WO2012056232A1 - Biomarqueurs - Google Patents

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Publication number
WO2012056232A1
WO2012056232A1 PCT/GB2011/052078 GB2011052078W WO2012056232A1 WO 2012056232 A1 WO2012056232 A1 WO 2012056232A1 GB 2011052078 W GB2011052078 W GB 2011052078W WO 2012056232 A1 WO2012056232 A1 WO 2012056232A1
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protein
apolipoprotein
alpha
schizophrenia
biomarker
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PCT/GB2011/052078
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English (en)
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Sabine Bahn
Yishai Levin
Hassan Rahmoune
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Cambridge Enterprise Limited
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Publication of WO2012056232A1 publication Critical patent/WO2012056232A1/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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • the invention relates to a method of diagnosing or monitoring schizophrenia or other psychotic disorder.
  • Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality. It most commonly manifests as auditory hallucinations, paranoid or playful delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, with approximately 0.4-0.6% of the population affected. Diagnosis is based on the patient's self-reported experiences and observed behavior. No laboratory test for schizophrenia currently exists.
  • Schizophrenia is treated primarily with antipsychotic medications which are also referred to as neuroleptic drugs or neuroleptics.
  • Newer antipsychotic agents such as clozapine, olanzapine, quetiapine or risperidone are thought to be more effective in improving negative symptoms of psychotic disorders than older medication like Chlorpromazine. Furthermore, they induce less extrapyramidal side effects (EPS) which are movement disorders resulting from antipsychotic treatment.
  • EPS extrapyramidal side effects
  • the history of neuroleptics dates back to the late 19th century. The flourishing dye industry catalyzed development of new chemicals that lay the background to modern day atypical antipsychotics. Developments in anti-malaria, antihistamine and anaesthetic compounds also produced various neuroleptics. The common phenomenon to all these processes is a fundamental lack of
  • Apolipoprotein C-II APOC2
  • APOC2 Apolipoprotein C-II
  • Lumican two or more analytes selected from Apolipoprotein C-II (APOC2), Lumican,
  • Apolipoprotein B-100 Apolipoprotein B-100 (ApoB) and Fetuin-B (FETUB) as a biomarker for
  • a method of diagnosing or monitoring schizophrenia or other psychotic disorder, or predisposition thereto comprising detecting and/or quantifying, in a sample from a test subject, the analyte biomarkers defined herein.
  • a method of diagnosing schizophrenia or other psychotic disorder, or predisposition in an individual thereto comprising:
  • a method of monitoring efficacy of a therapy in a subject having, suspected of having, or of being predisposed to schizophrenia or other psychotic disorder comprising detecting and/or quantifying, in a sample from said subject, the analyte biomarkers defined herein.
  • a method of determining the efficacy of therapy for schizophrenia or other psychotic disorder in an individual subject comprising:
  • a further aspect of the invention provides ligands, such as naturally occurring or chemically synthesised compounds, capable of specific binding to the peptide biomarker.
  • a ligand according to the invention may comprise a peptide, an antibody or a fragment thereof, or an aptamer or oligonucleotide, capable of specific binding to the peptide biomarker.
  • the antibody can be a monoclonal antibody or a fragment thereof capable of specific binding to the peptide biomarker.
  • a ligand according to the invention may be labelled with a detectable marker, such as a luminescent, fluorescent or radioactive marker; alternatively or additionally a ligand according to the invention may be labelled with an affinity tag, e.g .
  • a biosensor according to the invention may comprise the peptide biomarker or a structural/shape mimic thereof capable of specific binding to an antibody against the peptide biomarker. Also provided is an array comprising a ligand or mimic as described herein.
  • ligands as described herein, which may be naturally occurring or chemically synthesised, and is suitably a peptide, antibody or fragment thereof, aptamer or oligonucleotide, or the use of a biosensor of the invention, or an array of the invention, or a kit of the invention to detect and/or quantify the peptide.
  • the detection and/or quantification can be performed on a biological sample such as from the group consisting of CSF, whole blood, blood serum, plasma, urine, saliva, or other bodily fluid, breath, e.g . as condensed breath, or an extract or purification therefrom, or dilution thereof. Diagnostic or monitoring kits are provided for performing methods of the invention.
  • kits will suitably comprise a ligand according to the invention, for detection and/or quantification of the peptide biomarker, and/or a biosensor, and/or an array as described herein, optionally together with instructions for use of the kit.
  • a further aspect of the invention is a kit for monitoring or diagnosing schizophrenia or other psychotic disorder, comprising a biosensor capable of detecting and/or quantifying the analyte biomarkers as defined herein.
  • Biomarkers for schizophrenia or other psychotic disorder are essential targets for discovery of novel targets and drug molecules that retard or halt progression of the disorder.
