WO2006005461A2 - Diagnostic et traitement des maladies associees au recepteur 27 couple aux proteines g (rcpg 27) - Google Patents

Diagnostic et traitement des maladies associees au recepteur 27 couple aux proteines g (rcpg 27) Download PDF

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Publication number
WO2006005461A2
WO2006005461A2 PCT/EP2005/007146 EP2005007146W WO2006005461A2 WO 2006005461 A2 WO2006005461 A2 WO 2006005461A2 EP 2005007146 W EP2005007146 W EP 2005007146W WO 2006005461 A2 WO2006005461 A2 WO 2006005461A2
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WO
WIPO (PCT)
Prior art keywords
diseases
gpr27
polypeptide
cancer
cells
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PCT/EP2005/007146
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English (en)
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WO2006005461A3 (fr
Inventor
Stefan Golz
Ulf Brüggemeier
Andreas Geerts
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Bayer Healthcare Ag
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Publication of WO2006005461A2 publication Critical patent/WO2006005461A2/fr
Publication of WO2006005461A3 publication Critical patent/WO2006005461A3/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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the invention also relates to pharmaceutical compositions for the treatment of cardiovascular diseases, dermatological diseases, endocrinological diseases, metabolic diseases, cancer, inflammation, gastroenterological diseases, hematological diseases, respiratory diseases, muscle skeleton diseases, neurological diseases and urological diseases in a mammal comprising a GPR27 polypeptide, a GPR27 polynucleotide, or regulators of GPR27 or modulators of GPR27 activity.
  • the invention further comprises methods of diagnosing cardiovascular diseases, dermatological diseases, endocrinological diseases, metabolic diseases, cancer, inflammation, gastroenterological diseases, hematological diseases, respiratory diseases, muscle skeleton diseases, neurological diseases and urological diseases in a mammal.
  • Derivative refers to polypeptides which have been chemically modified by techniques such as ubiquitination, labeling (see above), pegylation (derivatization with polyethylene glycol), and chemical insertion or substitution of amino acids such as ornithine which do not normally occur in human proteins.
  • PCR primers i.e., preparations of primers that are heterogeneous at given sequence locations, can be designed to amplify nucleic acid sequences that are highly homologous to, but not identical with GPR27.
  • Strategies are now available that allow for only one of the primers to be required to specifically hybridize with a known sequence.
  • appropriate nucleic acid primers can be ligated to the nucleic acid sought to be amplified to provide the hybridization partner for one of the primers. In this way, only one of the primers need be based on the sequence of the nucleic acid sought to be amplified.
  • host cells which contain a GPR27 polynucleotide and which express GPR27 can be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations and protein bioassay or immunoassay techniques which include membrane, solution, or chip-based technologies for the detection and/or quantification of nucleic acid or protein.
  • these procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations and protein bioassay or immunoassay techniques which include membrane, solution, or chip-based technologies for the detection and/or quantification of nucleic acid or protein.
  • the presence of a polynucleotide sequence encoding GPR27 can be detected by DNA-DNA or DNA-RNA hybridization or amplification using probes or fragments or fragments of polynucleotides encoding GPR27.
  • Nucleic acid amplification-based assays involve the use of oligonucleotides selected from sequences en
  • an antibody which specifically binds to GPR27 provides a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in an immunochemical assay.
  • antibodies which specifically bind to GPR27 do not detect other proteins in immunochemical assays and can immunoprecipitate GPR27 from solution.
  • chimeric antibodies the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity
  • Monoclonal and other antibodies also can be "humanized” to prevent a patient from mounting an immune response against the antibody when it is used therapeutically.
  • Such antibodies may be sufficiently similar in sequence to human antibodies to be used directly in therapy or may require alteration of a few key residues. Sequence differences between rodent antibodies and human sequences can be minimized by replacing residues which differ from those in the human sequences by site directed mutagenesis of individual residues or by grating of entire complementarity determining regions.
  • Antibodies which specifically bind to GPR27 can contain antigen binding sites which are either partially or fully humanized, as disclosed in U.S. 5,565,332.
  • a nucleotide sequence encoding a single-chain antibody can be constructed using manual or automated nucleotide synthesis, cloned into an expression construct using standard recombinant DNA methods, and introduced into a cell to express the coding sequence, as described below.
  • single-chain antibodies can be produced directly using, for example, filamentous phage technology.
  • Antibodies which specifically bind to GPR27 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.
  • Non-complementary intervening sequences are preferably 1, 2, 3, or 4 nucleotides in length.
  • One skilled in the art can easily use the calculated melting point of an antisense-sense pair to determine the degree of mismatching which will be tolerated between a particular antisense oligonucleotide and a particular GPR27 polynucleotide sequence.
