WO2004083232A2 - Proteines receptrices - Google Patents

Proteines receptrices Download PDF

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Publication number
WO2004083232A2
WO2004083232A2 PCT/GB2004/001159 GB2004001159W WO2004083232A2 WO 2004083232 A2 WO2004083232 A2 WO 2004083232A2 GB 2004001159 W GB2004001159 W GB 2004001159W WO 2004083232 A2 WO2004083232 A2 WO 2004083232A2
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WO
WIPO (PCT)
Prior art keywords
inflammatory bowel
bowel disease
ccrl2
polynucleotide
individual
Prior art date
Application number
PCT/GB2004/001159
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English (en)
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WO2004083232A3 (fr
Inventor
Roy Pettipher
Original Assignee
Oxagen Limited
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Publication date
Application filed by Oxagen Limited filed Critical Oxagen Limited
Publication of WO2004083232A2 publication Critical patent/WO2004083232A2/fr
Publication of WO2004083232A3 publication Critical patent/WO2004083232A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the probe is used in a heteroduplex analysis based system, h such a system when the probe is bound to polynucleotide sequence containing the polymo ⁇ hism it forms a heteroduplex at the site where the polymo ⁇ hism occurs (i.e. it does not form a double strand structure).
  • a heteroduplex structure can be detected by the use of single or double strand specific enzyme.
  • the probe is an RNA probe, the heteroduplex region is cleaved using RNAase H and the polymo ⁇ hism is detected by detecting the cleavage products.
  • a computer system may also be used to determine the suitability of an individual to treatment using a particular therapeutic agent.
  • a computer system suitable for such a use typically comprises means for determining whether an individual predisposed to inflammatory bowel disease has a polymo ⁇ hism that enhances or reduces the efficacy of an agent used in the treatment of inflammatory bowel disease.
  • an agent for use in the treatment or prevention of inflammatory bowel disease is preferably an agonist or potentiator of CCRL2 activity or an agent which enhances expression of CCRL2.
  • a therapeutic agent is typically an antagonist of
  • the agent may bind to an endogenous chemokine that interacts with the CCRL2 receptor to prevent receptor activation, for example the agent may be an antibody to an endogenous chemokine.
  • the invention further provides an agent identified by such a method and the use of such an agent in the manufacture of a medicament for use in preventing or treating inflammatory bowel disease.
  • An agent identified by such a method and the use of such an agent in the manufacture of a medicament for use in preventing or treating inflammatory bowel disease is also provided.
  • the invention also provides a method of formulating a pharmaceutical composition comprising:
  • the invention provides a CCRL2 protein which contains a polymo ⁇ hism that causes, contributes or predisposes to or is associated with inflammatory bowel disease.
  • the polynucleotide is typically at least 10, 15, 20, 30, 50, 100, 200, 500, bases long, such as at least (or up to) lkb, lOkb, lOOkb, 1000 kb or more in length.
  • the polynucleotide may be RNA or DNA, including genomic DNA, synthetic DNA or cDNA.
  • the polynucleotide may be single or double stranded.
  • the polynucleotide may comprise synthetic or modified nucleotides, such as methylphosphonate and phosphorothioate backbones or the addition of acridine or polylysine chains at the 3' and/or 5' ends of the molecule.
  • Promoters and other expression regulation signals may be selected to be compatible with the host cell for which expression is designed.
  • yeast promoters include S. cerevisiae GAL4 and ADH promoters, S. pornbe nmt ⁇ and adh promoter.
  • Mammalian promoters include the metallothionein promoter which can be induced in response to heavy metals such as cadmium.
  • Viral promoters such as the SV40 large T antigen promoter or adenovirus promoters may also be used.
  • the polynucleotide may be a probe or primer which is capable of selectively binding to a CCRL2 nucleic acid or protein.
  • the probe or primer is capable of selectively binding to a polymo ⁇ hism in the nucleic acid or protein.
  • the probe or primer more preferably comprises a nucleic acid sequence corresponding to a SNP in the CCRL2 gene associated with an individual's predisposition to inflammatory bowel disease (such as in Table 4).
  • the invention thus provides a probe or primer for use in a diagnostic method according to the invention, which probe or primer is capable of selectively detecting a polymo ⁇ liism in the CCRL2 polynucleotide associated with inflammatory bowel disease.
  • the probe is isolated or recombinant nucleic acid. Preferably it is from 10, 15, 20, 25 bases in length. It may correspond to or be antisense to the sequences set out in Table 4.
  • the polypeptide with CCRL2 activity is typically (a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 2 (b) a homologue of (a), or
  • Such hybridisation may be performed under conditions of medium to high stringency (for example 0.03M sodium chloride and 0.003M sodium citrate at from about 50°C to about 60°C).
  • medium to high stringency for example 0.03M sodium chloride and 0.003M sodium citrate at from about 50°C to about 60°C.
  • the invention provides a cell line comprising a CCRL2 polynucleotide having a polymo ⁇ hism associated with inflammatory bowel disease.
  • the cell line may have been modified to express the polypeptide of the invention.