  • the biomarker is useful for identification of novel therapeutic compounds in in vitro and/or in vivo assays.
  • Biomarkers of the invention can be employed in methods for screening for compounds that modulate the activity of the peptide.
  • a ligand as described, which can be a peptide, antibody or fragment thereof or aptamer or oligonucleotide according to the invention; or the use of a biosensor according to the invention, or an array according to the invention; or a kit according to the invention, to identify a substance capable of promoting and/or of suppressing the generation of the biomarker.
  • Also there is provided a method of identifying a substance capable of promoting or suppressing the generation of the peptide in a subject comprising administering a test substance to a subject animal and detecting and/or quantifying the level of the peptide biomarker present in a test sample from the subject.
  • Apolipoprotein C-II APOC2
  • APOC2 Apolipoprotein C-II
  • APOC2 is a statistically significant biomarker for the diagnosis of schizophrenia after treatment with olanzapine, risperidone, quetiapine or a mixture thereof and APOC2 was additionally found to be statistically significant in samples obtained from two completely separate clinical centres. Furthermore, an additional validation study conducted with APOC2 demonstrated that increased levels of APOC2 were observed in serum following a 4 week treatment with either risperidone/quetiapine or olanzapine (see Table 2 and Figure 1).
  • Apolipoprotein B-100 Apolipoprotein B-100 (ApoB) and Fetuin-B (FETUB) as a biomarker for
  • the analyte is Apolipoprotein C-II (APOC2).
  • the use additionally comprises one or more further analytes selected from Lumican, Apolipoprotein B-100 (ApoB) and Fetuin-B (FETUB).
  • Apolipoprotein C-II APOC2
  • Lumican Apolipoprotein B-100
  • FETUB Fetuin- B
  • the use additionally comprises one or more further analytes selected from
  • Phospholipid transfer protein Cartilage oligomeric matrix protein, Keratin type II cytoskeletal 5 (KRT5), Zinc finger protein 57 (ZFP57), C-type mannose receptor 2 (MRC2), Beta-Ala-His dipeptidase (CNDPl), Mitogen-activated protein kinase 2 (M4K2), Apolipoprotein C-I, Attractin, Hemoglobin subunit epsilon (HBE), Ankyrin repeat domain-containing protein 58 (ANR58), Actin, aortic smooth muscle (ACTA), EGF-containing fibulin-like extracellular matrix protein 1
  • FBLN3 Dual specificity protein phosphatase CDC14B (CC14B), Nesprin-3 (SYNE3), Complement Clr subcomponent, Protein MCM 10 homolog (MCM10), Putative zinc-alpha-2-glycoprotein-like 1, Ceruloplasmin, Leucine-rich alpha-2- glycoprotein (A2GL), Elongation factor 1-gamma (EF1G), Ig gamma-1 chain C region (IGHG1), Insulin-like growth factor-binding protein 3 (IGFBP3), N- acetylated-alpha-linked acidic dipeptidase 2 (NALD2), Uncharacterized protein C9orf75 (CI075), Protein FAM83D (FA83D), Cytoplasmic aconitate hydratase, BTB/POZ domain-containing protein KCTD17, WD repeat-containing protein 23 (WDR23), Zinc finger protein 287 (ZN287), Mannan-binding lectin serine protease 1 (MASP1)
  • CFAH Complement factor H
  • SMC4 Structural maintenance of chromosomes protein 4
  • Kinesin-like protein KIF16B Kinesin-like protein KIF16B
  • MYPO Myelin protein PO
  • Forkhead box protein P3 (FOXP3), NACHT, LRR and PYD domains-containing protein 14, Apolipoprotein A-IV, Protein CLN8, Apolipoprotein C-III, Proteasome subunit alpha type-2 (PSA2), Glycosyltransferase-like protein LARGE1 (LARGE), Collagen alpha-l(XXII) chain (COMA1), Sulfhydryl oxidase 1 (QSOX1), RING finger protein 214 (RN214), Alpha-2-HS-glycoprotein, Plasma protease CI inhibitor (IC1), Apolipoprotein (a), Properdin (PROP), Complement factor H- related protein 1 (FHR1), Apolipoprotein C-I, Apolipoprotein E, Platelet basic protein (CXCL7), Paxillin (PAXI), Angiotensinogen, Clusterin, Complement component C8 beta chain (C08B), Pigment epithelium-derived factor (PEDF), CD
  • FBXOl l AP20 region protein 1 (APRG1), Gelsolin (GELS), Cold shock domain-containing protein El (CSDE1), KH domain-containing, RNA-binding, signal transduction-associated protein 1 (KHDRl), Keratin, type I cytoskeletal 26 (K1C26), Ig mu chain C region (IGHM), Complement component C7 (C07) and Synaptophysin-like protein 1 (SYPL1).
