereof.
  • the methods of computer based numerical modeling can be used to complete the structure or improve its accuracy.
  • Any recognized modeling method may be used, including parameterized models specific to particular biopolymers such as proteins or nucleic acids, molecular dynamics models based on computing molecular motions, statistical mechanics models based on thermal ensembles, or combined models.
  • standard molecular force fields representing the forces between constituent atoms and groups, are necessary, and can be selected from force fields known in physical chemistry.
  • the incomplete or less accurate experimental structures can serve as constraints on the complete and more accurate structures computed by these modeling methods.
  • the body has two adrenal glands.
  • the medulla of the adrenal glands secretes hormones such as adrenaline (epinephrine) that affect blood pressure, heart rate, sweating, and other activities also regulated by the sympathetic nervous system.
  • the cortex secretes many different hormones, including corticosteroids (cortisone-like hormones), androgens (male hormones), and mineral- ocorticoids, which control blood pressure and the levels of salt and potassium in the body.
  • corticosteroids cortisone-like hormones
  • androgens male hormones
  • mineral- ocorticoids which control blood pressure and the levels of salt and potassium in the body.
  • Thyroid cancer is any one of four main types of malignancy of the thyroid: papillary, follicular, anaplastic, or medullary.
  • cancer cells divide at a higher rate than do normal cells, but the distinction between the growth of cancerous and normal tissues is not so much the rapidity of cell division in the former as it is the partial or complete loss of growth restraint in cancer cells and their failure to differentiate into a useful, limited tissue of the type that characterizes the functional equilibrium of growth of normal tissue.
  • Cancer tissues may express certain molecular receptors and probably are influenced by the host's susceptibility and immunity and it is known that certain cancers of the breast and prostate, for example, are considered dependent on specific hormones for their existence.
  • Cancer according to 2) develops in connective tissues, including fibrous tissues, adipose (fat) tissues, muscle, blood vessels, bone, and cartilage like e.g. osteogenic sarcoma; liposarcoma, fibrosarcoma, synovial sarcoma.
  • Cancer according to 3) is cancer that develops in both epithelial and connective tissue.
  • Cancer disease within the scope of this definition may be primary or secondary, whereby primary indicates that the cancer originated in the tissue where it is found rather than was established as a secondary site through metastasis from another lesion.
  • Cancers and tumor diseases within the scope of this definition maybe benign or malign and may affect all anatomical structures of the body of a mammal.
  • malignant osteogenic sarcoma benign osteoma, cartilage tumors; like malignant chondrosarcoma or benign chondroma; bone marrow tumors like malignant myeloma or benign eosinophilic granuloma, as well as metastatic tumors from bone tissues at other locations of the body;
  • X) the mouth, throat, larynx, and the esophagus XI) the urinary bladder and the internal and external organs and structures of the urogenital system of male and female like ovaries, uterus, cervix of the uterus, testes, and prostate gland, XII) the prostate, XUI) the pancreas, like ductal carcinoma of the pancreas;
  • XIV) the lymphatic tissue like lymphomas and other tumors of lymphoid origin, XV) the skin, XVI) cancers and tumor diseases of all anatomical structures belonging to the respiration and respiratory systems including thoracal muscles
  • the human H963 is highly expressed in the following cancer tissues: stomach tumor, colon tumor, ileum tumor, liver tumor, lung tumor, breast tumor.
  • the expression in the above mentioned tissues and in particular the differential expression between diseased tissue stomach tumor and healthy tissue stomach, between diseased tissue colon tumor and healthy tissue colon, between diseased tissue ileum tumor and healthy tissue ileum, between diseased tissue liver tumor and healthy tissue liver, between diseased tissue lung tumor and healthy tissue lung, between diseased tissue breast tumor and healthy tissue breast demonstrates that the human H963 or mRNA can be utilized to diagnose of cancer. Additionally the activity of the human H963 can be modulated to treat cancer.
  • Inflammatory diseases comprise diseases triggered by cellular or non-cellular mediators of the immune system or tissues causing the inflammation of body tissues and subsequently producing an acute or chronic inflammatory condition.