  • Antisense oligonucleotides can be modified without affecting their ability to hybridize to a GPR27 polynucleotide. These modifications can be internal or at one or both ends of the antisense molecule.
  • the assay comprises contacting GPR27 expressing cell with a known compound which binds to GPR27 to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the GPR27 expressing cell, wherein determining the ability of the test compound to interact with the GPR27 expressing cell comprises determining the ability of the test compound to preferentially bind the GPR27 expressing cell as compared to the known compound.
  • a GPR27-like polypeptide can be used as a "bait protein" in a two-hybrid assay or three-hybrid assay [Szabo, (1995); U.S. 5,283,317), to identify other proteins which bind to or interact with GPR27 and modulate its activity.
  • the two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains.
  • the assay utilizes two different DNA constructs.
  • polynucleotide encoding GPR27 can be fused to a polynucleotide encoding the DNA binding domain of a known transcription factor (e.g., GAL-4).
  • a DNA sequence that encodes an unidentified protein (“prey" or "sample” can be fused to a polynucleotide that codes for the activation domain of the known transcription factor.
  • GPR27-like polypeptide or polynucleotide
  • test compound any method known in the art can be used to attach GPR27-like polypeptide (or polynucleotide) or test compound to a solid support, including use of covalent and non-covalent linkages, passive absorption, or pairs of binding moieties attached respectively to the polypeptide
  • microarray refers to an array of distinct polynucleotides or oligonucleotides arrayed on a substrate, such as paper, nylon or any other type of membrane, filter, chip, glass slide, or any other suitable solid support.
  • a GPR27 polynucleotide is contacted with a test compound, and the expression of an RNA or polypeptide product of GPR27 polynucleotide is determined.
  • the level of expression of appropriate mRNA or polypeptide in the presence of the test compound is compared to the level of expression of mRNA or polypeptide in the absence of the test compound.
  • the test compound can then be identified as a regulator of expression based on this comparison.
  • the three dimensional geometric structure of the active site is determined. This can be done by known methods, including X-ray crystallography, which can determine a complete molecular structure. On the other hand, solid or liquid phase NMR can be used to determine certain intramolecular distances. Any other experimental method of structure determination can be used to obtain partial or complete geometric structures.
  • the geometric structures may be measured with a complexed ligand, natural or artificial, which may increase the accuracy of the active site structure determined.
  • Visceral pain such as pancreatits, intestinal cystitis, dysmenorrhea, irritable Bowel syndrome, Crohn's disease, biliary colic, ureteral colic, myocardial infarction and pain syndromes of the pelvic cavity, e.g., vulvodynia, orchialgia, urethral syndrome and protatodynia are also CNS disorders.
  • Heart failure is defined as a pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirement of the metabolizing tissue. It includes all forms of pumping failures such as high-output and low- output, acute and chronic, right-sided or left-sided, systolic or diastolic, independent of the underlying cause.
  • Ischemic diseases are conditions in which the coronary flow is restricted resulting in a perfusion which is inadequate to meet the myocardial requirement for oxygen.
  • This group of diseases includes stable angina, unstable angina and asymptomatic ischemia.
  • hyperlipidemia abnormally high levels of fats (cholesterol, triglycerides, or both) in the blood, may be caused by family history of hyperlipidemia), obesity, a high-fat diet, lack of exercise, moderate to high alcohol consumption, cigarette smoking, poorly controlled diabetes, and an underactive thyroid gland), hereditary hyperlipidemias (type I hyperlipoproteinemia (familial hyperchylomicronemia), type II hyperlipoproteinemia (familial hypercholesterolemia), type IH hyperlipoproteinemia, type IV hyperlipoproteinemia, or type V hyperlipoproteinemia), hypol- ipoproteinemia, lipidoses (caused by abnormalities in the enzymes that metabolize fats), Gaucher's disease, Niemann-Pick disease, Fabry's disease, Wolman's disease, cerebrotendinous xanthomatosis, sitosterolemia, Refsum's disease, or Tay-Sachs disease.
  • hyperlipidemia abnormally high levels of fats (cholesterol,
  • the human GPR27 is highly expressed in adipose tissues. Expression in adipose demonstrates that the human GPR27 or mRNA can be utilized to diagnose of dyslipidemia diseases as an cardiovascular disorder. Additionally the activity of the human GPR27 can be modulated to treat - but not limited to - dyslipidemia diseases.
  • Granuloma annulare is a chronic skin condition of unknown cause in which small, firm, raised bumps form a ring with normal or slightly sunken skin in the center.
  • Sweating disorders also belong to skin disorders.
  • Sebaceous gland disorders can affect the sebaceous glands.
  • the sebaceous glands which secrete oil onto the skin, lie in the dermis, the skin layer just below the surface layer (epidermis).
  • Sebaceous gland disorders include acne, rosacea, perioral dermatitis, and sebaceous cysts.
  • Folliculitis is an inflammation of the hair follicles caused by infection with Staphylococcus. The infection damages the hairs, which can be easily pulled out.