  • Protein MCM 10 homolog Putative zinc-alpha-2-glycoprotein-like 1, Ceruloplasmin, Leucine-rich alpha-2-glycoprotein, Elongation factor 1-gamma, Ig gamma-1 chain C region, Insulin-like growth factor-binding protein 3, N- acetylated-alpha-linked acidic dipeptidase 2, Uncharacterized protein C9orf75, Protein FAM83D, Cytoplasmic aconitate hydratase, BTB/POZ domain-containing protein KCTD17, WD repeat-containing protein 23, Zinc finger protein 287, Mannan-binding lectin serine protease 1, Thrombospondin-2, Ras-related protein Rab-18, Protein FAM98C, DNA-directed RNA polymerase I subunit RPA1, Zinc- alpha-2-glycoprotein, Ig lambda chain V-II region VIL, Carboxypeptidase N subunit 2, Polyadenylate-binding protein 4, Septin
  • the analyte biomarkers are selected from : Apolipoprotein C-II, Lumican,
  • the analyte biomarkers are selected from : Zinc-alpha-2-glycoprotein,
  • Carboxypeptidase N subunit 2 Inter-alpha-trypsin inhibitor heavy chain H I and Serine/threonine-protein kinase PDIK1 L
  • Apolipoprotein C-III Proteasome subunit alpha type-2, Glycosyltransferase-like protein LARGEl, Collagen alpha-l(XXII) chain, Sulfhydryl oxidase 1, RING finger protein 214, Alpha-2-HS-glycoprotein, Plasma protease CI inhibitor,
  • Apolipoprotein C-I Apolipoprotein C-I
  • Apolipoprotein E Platelet basic protein
  • Paxillin Paxillin
  • the analyte biomarkers are selected from : Apolipoprotein C-II, Lumican,
  • chromosomes protein 4 Kinesin-like protein KIF16B, Myelin protein PO,
  • Apolipoprotein C-I Apolipoprotein E, Paxillin, Clusterin, Pigment epithelium- derived factor, CD5 antigen-like, Complement Clr subcomponent, Keratin type I cytoskeletal 10, Biotinidase, Apolipoprotein M, Pregnancy zone protein, F-box only protein 11, AP20 region protein 1, Gelsolin, Cold shock domain-containing protein El, KH domain-containing RNA-binding signal transduction-associated protein 1, Keratin type I cytoskeletal 26 and Ig mu chain C region.
  • the analyte biomarkers are selected from : Plasma protease CI inhibitor, Platelet basic protein, Angiotensinogen, Complement component C8 beta chain, Complement component C7 and Synaptophysin-like protein 1.
  • Data is provided herein which demonstrates that levels of these analyte biomarkers were statistically decreased following treatment with olanzapine, risperidone, quetiapine or a mixture thereof in samples obtained from clinical centre 2.
  • one or more first analyte biomarkers selected from : Apolipoprotein C-II (APOC2), Keratin type II cytoskeletal 5 (KRT5), Zinc finger protein 57 (ZFP57), C-type mannose receptor 2 (MRC2), Beta-Ala-His dipeptidase (CNDP1), Mitogen- activated protein kinase 2 (M4K2), Hemoglobin subunit epsilon (HBE), Ankyrin repeat domain-containing protein 58 (ANR58), EGF-containing fibulin-like extracellular matrix protein 1 (FBLN3), Dual specificity protein phosphatase CDC14B (CC14B), Nesprin-3 (SYNE3), Protein MCM 10 homolog (MCM 10), Leucine-rich alpha-2-glycoprotein (A2GL), Elongation factor 1-gamma (EF1G), Uncharacterized protein C9orf75 (CI075), Protein FAM
  • Thrombospondin-4 (TSP4), Beta-l,4-galactosyltransferase 3 (B4GT3), 60S ribosomal export protein NMD3, Complement factor H (CFAH), Structural maintenance of chromosomes protein 4 (SMC4), Myelin protein PO (MYPO), Forkhead box protein P3 (FOXP3), NACHT, LRR and PYD domains-containing protein 14, Protein CLN8, Apolipoprotein C-III, Glycosyltransferase-like protein LARGE1 (LARGE), Collagen alpha-l(XXII) chain (COMA1), Sulfhydryl oxidase 1 (QSOXl), RING finger protein 214 (RN214), Plasma protease CI inhibitor (ICl), Properdin (PROP), Platelet basic protein (CXCL7), Paxillin (PAXI), Complement component C8 beta chain (C08B), Pigment epithelium-derived factor (
  • Synaptophysin-like protein 1 (SYPL1) as a biomarker for schizophrenia or other psychotic disorder, or predisposition thereto.