  • hypersensitivity reactions of type I - IV, for example but not limited to hypersensitivity diseases of the lung including asthma, atopic diseases, allergic rhinitis or conjunctivitis, angioedema of the lids, hereditary angioedema, antireceptor hypersensitivity reactions and autoimmune diseases, Hashimoto's thyroiditis, systemic lupus erythematosus, Goodpasture's syndrome, pemphigus, myasthenia gravis, Grave's and Raynaud's disease, type B insulin-resistant diabetes, rheumatoid arthritis, psoriasis, Crohn's disease, scleroderma, mixed connective tissue disease, polymyositis, sarcoidosis, glomerulonephritis, acute or chronic host versus
  • the human H963 is highly expressed in the following tissues of the immune system and tissues responsive to components of the immune system as well as in the following tissues responsive to mediators of inflammation: pancreas liver cirrhosis, liver liver cirrhosis, leukocytes (peripheral blood), bone marrow, spleen liver cirrhosis.
  • pancreas liver cirrhosis pancreas liver cirrhosis, liver liver cirrhosis, leukocytes (peripheral blood), bone marrow, spleen liver cirrhosis.
  • pancreas liver cirrhosis pancreas liver cirrhosis and healthy tissue pancreas
  • diseased tissue liver liver cirrhosis and healthy tissue liver between diseased tissue spleen liver cirrhosis and healthy tissue spleen
  • the human H963 or mRNA can be utilized to diagnose of inflammatory diseases.
  • the activity of the human H963 can be modulated to treat inflammatory diseases.
  • Other resident cells such as smooth muscle cells, lung epithelial cells, mucus-producing cells, and nerve cells may also be abnormal in individuals with asthma and may contribute to its pathology. While the airway obstruction of asthma, presenting clinically as an intermittent wheeze and shortness of breath, is generally the most pressing symptom of the disease requiring immediate treatment, the inflammation and tissue destruction associated with the disease can lead to irreversible changes that eventually make asthma a chronic and disabling disorder requiring long-term management.
  • the human H963 is highly expressed in the following tissues of the respiratory system: leukocytes (peripheral blood), fetal lung, lung tumor, trachea.
  • leukocytes peripheral blood
  • fetal lung fetal lung
  • lung tumor trachea.
  • the expression in the above mentioned tissues demonstrates that the human H963 or mRNA can be utilized to diagnose of respiratory diseases. Additionally the activity of the human H963 can be modulated to treat those diseases.
  • the human H963 is highly expressed in the following urological tissues: spinal cord, prostate, bladder, penis.
  • the expression in the above mentioned tissues demonstrates that the human H963 or mRNA can be utilized to diagnose of urological disorders. Additionally the activity of the human H963 can be modulated to treat urological disorders.
  • Metabolic diseases often are caused by single defects in particular biochemical pathways, defects that are due to the deficient activity of individual enzymes or molecular receptors leading to the regulation of such enzymes. Hence in a broader sense disturbances of the underlying genes, their products and their regulation lie well within the scope of this definition of a metabolic disease.
  • metabolic diseases may affect 1) biochemical processes and tissues ubiquitous all over the body, 2) the bone, 3) the nervous system, 4) the endocrine system, 5) the muscle including the heart, 6) the skin and nervous tissue, 7) the urogenital system, 8) the homeostasis of body systems like water and electrolytes.
  • metabolic diseases according to 1) comprise obesity, amyloidosis, disturbances of the amino acid metabolism like branched chain disease, hyperaminoacidemia, hyperaminoaciduria, disturbances of the metabolism of urea, hyperammonemia, mucopolysaccharidoses e.g.