  • Such cell lines include transient, or preferably stable higher eukaryotic cell lines, such as mammalian cells or insect cells, lower eukaryotic cells, such as yeast, or prokaryotic cells such as bacterial cells.
  • Particular examples of cells which may be modified by insertion of vectors encoding for a polypeptide according to the invention include mammalian HEK293T, CHO, HeLa and COS cells.
  • the cell line selected will be one which is not only stable, but also allows for mature glycosylation of a polypeptide. Expression may be achieved in transformed oocytes.
  • a non-human animal which is transgenic for a CCRL2 polynucleotide having a polymo ⁇ hism associated with inflammatory bowel disease or is a knockout for CCRL2 is also provided by the invention. Such an animal may thus not be able to express a functional
  • a still further aspect of the invention provides a method for determining the efficacy of an agent useful in the treatment of inflammatory bowel disease in an individual having a polymo ⁇ hism associated with inflammatory bowel disease in the CCRL2 polynucleotide, which method comprises: (i) providing a CCRL2 polynucleotide having said polymo ⁇ hism, or a protein encoded thereby; (ii) contacting said protein or gene with said agent; and (iii) determining whether said protein or gene interacts with said agent.
  • the gene or protein may be in a subject having the polymo ⁇ hism or in a non-human animal according to the invention.
  • Step (iii) may comprise monitoring the effect of administering the agent on one or more phenotype of inflammatory bowel disease.
  • homologues typically have at least 70% homology, preferably at least 80, 90%, 95%o, 97%o or 99%o homology, for example over a region of at least 15, 20, 30, 100 more contiguous nucleotides or amino acids.
  • polynucleotide or proteins will be homologues of SEQ ID NO's 1 and 2.
  • the homology may be calculated on the basis of nucleotide or amino acid identity (sometimes referred to as "hard homology").
  • the BLAST algorithm performs a statistical analysis of the similarity between two sequences; see e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5787.
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability
  • Antibodies of the invention can be produced by any suitable method. Means for preparing and characterising antibodies are well known in the art, see for example Harlow and Lane (1988) "Antibodies: A Laboratory Manual", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
  • an antibody may be produced by raising antibody in a host animal against the whole polypeptide or a fragment thereof, for example an antigenic epitope thereof, herein after the "immunogen".
  • the fragment may be any of the fragments mentioned herein (typically at least 10 or at least 15 amino acids long) and comprise a polymo ⁇ hism (such as any of the polymo ⁇ hisms mentioned herein).
  • the experimental animal is suitably a goat, rabbit, rat, mouse, guinea pig, chicken, sheep or horse.
  • the immimogen may be administered as a conjugate in which the inimunogen is coupled, for example via a side chain of one of the amino acid residues, to a suitable carrier.
  • the carrier molecule is typically a physiologically acceptable carrier.
  • the antibody obtained may be isolated and, if desired, purified.
  • Such reagents or instruments include one or more of the following: a means to detect the binding of the agent to the polymo ⁇ hism, a detectable label (such as a fluorescent label), an enzyme able to act on a polynucleotide (typically a polymerase, restriction enzyme, ligase, RNAse H or an enzyme which can attach a label to a polynucleotide), suitable buffer(s) (aqueous solutions) for enzyme reagents, PCR primers which bind to regions flanking the polymo ⁇ hism (e.g.
  • the kit may be, or include, an array such as a "DNAchip” comprising the specific binding agent, preferably a probe, of the invention.
  • an array such as a "DNAchip” comprising the specific binding agent, preferably a probe, of the invention.
  • the pharmaceutical carrier or diluent may be, for example, an isotonic solution.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • the dose may be determined according to various parameters, especially according to the substance used; the age, weight and condition of the patient to be treated; the route of administration; and the required regimen. Again, a physician will be able to detenmne the required route of administration and dosage for any particular patient.
  • a typical daily dose is from about 0.1 to 50 mg per kg, preferably from about O.lmg/kg to lOmg/kg of body weight, according to the activity of the specific inhibitor, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to 2 g.
  • Example 1 Determination of CCRL2 Gene Structure, Fragment design and PCR amplification
  • melting curves were empirically calculated by ninning each fragment at series of temperatures. Melting domains were analysed for each fragment and the optimum temperature identified by selecting the temperature at which the DNA fragment is 25% melted. This was carried out in conjunction with the WAVEMAKER Software (Transgenomic Inc), which predicts the temperature at which the double stranded DNA fragment will melt into separate strands.
  • the mutation detection temperatures selected for each fragment are detailed in Table 1.