  • SYPL1 Synaptophysin-like protein 1
  • two or more second analyte biomarkers selected from : Lumican, Apolipoprotein B-100 (ApoB), Fetuin-B (FETUB), Phospholipid transfer protein, Cartilage oligomeric matrix protein, Apolipoprotein C-I, Attractin, Actin, aortic smooth muscle
  • ACTA Complement Clr subcomponent, Putative zinc-alpha-2-glycoprotein-like 1, Ceruloplasmin, Ig gamma-1 chain C region (IGHG1), Insulin-like growth factor-binding protein 3 (IGFBP3), N-acetylated-alpha-linked acidic dipeptidase 2 (NALD2), Cytoplasmic aconitate hydratase, WD repeat-containing protein 23 (WDR23), Zinc-alpha-2-glycoprotein, Leucine-rich glioma-inactivated protein 1 (LGI1), Transthyretin, Ig mu heavy chain, Ubiquilin-3 (UBQL3),
  • LGI1 Leucine-rich glioma-inactivated protein 1
  • Ubiquilin-3 Ubiquilin-3
  • Serine/threonine-protein kinase PDIK1L Kinesin-like protein KIF16B (KI16B), Apolipoprotein A-IV, Proteasome subunit alpha type-2 (PSA2), Alpha-2-HS- glycoprotein, Apolipoprotein (a), Complement factor H-related protein 1 (FHR1), Apolipoprotein C-I, Apolipoprotein E, Angiotensinogen, Clusterin, CD5 antigenlike (CD5L), Complement Clr subcomponent (C1R), Apolipoprotein M, Pregnancy zone protein (PZP), F-box only protein 11 (FBX11.
  • a method for classifying a psychotic patient such as a schizophrenia patient, as a responder or non-responder to antipsychotic therapy, such as schizophrenia therapy, comprising the steps of:
  • the data presented herein provides the applicability of the analyte biomarkers of the invention to predict which patients would respond well to antipsychotic treatment, based on a molecular signature rather than a subjective clinical assessment.
  • a method for monitoring patient compliance with antipsychotic therapy comprising the steps of:
  • biomarker means a distinctive biological or biologically derived indicator of a process, event, or condition.
  • Peptide biomarkers can be used in methods of diagnosis, e.g . clinical screening, and prognosis assessment and in monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, drug screening and development. Biomarkers and uses thereof are valuable for identification of new drug treatments and for discovery of new targets for drug treatment.
  • biosensor means anything capable of detecting the presence of the biomarker. Examples of biosensors are described herein.
  • references herein to "other psychotic disorder” relate to any appropriate psychotic disorder according to DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Assoc, Washington, D.C., 2000.
  • the other psychotic disorder is a psychotic disorder related to schizophrenia.
  • Examples of psychotic disorders related to schizophrenia include brief psychotic disorder delusional disorder, psychotic disorder due to a general medical condition, schizoeffective disorder, schizophreniform disorder, and substance-induced psychotic disorder.
  • one or more of the biomarkers defined hereinbefore may be replaced by a molecule, or a measurable fragment of the molecule, found upstream or downstream of the biomarker in a biological pathway.
  • Biosensors according to the invention may comprise a ligand or ligands, as described herein, capable of specific binding to the peptide biomarker. Such biosensors are useful in detecting and/or quantifying a peptide of the invention.
  • kits for the diagnosis and monitoring of schizophrenia or other psychotic disorder are described herein.
  • the kits additionally contain a biosensor capable of detecting and/or quantifying a peptide biomarker.
  • Monitoring methods of the invention can be used to monitor onset, progression, stabilisation, amelioration and/or remission.
  • detecting and/or quantifying the peptide biomarker in a biological sample from a test subject may be performed on two or more occasions. Comparisons may be made between the level of biomarker in samples taken on two or more occasions. Assessment of any change in the level of the peptide biomarker in samples taken on two or more occasions may be performed. Modulation of the peptide biomarker level is useful as an indicator of the state of schizophrenia or other psychotic disorder or predisposition thereto. An increase in the level of the biomarker, over time is indicative of onset or progression, i.e. worsening of this disorder, whereas a decrease in the level of the peptide biomarker indicates amelioration or remission of the disorder, or vice versa.
  • a method of diagnosis of or monitoring according to the invention may comprise quantifying the peptide biomarker in a test biological sample from a test subject and comparing the level of the peptide present in said test sample with one or more controls.
  • the control used in a method of the invention can be one or more control(s) selected from the group consisting of: the level of biomarker peptide found in a normal control sample from a normal subject, a normal biomarker peptide level; a normal biomarker peptide range, the level in a sample from a subject with schizophrenia or other psychotic disorder, or a diagnosed predisposition thereto; schizophrenia or other psychotic disorder biomarker peptide level, or schizophrenia or other psychotic disorder biomarker peptide range.