  • Maroteaux-Lamy syndrom storage diseases like glycogen storage diseases and lipid storage diseases, glycogenosis diseases like Cori's disease, malabsorption diseases like intestinal carbohydrate malabsorption, oligosaccharidase deficiency like maltase-, lactase-, sucrase-insuff ⁇ ciency, disorders of the metabolism of fructose, disorders of the metabolism of galactose, galactosaemia, disturbances of carbohydrate utilization like diabetes, hypoglycemia, disturbances of pyruvate metabolism, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, disturbances of the porphyrin metabolism, porphyrias, disturbances of the purine metabolism, lysosomal diseases, metabolic diseases of nerves and nervous systems like gangliosidoses, sphingolipidoses, sulfatidoses, leucodystroph
  • metabolic diseases comprise primary and secondary metabolic disorders associated with hormonal defects like any disorder stemming from either an hyperfunction or hypofunction of some hormone-secreting endocrine gland and any combination thereof. They comprise Sipple's syndrome, pituitary gland dysfunction and its effects on other endocrine glands, such as the thyroid, adrenals, ovaries, and testes, acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis, and thyroid cancer, over- or underproduction of the adrenal steroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, carcinoid syndrome, disturbances caused by the dysfunction of the parathyroid glands, pancreatic islet cell dysfunction, diabetes, disturbances of the endocrine system of the female like estrogen deficiency,
  • metabolic diseases comprise muscle weakness, myotonia, Duchenne's and other muscular dystrophies, dystrophia myotonica of Steinert, mitochondrial myopathies like disturbances of the catabolic metabolism in the muscle, carbohydrate and lipid storage myopathies, glycogenoses, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, primary myocardial disease, cardiomyopathy.
  • metabolic diseases according to 5 comprise muscle weakness, myotonia, Duchenne's and other muscular dystrophies, dystrophia myotonica of Steinert, mitochondrial myopathies like disturbances of the catabolic metabolism in the muscle, carbohydrate and lipid storage myopathies, glycogenoses, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, primary myocardial disease, cardiomyopathy.
  • metabolic diseases according to 6 comprise disorders of the ectoderm, neurofibromatosis, scleroderma and polyarteritis, Louis-Bar syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria.
  • metabolic diseases according to 7 comprise sexual dysfunction of the male and female.
  • metabolic diseases according to 8) comprise confused states and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, Liddle's syndrome, Bartter's syndrome, Fanconi's syndrome, renal electrolyte wasting, diabetes insipidus.
  • the human H963 is highly expressed in the following metabolic disease related tissues: pancreas liver cirrhosis, liver liver cirrhosis, spleen liver cirrhosis.
  • the expression in the above mentioned tissues and in particular the differential expression between diseased tissue pancreas liver cirrhosis and healthy tissue pancreas, between diseased tissue liver liver cirrhosis and healthy tissue liver, between diseased tissue spleen liver cirrhosis and healthy tissue spleen demonstrates that the human H963 or mRNA can be utilized to diagnose of metabolic diseases. Additionally the activity of the human H963 can be modulated to treat metabolic diseases.
  • the present invention provides for both prophylactic and therapeutic methods for cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders.
  • the regulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of H963.
  • An agent that modulates activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of the polypeptide, a peptide, a peptidomimetic, or any small molecule.
  • the agent stimulates one or more of the biological activities of H963. Examples of such stimulatory agents include the active H963 and nucleic acid molecules encoding a portion of H963.
  • the agent inhibits one or more of the biological activities of H963. Examples of such inhibitory agents include antisense nucleic acid molecules and antibodies.
  • the present invention provides methods of treating an individual afflicted with a disease or disorder characterized by unwanted expression or activity of H963 or a protein in the H963 signaling pathway.
  • the method involves administering an agent like any agent identified or being identifiable by a screening assay as described herein, or combination of such agents that modulate say upregulate or downregulate the expression or activity of H963 or of any protein in the H963 signaling pathway.
  • the method involves administering a regulator of H963 as therapy to compensate for reduced or undesirably low expression or activity of H963 or a protein in the H963 signaling pathway.
  • Stimulation of activity or expression of H963 is desirable in situations in which activity or expression is abnormally low and in which increased activity is likely to have a beneficial effect. Conversely, inhibition of activity or expression of H963 is desirable in situations in which activity or expression of H963 is abnormally high and in which decreasing its activity is likely to have a beneficial effect.