  • Boils are large, tender, swollen, raised areas caused by staphylococcal infection around hair follicles.
  • Tinea versicolor is a fungal infection that causes white to light brown patches on the skin.
  • Scabies is a mite infestation that produces tiny reddish pimples and severe itching. Scabies is caused by the itch mite Sarcoptes scabiei.
  • Lice infestation causes intense itching and can affect almost any area of the skin. Head lice and pubic lice are two different species.
  • Vitiligo is a condition in which a loss of melanocytes results in smooth, whitish patches of skin, which may occur after unusual physical trauma and tends to occur with certain other diseases, including Addison's disease, diabetes, pernicious anemia, and thyroid disease.
  • osteomyelitis examples for bone and joint infections are osteomyelitis, and infectious arthritis.
  • cancer under the scope of the definition is not limited to simple benign neoplasia but comprises any other benign and malign neoplasia like 1) Carcinoma, 2) Sarcoma, 3) Carcinosarcoma, 4) Cancers of the blood-forming tissues, 5) tumors of nerve tissues including the brain, 6) cancer of skin cells.
  • Cancer according to 1) occurs in epithelial tissues, which cover the outer body (the skin) and line mucous membranes and the inner cavitary structures of organs e.g. such as the breast, lung, the respiratory and gastrointestinal tracts, the endocrine glands, and the genitourinary system.
  • 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;
  • XTV 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 and
  • the human GPR27 is highly expressed in the following tissues of the respiratory system: leukocytes (peripheral blood), bone marrow CD 15+ cells, neutrophils cord blood, neutrophils peripheral blood, fetal lung, lung, lung right upper lobe, lung tumor, lung COPD, trachea, primary bronchia, secondary bronchia.
  • leukocytes peripheral blood
  • bone marrow CD 15+ cells neutrophils cord blood
  • neutrophils peripheral blood fetal lung
  • lung lung right upper lobe
  • lung tumor lung COPD
  • trachea primary bronchia
  • secondary bronchia secondary bronchia
  • the human GPR27 is highly expressed in the following metabolic disease related tissues: thyroid, thyroid tumor, pancreas, pancreas liver cirrhosis, liver liver cirrhosis, spleen liver cirrhosis and adipose.
  • the expression in the above mentioned tissues and in particular the differential expression between diseased tissue pancreas liver cirrhosis and healthy tissue pancreas demonstrates that the human GPR27 or mRNA can be utilized to diagnose of metabolic diseases. Additionally the activity of the human GPR27 can be modulated to treat metabolic diseases.
  • the polynucleotides encoding GPR27 may be used for therapeutic purposes.
  • the complement of the polynucleotide encoding GPR27 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 GPR27.
  • complementary molecules or frag ⁇ ments may be used to modulate GPR27 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 GPR27.
  • a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding GPR27, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained from normal samples may be compared with values obtained from samples from patients who are symptomatic for a disorder. Deviation from standard values is used to establish the presence of a disorder.
  • 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.
  • Another object of the invention is a method of diagnosing a disease comprised in a group of diseases consisting of cardiovascular diseases, dermatological diseases, endocrinological diseases, metabolic diseases, cancer, inflammation, gastroenterological diseases, hematological diseases, respiratory diseases, muscle skeleton diseases, neurological diseases and urological diseases in a mammal comprising the steps of (i) determining the amount of a GPR27 polynucleotide in a sample taken from said mammal, (ii) determining the amount of GPR27 polynucleotide in healthy and/or diseased mammal.
  • a disease is diagnosed, e.g., if there is a substantial similarity in the amount of GPR27 polynucleotide in said test mammal as compared to a diseased mammal.
  • Another object of the invention is the use of regulators of a GPR27 for the preparation of a pharmaceutical composition for the treatment of a disease comprised in a group of diseases consisting of cardiovascular diseases, dermatological diseases, endocrinological diseases, metabolic diseases, cancer, inflammation, gastroenterological diseases, hematological diseases, respiratory diseases, muscle skeleton diseases, neurological diseases and urological diseases in a mammal.
  • the following reagents were prepared in a total of 25 ⁇ l : Ix TaqMan buffer A, 5.5 mM MgCl 2 , 200 nM of dATP, dCTP, dGTP, and dUTP, 0.025 U/ ⁇ l AmpliTaq GoldTM, 0.01 U/ ⁇ l AmpErase and Probel (SEQ ID NO: 5), GPR27 forward and reverse primers each at 200 nM, 200 nM GPR27 FAM/TAMRA-labelled probe, and 5 ⁇ l of template cDNA.
  • Thermal cycling parameters were 2 min at 5O 0 C, followed by 10 min at 95°C, followed by 40 cycles of melting at 95°C for 15 sec and annealing/extending at 60 0 C for 1 min.
  • PCR reactions were set up to quantitate the housekeeping genes (HKG) for each cDNA sample.
  • a target-specific antibody selected by functional assay, as described above, and then to solve its crystal structure.
  • This approach in principle, yields a pharmacore upon which subsequent drug design is based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids is expected to be an analog of the original receptor. The anti-id is then used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides then act as the pharmacore.
  • anti-ids anti-idiotypic antibodies