  • a method of diagnosing schizophrenia or other psychotic disorder, or predisposition thereto which comprises:
  • a lower level of the peptide biomarker in the test sample relative to the level in the normal control is indicative of the presence of schizophrenia or other psychotic disorder, or predisposition thereto; an equivalent or lower level of the peptide in the test sample relative to the normal control is indicative of absence of schizophrenia or other psychotic disorder and/or absence of a predisposition thereto.
  • diagnosis encompasses identification, confirmation, and/or characterisation of schizophrenia or other psychotic disorder, or predisposition thereto.
  • predisposition it is meant that a subject does not currently present with the disorder, but is liable to be affected by the disorder in time.
  • Methods of monitoring and of diagnosis according to the invention are useful to confirm the existence of a disorder, or predisposition thereto; to monitor development of the disorder by assessing onset and progression, or to assess amelioration or regression of the disorder.
  • Methods of monitoring and of diagnosis are also useful in methods for assessment of clinical screening, prognosis, choice of therapy, evaluation of therapeutic benefit, i.e. for drug screening and drug development.
  • Efficient diagnosis and monitoring methods provide very powerful "patient solutions” with the potential for improved prognosis, by establishing the correct diagnosis, allowing rapid identification of the most appropriate treatment (thus lessening unnecessary exposure to harmful drug side effects), reducing "downtime” and relapse rates.
  • test samples may be taken on two or more occasions.
  • the method may further comprise comparing the level of the biomarker(s) present in the test sample with one or more control(s) and/or with one or more previous test sample(s) taken earlier from the same test subject, e.g. prior to commencement of therapy, and/or from the same test subject at an earlier stage of therapy.
  • the method may comprise detecting a change in the level of the biomarker(s) in test samples taken on different occasions.
  • the invention provides a method for monitoring efficacy of therapy for schizophrenia or other psychotic disorder in a subject, comprising :
  • a decrease in the level of the peptide biomarker in the test sample relative to the level in a previous test sample taken earlier from the same test subject is indicative of a beneficial effect, e.g . stabilisation or improvement, of said therapy on the disorder, suspected disorder or predisposition thereto.
  • an increase in the level of the peptide biomarker in the test sample relative to the level in a previous test sample taken earlier from the same test subject is indicative of a beneficial effect, e.g . stabilisation or improvement, of said therapy on the disorder, suspected disorder or predisposition thereto.
  • Methods for monitoring efficacy of a therapy can be used to monitor the therapeutic effectiveness of existing therapies and new therapies in human subjects and in non-human animals (e.g. in animal models). These monitoring methods can be incorporated into screens for new drug substances and combinations of substances.
  • the time elapsed between taking samples from a subject undergoing diagnosis or monitoring will be 3 days, 5 days, a week, two weeks, a month, 2 months, 3 months, 6 or 12 months.
  • Samples may be taken prior to and/or during and/or following an anti-psychotic therapy. Samples can be taken at intervals over the remaining life, or a part thereof, of a subject.
  • detecting means confirming the presence of the peptide biomarker present in the sample.
  • Quantifying the amount of the biomarker present in a sample may include determining the concentration of the peptide biomarker present in the sample. Detecting and/or quantifying may be performed directly on the sample, or indirectly on an extract therefrom, or on a dilution thereof.
  • the presence of the peptide biomarker is assessed by detecting and/or quantifying antibody or fragments thereof capable of specific binding to the biomarker that are generated by the subject's body in response to the peptide and thus are present in a biological sample from a subject having schizophrenia or other psychotic disorder or a predisposition thereto.
  • Detecting and/or quantifying can be performed by any method suitable to identify the presence and/or amount of a specific protein in a biological sample from a patient or a purification or extract of a biological sample or a dilution thereof.
  • quantifying may be performed by measuring the concentration of the peptide biomarker in the sample or samples.
  • Biological samples that may be tested in a method of the invention include cerebrospinal fluid (CSF), whole blood, blood serum, plasma, urine, saliva, or other bodily fluid (stool, tear fluid, synovial fluid, sputum), breath, e.g . as condensed breath, or an extract or purification therefrom, or dilution thereof.
  • Biological samples also include tissue homogenates, tissue sections and biopsy specimens from a live subject, or taken post-mortem. The samples can be prepared, for example where appropriate diluted or concentrated, and stored in the usual manner.
  • the biomarker may be directly detected, e.g. by SELDI or MALDI-TOF.
  • the biomarker may be detected directly or indirectly via interaction with a ligand or ligands such as an antibody or a biomarker-binding fragment thereof, or other peptide, or ligand, e.g. aptamer, or oligonucleotide, capable of specifically binding the biomarker.