  • compositions suitable for administration typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • the invention includes pharmaceutical compositions comprising a regulator of H963 expression or activity (and/or a regulator of the activity or expression of a protein in the H963 signaling pathway) as well as methods for preparing such compositions by combining one or more such regulators and a pharmaceutically acceptable carrier. Also within the invention are pharmaceutical compositions comprising a regulator identified using the screening assays of the invention packaged with instructions for use. For regulators that are antagonists of H963 activity or which reduce H963 expression, the instructions would specify use of the pharmaceutical composition for treatment of cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders.
  • the polynucleotides encoding H963, or any fragment or complement thereof may be used for therapeutic purposes.
  • the complement of the polynucleotide encoding H963 may be used in situations in which it would be desirable to block the transcription of the mRNA.
  • cells may be transformed with sequences complementary to polynucleotides encoding H963.
  • complementary molecules or fragments may be used to modulate H963 activity, or to achieve regulation of gene function.
  • sense or antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding H963.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or sterotes
  • a glidant such as colloidal silicon dioxide
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • instructions for administration will specify use of the composition for cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders.
  • compositions which include an agonist of H963 activity, a compound which increases expression of H963, or a compound which increases expression or activity of a protein in the H963 signaling pathway or any combination thereof
  • the instructions for administration will specify use of the composition for cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders.
  • H963 A variety of protocols for measuring H963, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of H963 expression.
  • Normal or standard values for H963 expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably human, with antibody to H963 under conditions suitable for complex formation The amount of standard complex formation may be quantified by various methods, preferably by photometric means. Quantities of H963 expressed in subject samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.
  • the polynucleotides encoding H963 may be used for diagnostic purposes.
  • the polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs.
  • the polynucleotides may be used to detect and quantitate gene expression in biopsied tissues in which expression of H963 may be correlated with disease.
  • the diagnostic assay may be used to distinguish between absence, presence, and excess expression of H963, and to monitor regulation of H963 levels during therapeutic intervention.
  • Polynucleotide sequences encoding H963 may be used for the diagnosis of cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders associated with expression of H963.
  • the polynucleotide sequences encoding H963 may be used in Southern, Northern, or dot-blot analysis, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and ELISA assays; and in microarrays utilizing fluids or tissues from patient biopsies to detect altered H963 expression. Such qualitative or quantitative methods are well known in the art.
  • nucleotide sequences have hybridized with nucleotide sequences in the sample, and the presence of altered levels of nucleotide sequences encoding H963 in the sample indicates the presence of the associated disorder.
  • assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or in monitoring the treatment of an individual patient.
  • Another technique for drug screening which may be used provides for high throughput screening of compounds having suitable binding affinity to the protein of interest as described in published PCT application WO84/03564.
  • large numbers of different small test compounds are synthesized on a solid substrate, such as plastic pins or some other surface.
  • the test compounds are reacted with H963, or fragments thereof, and washed.
  • Bound H963 is then detected by methods well known in the art.
  • Purified H963 can also be coated directly onto plates for use in the aforementioned drug screening techniques.
  • non-neutralizing anti- bodies can be used to capture the peptide and immobilize it on a solid support.
  • compounds which inhibit activation of the G-protein coupled receptor may be employed for a variety of therapeutic purposes, for example, for the treatment of hypotension and/or hypertension, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders including schizophrenia, manic excitement, depression, delirium, dementia or severe mental retardation, dysMnesias, such as Huntington's disease or Tourett's syndrome, among others.
  • Compounds which inhibit G-protein coupled receptors have also been useful in reversing endogenous anorexia and in the control of bulimia.
  • Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals.
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD 50 /ED 50 .
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use.
  • the dosage contained in such compositions is preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Normal dosage amounts can vary from 0.1 micrograms to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
  • the reagent is preferably an antisense oligonucleotide or a ribozyme.
  • Polynucleotides which express antisense oligonucleotides or ribozymes can be intro- pokerd into cells by a variety of methods, as described above.
  • a reagent reduces expression of H963 gene or the activity of H963 by at least about 10, preferably about 50, more preferably about 75, 90, or 100% relative to the absence of the reagent.
  • test compound displaces a ligand which is first bound to the polypeptide.
  • Another object of the invention is a method of the above, wherein the contacting step is in a cell- free system.