  • DNA samples from 23 control individuals were amplified by PCR using the oligonucleotides and conditions in Tables 1-3. Individuals were analysed separately by DHPLC to scan for heteroduplex samples indicative of the presence of polymo ⁇ hisms in the DNA fragment. Heteroduplexes were identified based on separation differences when compared to homozygous individuals. To identify the position and nature of the polymo ⁇ hism, PCR products were sequenced initially using the Dynamic ET Terminator on an ABI 377 sequencer.
  • sequence chromatogram files were imported into the Sequencher sequence analysis program (GENE CODES Corp) and aligned to search for sequence variations. Products from both heterozygous and wild type individuals were sequenced in forward and reverse orientations to compare traces ( Figure 1). Table 1 : Annealing temperatures, primer sequences and TG Wave mutation and detection temperatures used for each CCRL2 scanning fragment.
  • CCRL201 and CCRL202 were to occur on the same chromosome (theoretical frequency 0.06%), the GAT sequence would encode Asp.
  • a pair of oligonucleotides for amplification by PCR was designed on either side of , each biallelic polymo ⁇ hism to produce a product size between 50bp and 350bp.
  • a sequencing oligonucleotide was designed to end within 30bp either 5' or 3' to each polymo ⁇ hic site. All amplification oligonucleotides used to generate the complementary strand to the sequencing primer were labelled with a 5' - Biotin.
  • sequencing oligonucleotide was annealed to the template by denaturing at 80°C for 2min and then cooling to room temperature for 10 min. Each marker/sample combination was then sequenced/genotyped by pyrosequencingTM on a PSQ96TM (Pyrosequencing AB). Genotype results were stored in the PSQ oracle® database ready for statistical analysis.
  • CCRL2 assay TD: Hs00243702_sl
  • the CCRL2 assay is not cDNA specific and a genomic RT negative control sample was also amplified to enable adjustment for any genomic contamination of samples.
  • An internal reference 'housekeeping' gene, L32 was also amplified from the same sample set in a separate reaction to enable the quantitative
  • PCR results for CCRL2 to be normalised for amount of input cDNA The L32 housekeeping assay was designed using Primer Express v 2.0.
  • the forward and reverse primer sequences were; For TCATCCGGCACCAGTCAGA, Rev TCTGGGTTTCCGCCAGTTAC.
  • the VIC labelled Taqman probe sequence was CTT AAT TTT GAC ATA TCG.
  • cDNA Approximately 50ng of cDNA was used in a 20ul PCR reaction with lx Universal Taqman master mix (Applied Biosystems).
  • the CCRL2 assay on demand primers were added at a concentration of 900nM and the probe at 250nM (Applied Biosystems).
  • the L32 housekeeping assay was optimised at a concentration of 200nM for the primers and 125nM of probe.
  • Real time amplification was performed using the 7900HT thermal cycler (Applied Biosystems).
  • An assay on demand product was used to amplify CCRL2 by quantitative PCR.
  • a genomic RT-negative control sample was also amplified to enable adjustment for any genomic contamination of samples.
  • a housekeeping gene L32 was run to adjust for varying levels of cDNA input.
  • the CCRL2 quantity values were extracted from the standard curve and normalised to the L32 values.
  • Figure 3 and 5 are graphs showing the normalised quantity versus tissue type. A full list of results can be found in Table 11. The results show a wide range of expression.
  • CCRL2 is expressed throughout the digestive tract. These data are presented in Figure 6.
  • the tissues showing highest expression of CCRL2 were the rectum, ascending and transverse Colon. Lower levels of expression were observed in the oseophagus, stomach, duodenum, jejunum, ileum, ileocecum, cecem descending colon and liver.
  • Chips were generated using Affymetrix 's standard photolithography methodology.
  • Hybridisation of the CustomExpress array was performed using the Affymetrix GeneChip® system. Hybridisation probes were prepared from 5ug of total RNA according to manufacturers instructions. 5ug of fragmented probe was hybridised to an Affymetrix Test3 array at 45°C for 16 hours. Array washing and probe detection was performed using the manufacturers standard protocols (Affymetrix). The Test3 arrays were scanned with the Agilent Gene Array scanner and data extracted using the MAS5 software (Affymetrix). Test array QC was performed according to the manufacturer's instructions. For probes passing test array QC, lOug were hybridised to the CustomExpress array at 45°C for 1.6 hours. Hybridisation, washing and detection conditions were performed according to manufacturers provided protocols The expression data was extracted using MAS 5 software (Affymetrix) to a target value of 100.
  • a custom Affymetrix array was manufactured with the probe sets TPC2138_s_at and TPC2078_s_at representing CCRL2.
  • the arrays were hybridised with cRNA from 28 tissues and cell lines. Five tissues have been duplicated using RNA from an alternative source.
  • Figure 5 graph shows the signal for each probe type versus tissue type with the call highlighted by colour. Present calls are white, marginal are grey and absent are black. All the results are smrmiarised in Table 13 the signal, P value and call (present or absent) for each tissue type.
  • TPC2138_s_at is called absent in Skin and TPC2078_at is present; TPC2138_s_at is called marginal in Stomach and TPC207_at is present; TPC2078_at being marginal in Heart (pooled) and TPC2138_s_at is absent;TPC2078_at is called marginal in Ovary and TPC2138_s_at is absent; TPC2078_at is called present in 28SC and TPC2138_s_at is absent; TPC2078_at is called marginal in Stimulated Jurkat and TPC2138_s_at is absent; TPC2078_at is called present in U937 Monocytes TPC2138_s_at is marginal.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