  • the ligand may possess a detectable label, such as a luminescent, fluorescent or radioactive label, and/or an affinity tag.
  • detecting and/or quantifying can be performed by one or more method(s) selected from the group consisting of: SELDI (-TOF), MALDI (- TOF), a 1-D gel-based analysis, a 2-D gel-based analysis, Mass spec (MS), reverse phase (RP) LC, size permeation (gel filtration), ion exchange, affinity, HPLC, UPLC and other LC or LC MS-based techniques.
  • Appropriate LC MS techniques include ICAT® (Applied Biosystems, CA, USA), or iTRAQ® (Applied Biosystems, CA, USA).
  • Liquid chromatography e.g. high pressure liquid chromatography (HPLC) or low pressure liquid chromatography (LPLC)
  • thin- layer chromatography e.g. high pressure liquid chromatography (HPLC) or low pressure liquid chromatography (LPLC)
  • NMR nuclear magnetic resonance
  • Methods of diagnosing or monitoring according to the invention may comprise analysing a sample of cerebrospinal fluid (CSF) by SELDI TOF or MALDI TOF to detect the presence or level of the peptide biomarker.
  • CSF cerebrospinal fluid
  • SELDI TOF or MALDI TOF a sample of cerebrospinal fluid
  • Detecting and/or quantifying the peptide biomarkers may be performed using an immunological method, involving an antibody, or a fragment thereof capable of specific binding to the peptide biomarker.
  • Suitable immunological methods include sandwich immunoassays, such as sandwich ELISA, in which the detection of the peptide biomarkers is performed using two antibodies which recognize different epitopes on a peptide biomarker; radioimmunoassays (RIA), direct, indirect or competitive enzyme linked immunosorbent assays (ELISA), enzyme immunoassays (EIA), Fluorescence immunoassays (FIA), western blotting, immunoprecipitation and any particle-based immunoassay (e.g . using gold, silver, or latex particles, magnetic particles, or Q-dots). Immunological methods may be performed, for example, in microtitre plate or strip format.
  • sandwich immunoassays such as sandwich ELISA, in which the detection of the peptide biomarkers is performed using two antibodies which recognize different epitopes on a peptide biomarker
  • RIA radioimmunoassays
  • ELISA direct, indirect or competitive enzyme linked immunosorbent assays
  • Immunological methods in accordance with the invention may be based, for example, on any of the following methods.
  • Immunoprecipitation is the simplest immunoassay method; this measures the quantity of precipitate, which forms after the reagent antibody has incubated with the sample and reacted with the target antigen present therein to form an insoluble aggregate. Immunoprecipitation reactions may be qualitative or quantitative.
  • particle immunoassays In particle immunoassays, several antibodies are linked to the particle, and the particle is able to bind many antigen molecules simultaneously. This greatly accelerates the speed of the visible reaction. This allows rapid and sensitive detection of the biomarker.
  • biomarker In immunonephelometry, the interaction of an antibody and target antigen on the biomarker results in the formation of immune complexes that are too small to precipitate. However, these complexes will scatter incident light and this can be measured using a nephelometer.
  • the antigen, i.e. biomarker, concentration can be determined within minutes of the reaction.
  • Radioimmunoassay (RIA) methods employ radioactive isotopes such as I 125 to label either the antigen or antibody.
  • the isotope used emits gamma rays, which are usually measured following removal of unbound (free) radiolabel .
  • the major advantages of RIA compared with other immunoassays, are higher sensitivity, easy signal detection, and well-established, rapid assays.
  • the major disadvantages are the health and safety risks posed by the use of radiation and the time and expense associated with maintaining a licensed radiation safety and disposal program. For this reason, RIA has been largely replaced in routine clinical laboratory practice by enzyme immunoassays.
  • EIA Enzyme immunoassays were developed as an alternative to radioimmunoassays (RIA). These methods use an enzyme to label either the antibody or target antigen. The sensitivity of EIA approaches that for RIA, without the danger posed by radioactive isotopes. One of the most widely used
  • EIA methods for detection is the enzyme-linked immunosorbent assay (ELISA).
  • ELISA methods may use two antibodies one of which is specific for the target antigen and the other of which is coupled to an enzyme, addition of the substrate for the enzyme results in production of a chemiluminescent or fluorescent signal.
  • Fluorescent immunoassay refers to immunoassays which utilize a fluorescent label or an enzyme label which acts on the substrate to form a fluorescent product. Fluorescent measurements are inherently more sensitive than colorimetric (spectrophotometric) measurements. Therefore, FIA methods have greater analytical sensitivity than EIA methods, which employ absorbance (optical density) measurement.