  • Another object of the invention is a method of the above, wherein the polynucleotide is coupled to a detectable label.
  • Another object of the invention is a method of diagnosing a disease comprised in a group of diseases consisting of cardiovascular disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, gastrointestinal and liver diseases, cancer disorders, hematological disorders, respiratory diseases, neurological disorders and urological disorders in a mammal comprising the steps of (i) determining the amount of a H963 polynucleotide in a sample taken from said mammal, (ii) determining the amount of H963 polynucleotide in healthy and/or diseased mammal.
  • a disease is diagnosed, e.g., if there is a substantial similarity in the amount of H963 polynucleotide in said test mammal as compared to a diseased mammal.
  • selected peptides typically, about 15 residues in length, are synthesized using an Applied Biosystems Peptide Synthesizer Model 431 A using fmoc-chemistry and coupled to keyhole limpet hemocyanin (KLH; Sigma, St. Louis, MO) by reaction with M-maleimidobenzoyl-N- hydroxysuccimmide ester, MBS. If necessary, a cysteine is introduced at the N-terminus of the peptide to permit coupling to KLH. Rabbits are immunized with the peptide-KLH complex in complete Freund's adjuvant.
  • KLH keyhole limpet hemocyanin
  • MBS M-maleimidobenzoyl-N- hydroxysuccimmide ester
  • This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding H963 specifically compete with a test compound for binding to H963 polypeptides or fragments thereof. In this manner, the antibodies are used to detect the presence of any peptide which shares one or more antigenic determinants with H963.
  • the three-dimensional structure of a protein of interest, or of a protein-inhibitor complex is determined by x-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the polypeptide must be ascertained to elucidate the structure and to determine active site(s) of the molecule. Less often, useful information regarding the structure of a polypeptide is gained by modeling based on the structure of homologous proteins. In both cases, relevant structural information is used to design efficient inhibitors. Useful examples of rational drug design include molecules which have improved activity or stability or which act as inhibitors, agonists, or antagonists of native peptides.
  • Example 13 Use and Administration of Antibodies. Inhibitors, or Antagonists
  • LSTs Antibodies, inhibitors, or antagonists of H963 or other treatments and compunds that are limiters of signal transduction (LSTs), provide different effects when administered therapeutically.
  • LSTs are formulated in a nontoxic, inert, pharmaceutically acceptable aqueous carrier medium preferably at a pH of about 5 to 8, more preferably 6 to 8, although pH may vary according to the characteristics of the antibody, inhibitor, or antagonist being formulated and the condition to be treated. Characteristics of LSTs include solubility of the molecule, its half-life and antigenicity/immunogenicity. These and other characteristics aid in defining an effective carrier. Native human proteins are preferred as LSTs, but organic or synthetic molecules resulting from drug screens are equally effective in particular situations.
  • LSTs are delivered by known routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol; transdermal patch and bandage; injectable, intravenous and lavage formulations; and orally administered liquids and pills particularly formulated to resist stomach acid and enzymes.
  • routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol; transdermal patch and bandage; injectable, intravenous and lavage formulations; and orally administered liquids and pills particularly formulated to resist stomach acid and enzymes.
  • the particular formulation, exact dosage, and route of administration is determined by the attending physician and varies according to each specific situation.
  • Normal dosage amounts vary from 0.1 to 10 5 ⁇ g, up to a total dose of about 1 g, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature; see U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212.
  • Those skilled in the art employ different formulations for different LSTs.
  • Administration to cells such as nerve cells necessitates delivery in a manner different from that to other cells such as vascular endothelial cells.
  • Examples of these techniques include, but are not limited to: 1) Insertion of normal or mutant versions of DNA encoding a H963, by microinjection, electroporation, retroviral transfection or other means well known to those skilled in the art, into appropriately fertilized embryos in order to produce a transgenic animal or 2) homologous recombination of mutant or normal, human or animal versions of these genes with the native gene locus in transgenic animals to alter the regulation of expression or the structure of these H963 sequences.
  • the technique of homologous recombination is well known in the art.
  • microinjection needle which may be made from capillary tubing using a piper puller
  • the egg to be injected is put in a depression slide.