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention porte sur un récepteur RCPG27 qui est associé aux maladies cardio-vasculaires, aux maladies dermatologiques, aux maladies endocriniennes, aux maladies métaboliques, aux cancers, aux inflammations, aux maladies gastro-entérologiques, aux maladies hématologiques, aux maladies respiratoires, aux troubles musculo-squelettiques, aux maladies neurologiques, et aux maladies urologiques. L'invention porte également sur des méthodes d'analyse permettant d'identifier des composés pouvant servir au traitement ou à la prévention des maladies cardio-vasculaires, des maladies dermatologiques, des maladies endocriniennes, des maladies métaboliques, des cancers, des inflammations, des maladies gastro-entérologiques, des maladies hématologiques, des maladies respiratoires, des troubles musculo-squelettiques, des maladies neurologiques, et des maladies urologiques. L'invention concerne en outre des composés qui se lient au récepteur RCPG27 et/ou stimulent ou inhibent son activité, ainsi que des compositions pharmaceutiques contenant de tels composés.
PCT/EP2005/007146 2004-07-15 2005-07-02 Diagnostic et traitement des maladies associees au recepteur 27 couple aux proteines g (rcpg 27) WO2006005461A2 (fr)

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EP04016640.7 2004-07-15
EP04016640 2004-07-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014129895A1 (fr) * 2013-02-19 2014-08-28 Stichting Vu-Vumc Moyen et méthode d'augmentation de la sensibilité de cancers à la radiothérapie

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1067183A1 (fr) * 1998-03-12 2001-01-10 Yamanouchi Pharmaceutical Co. Ltd. Nouvelles proteines receptrices couplees aux proteines g
WO2001007482A1 (fr) * 1999-07-27 2001-02-01 Smithkline Beecham Corporation Gpr27, un recepteur couple a la proteine g
WO2002012344A2 (fr) * 2000-08-09 2002-02-14 Millennium Pharmaceuticals, Inc. Methodes d'utilisation d'un recepteur (14266) couple aux proteines g humaines
WO2005083128A2 (fr) * 2004-02-25 2005-09-09 University Of South Florida Methodes de prevision de l'issue d'un cancer et signatures genetiques utilisees dans celles-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1067183A1 (fr) * 1998-03-12 2001-01-10 Yamanouchi Pharmaceutical Co. Ltd. Nouvelles proteines receptrices couplees aux proteines g
US20030077662A1 (en) * 1998-03-12 2003-04-24 Yamanouchi Pharmaceutical Co., Ltd. Polynucleotides encoding SREB2 receptor
WO2001007482A1 (fr) * 1999-07-27 2001-02-01 Smithkline Beecham Corporation Gpr27, un recepteur couple a la proteine g
WO2002012344A2 (fr) * 2000-08-09 2002-02-14 Millennium Pharmaceuticals, Inc. Methodes d'utilisation d'un recepteur (14266) couple aux proteines g humaines
WO2005083128A2 (fr) * 2004-02-25 2005-09-09 University Of South Florida Methodes de prevision de l'issue d'un cancer et signatures genetiques utilisees dans celles-ci

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014129895A1 (fr) * 2013-02-19 2014-08-28 Stichting Vu-Vumc Moyen et méthode d'augmentation de la sensibilité de cancers à la radiothérapie

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