  • Chemiluminescent immunoassays utilize a chemiluminescent label, which produces light when excited by chemical energy; the emissions are measured using a light detector. Immunological methods according to the invention can thus be performed using well-known methods. Any direct (e.g ., using a sensor chip) or indirect procedure may be used in the detection of peptide biomarkers of the invention.
  • the Biotin-Avidin or Biotin-Streptavidin systems are generic labelling systems that can be adapted for use in immunological methods of the invention.
  • One binding partner hapten, antigen, ligand, aptamer, antibody, enzyme etc
  • biotin and the other partner surface, e.g .
  • biotinylated ligand e.g. antibody or aptamer
  • avidin or streptavidin an indirect immobilisation route rather than a direct one.
  • a biotinylated ligand e.g. antibody or aptamer
  • a sample containing or suspected of containing the peptide biomarker in order to detect and/or quantify a peptide biomarker of the invention.
  • Detection and/or quantification of the immobilised antigen may then be performed by an immunological method as described herein.
  • antibody as used herein includes, but is not limited to : polyclonal, monoclonal, bispecific, humanised or chimeric antibodies, single chain antibodies, Fab fragments and F(ab') 2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies and epitope-binding fragments of any of the above.
  • antibody as used herein also refers to immunoglobulin molecules and immunologically-active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen.
  • the immunoglobulin molecules of the invention can be of any class (e. g ., IgG, IgE, IgM, IgD and IgA) or subclass of immunoglobulin molecule.
  • biosensors appropriate diagnostic tools such as biosensors can be developed, accordingly, in methods and uses of the invention, detecting and quantifying can be performed using a biosensor, microanalytical system, microengineered system, microseparation system, immunochromatography system or other suitable analytical devices.
  • the biosensor may incorporate an immunological method for detection of the biomarker(s), electrical, thermal, magnetic, optical (e.g. hologram) or acoustic technologies. Using such biosensors, it is possible to detect the target biomarker(s) at the anticipated concentrations found in biological samples.
  • an apparatus for diagnosing or monitoring schizophrenia or other psychotic disorder which comprises a biosensor, microanalytical, microengineered, microseparation and/or immunochromatography system configured to detect and/or quantify any of the biomarkers defined herein.
  • the biomarker(s) of the invention can be detected using a biosensor incorporating technologies based on "smart" holograms, or high frequency acoustic systems, such systems are particularly amenable to "bar code" or array configurations.
  • a holographic image is stored in a thin polymer film that is sensitised to react specifically with the biomarker.
  • the biomarker reacts with the polymer leading to an alteration in the image displayed by the hologram.
  • the test result read-out can be a change in the optical brightness, image, colour and/or position of the image.
  • a sensor hologram can be read by eye, thus removing the need for detection equipment.
  • a simple colour sensor can be used to read the signal when quantitative measurements are required. Opacity or colour of the sample does not interfere with operation of the sensor.
  • the format of the sensor allows multiplexing for simultaneous detection of several substances. Reversible and irreversible sensors can be designed to meet different requirements, and continuous monitoring of a particular biomarker of interest is feasible.
  • biosensors for detection of one or more biomarkers of the invention combine biomolecular recognition with appropriate means to convert detection of the presence, or quantitation, of the biomarker in the sample into a signal .
  • Biosensors can be adapted for "alternate site" diagnostic testing, e.g. in the ward, outpatients' department, surgery, home, field and workplace.
  • Biosensors to detect one or more biomarkers of the invention include acoustic, plasmon resonance, holographic and microengineered sensors. Imprinted recognition elements, thin film transistor technology, magnetic acoustic resonator devices and other novel acousto-electrical systems may be employed in biosensors for detection of the one or more biomarkers of the invention.
  • Methods involving detection and/or quantification of one or more peptide biomarkers of the invention can be performed on bench-top instruments, or can be incorporated onto disposable, diagnostic or monitoring platforms that can be used in a non-laboratory environment, e.g . in the physician's office or at the patient's bedside.
  • Suitable biosensors for performing methods of the invention include "credit" cards with optical or acoustic readers. Biosensors can be configured to allow the data collected to be electronically transmitted to the physician for interpretation and thus can form the basis for e-neuromedicine.
  • Any suitable animal may be used as a subject non-human animal, for example a non-human primate, horse, cow, pig, goat, sheep, dog, cat, fish, rodent, e.g . guinea pig, rat or mouse; insect (e.g . Drosophila), amphibian (e.g . Xenopus) or C. elegans.
  • a non-human primate horse, cow, pig, goat, sheep, dog, cat, fish
  • rodent e.g . guinea pig, rat or mouse
  • insect e.g . Drosophila
  • amphibian e.g . Xenopus
  • C. elegans C. elegans.
  • the test substance can be a known chemical or pharmaceutical substance, such as, but not limited to, an anti-psychotic disorder therapeutic; or the test substance can be novel synthetic or natural chemical entity, or a combination of two or more of the aforesaid substances.