  • the needle is inserted into the pronucleus of the egg, and the DNA solution is injected.
  • the injected egg is then transferred into the oviduct of a pseudopregnant mouse which is a mouse stimulated by the appropriate hormones in order to maintain false pregnancy, where it proceeds to the uterus, implants, and develops to term.
  • microinjection is not the only method for inserting DNA into the egg but is used here only for exemplary purposes.
  • McConnell et al. 1992 , Science 257, 1906-1912 Nicholls et al, 1993, J. Immunol. Meth. 165, 81-91 Piatak et al., 1993, BioTechmques 14:70-81 Piatak et al., 1993, Science 259:1749-1754 Porath et al, 1992, Prot. Exp. Purifi 3, 263-281 Roberge et al, 1995, Science 269, 202-204

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Abstract

L'invention concerne une H963 humaine qui est associée aux troubles cardio-vasculaires, aux troubles du système endocrinien et des hormones, aux maladies métaboliques, aux maladies inflammatoires, aux maladies gastro-intestinales et hépatiques, aux troubles cancéreux, aux troubles hématologiques, aux maladies respiratoires, aux troubles neurologiques et aux troubles urologiques. L'invention concerne également des dosages permettant d'identifier des composés utilisés pour traiter ou prévenir les troubles cardio-vasculaires, les troubles du système endocrinien et des hormones, les maladies métaboliques, les maladies inflammatoires, les maladies gastro-intestinales et hépatiques, les troubles cancéreux, les troubles hématologiques, les maladies respiratoires, les troubles neurologiques et les troubles urologiques. L'invention concerne enfin des composés qui se lient et/ou activent ou inhibent l'activité de H963 ainsi que des compositions pharmaceutiques comprenant lesdits composés.
PCT/EP2004/013553 2003-12-12 2004-11-30 Diagnostics et therapeutique pour maladies associees au recepteur h963 couple a la proteine g WO2005059543A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2390357A1 (fr) * 2006-06-02 2011-11-30 GlaxoSmithKline Biologicals S.A. Procédé d'identification si un patient est réactif ou non à l'immunothérapie basé sur l'expression différentielle du gène GPR171
KR101525229B1 (ko) * 2011-08-23 2015-06-01 한국생명공학연구원 Ｇｐｒ１７１ 단백질의 발현 또는 활성 억제제를 포함하는 암 치료 또는 암 전이 억제용 약학적 조성물

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Publication number Priority date Publication date Assignee Title
US5723315A (en) * 1996-08-23 1998-03-03 Genetics Institute, Inc. Secreted proteins and polynucleotides encoding them
WO2001046454A1 (fr) * 1999-12-23 2001-06-28 Cor Therapeutics, Inc. Recepteur p2y12

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US5723315A (en) * 1996-08-23 1998-03-03 Genetics Institute, Inc. Secreted proteins and polynucleotides encoding them
WO2001046454A1 (fr) * 1999-12-23 2001-06-28 Cor Therapeutics, Inc. Recepteur p2y12

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Title
GONZALEZ, NATHALIE SUAREZ ET AL: "The fate of P2Y-related orphan receptors: GPR80/99 and GPR91 are receptors of dicarboxylic acids", PURINERGIC SIGNALLING , 1(1), 17-20 CODEN: PSUIA9; ISSN: 1573-9538, 2004, XP002326644 *
SIMON, J. ET AL: "The P2Y nucleotide receptors in the human genome", ACTA BIOLOGICA HUNGARICA , 54(2), 191-201 CODEN: ABHUE6; ISSN: 0236-5383, 2003, XP009047148 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2390357A1 (fr) * 2006-06-02 2011-11-30 GlaxoSmithKline Biologicals S.A. Procédé d'identification si un patient est réactif ou non à l'immunothérapie basé sur l'expression différentielle du gène GPR171
KR101525229B1 (ko) * 2011-08-23 2015-06-01 한국생명공학연구원 Ｇｐｒ１７１ 단백질의 발현 또는 활성 억제제를 포함하는 암 치료 또는 암 전이 억제용 약학적 조성물

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