Cette invention concerne une méthode servant à déterminer si un individu est prédisposé à une maladie intestinale inflammatoire, laquelle méthode consiste à déterminer si l'individu présente un polymorphisme dans le polynucléotide ou la protéine CCRL2, lequel polymorphisme est associé à la maladie intestinale inflammatoire.
PCT/GB2004/001159 2003-03-20 2004-03-18 Proteines receptrices WO2004083232A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0306428.4 2003-03-20
GBGB0306428.4A GB0306428D0 (en) 2003-03-20 2003-03-20 Receptor proteins

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WO2004083232A2 true WO2004083232A2 (fr) 2004-09-30
WO2004083232A3 WO2004083232A3 (fr) 2005-01-20

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005057220A2 (fr) * 2003-12-05 2005-06-23 Oxagen Limited Ligands
WO2007055636A1 (fr) * 2005-11-08 2007-05-18 Astrazeneca Ab Polymorphismes à nucléotide unique dans le gène ckrx associés à une maladie respiratoire
WO2010072389A1 (fr) 2008-12-22 2010-07-01 Robert Bosch Gesellschaft mbH für medizinische Forschung Procédé de détermination de la prédisposition pour la maladie de crohn

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998039441A1 (fr) * 1997-03-06 1998-09-11 Incyte Pharmaceuticals, Inc. Chemokine de type recepteur de chemokine humaine
WO2001046698A2 (fr) * 1999-12-20 2001-06-28 Chemocentryx, Inc. Ligands captifs et procedes d'utilisation
WO2002061087A2 (fr) * 2000-12-19 2002-08-08 Lifespan Biosciences, Inc. Peptides antigeniques destines a des recepteurs couples a la proteine g (gpcr), anticorps s'y rapportant, et systeme d'identification desdits peptides antigeniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998039441A1 (fr) * 1997-03-06 1998-09-11 Incyte Pharmaceuticals, Inc. Chemokine de type recepteur de chemokine humaine
WO2001046698A2 (fr) * 1999-12-20 2001-06-28 Chemocentryx, Inc. Ligands captifs et procedes d'utilisation
WO2002061087A2 (fr) * 2000-12-19 2002-08-08 Lifespan Biosciences, Inc. Peptides antigeniques destines a des recepteurs couples a la proteine g (gpcr), anticorps s'y rapportant, et systeme d'identification desdits peptides antigeniques

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005057220A2 (fr) * 2003-12-05 2005-06-23 Oxagen Limited Ligands
WO2005057220A3 (fr) * 2003-12-05 2006-02-02 Oxagen Ltd Ligands
US7521194B2 (en) 2003-12-05 2009-04-21 Oxagen Limited Method for detection of MIP-4 and CCRL2 binding and activity modulating agents
WO2007055636A1 (fr) * 2005-11-08 2007-05-18 Astrazeneca Ab Polymorphismes à nucléotide unique dans le gène ckrx associés à une maladie respiratoire
WO2010072389A1 (fr) 2008-12-22 2010-07-01 Robert Bosch Gesellschaft mbH für medizinische Forschung Procédé de détermination de la prédisposition pour la maladie de crohn
DE102008064509A1 (de) 2008-12-22 2010-10-21 Robert Bosch Gesellschaft mbH für medizinische Forschung Verfahren zur Bestimmung der Prädisposition für Morbus Crohn

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GB0306428D0 (en) 2003-04-23

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