  • a method of identifying a substance capable of promoting or suppressing the generation of the peptide biomarker in a subject comprising exposing a test cell to a test substance and monitoring the level of the peptide biomarker within said test cell, or secreted by said test cell .
  • the test cell could be prokaryotic, however a eukaryotic cell will suitably be employed in cell-based testing methods.
  • the eukaryotic cell is a yeast cell, insect cell, Drosophila cell, amphibian cell (e.g . from Xenopus), C. elegans cell or is a cell of human, non-human primate, equine, bovine, porcine, caprine, ovine, canine, feline, piscine, rodent or murine origin.
  • non-human animals or cells can be used that are capable of expressing the peptide.
  • Screening methods also encompass a method of identifying a ligand capable of binding to the peptide biomarker according to the invention, comprising incubating a test substance in the presence of the peptide biomarker in conditions appropriate for binding, and detecting and/or quantifying binding of the peptide to said test substance.
  • High-throughput screening technologies based on the biomarker, uses and methods of the invention, e.g . configured in an array format, are suitable to monitor biomarker signatures for the identification of potentially useful therapeutic compounds, e.g. ligands such as natural compounds, synthetic chemical compounds (e.g. from combinatorial libraries), peptides, monoclonal or polyclonal antibodies or fragments thereof, which may be capable of binding the biomarker.
  • potentially useful therapeutic compounds e.g. ligands such as natural compounds, synthetic chemical compounds (e.g. from combinatorial libraries), peptides, monoclonal or polyclonal antibodies or fragments thereof, which may be capable of binding the biomarker.
  • Methods of the invention can be performed in array format, e.g . on a chip, or as a multiwell array. Methods can be adapted into platforms for single tests, or multiple identical or multiple non-identical tests, and can be performed in high throughput format. Methods of the invention may comprise performing one or more additional, different tests to confirm or exclude diagnosis, and/or to further characterise a condition.
  • the invention further provides a substance, e.g . a ligand, identified or identifiable by an identification or screening method or use of the invention.
  • a substance e.g . a ligand, identified or identifiable by an identification or screening method or use of the invention.
  • Such substances may be capable of inhibiting, directly or indirectly, the activity of the peptide biomarker, or of suppressing generation of the peptide biomarker.
  • the term "substances" includes substances that do not directly bind the peptide biomarker and directly modulate a function, but instead indirectly modulate a function of the peptide biomarker.
  • Ligands are also included in the term substances; ligands of the invention (e.g . a natural or synthetic chemical compound, peptide, aptamer, oligonucleotide, antibody or antibody fragment) are capable of binding, suitably specific binding, to the peptide.
  • the invention further provides a substance according to the invention for use in the treatment of schizophrenia or other psychotic disorder
  • a substance according to the invention in the treatment of schizophrenia or other psychotic disorder, or predisposition thereto.
  • kits for diagnosing or monitoring schizophrenia or other psychotic disorder, or predisposition thereto are provided .
  • a kit according to the invention may contain one or more components selected from the group : a ligand specific for the peptide biomarker or a structural/shape mimic of the peptide biomarker, one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit in accordance with any of the methods defined herein.
  • biomarkers for schizophrenia or other psychotic disorder permits integration of diagnostic procedures and therapeutic regimes.
  • many anti-psychotic therapies have required treatment trials lasting weeks to months for a given therapeutic approach.
  • Detection of a peptide biomarker of the invention can be used to screen subjects prior to their participation in clinical trials.
  • the biomarkers provide the means to indicate therapeutic response, failure to respond, unfavourable side-effect profile, degree of medication compliance and achievement of adequate serum drug levels.
  • the biomarkers may be used to provide warning of adverse drug response.
  • Biomarkers are useful in development of personalized brain therapies, as assessment of response can be used to fine-tune dosage, minimise the number of prescribed medications, reduce the delay in attaining effective therapy and avoid adverse drug reactions.
  • patient care can be tailored precisely to match the needs determined by the disorder and the pharmacogenomic profile of the patient, the biomarker can thus be used to titrate the optimal dose, predict a positive therapeutic response and identify those patients at high risk of severe side effects.
  • Biomarker-based tests provide a first line assessment of 'new' patients, and provide objective measures for accurate and rapid diagnosis, in a time frame and with precision, not achievable using the current subjective measures.
  • diagnostic biomarker tests are useful to identify family members or patients at high risk of developing schizophrenia or other psychotic disorder. This permits initiation of appropriate therapy, or preventive measures, e.g . managing risk factors. These approaches are recognised to improve outcome and may prevent overt onset of the disorder.
  • Biomarker monitoring methods, biosensors and kits are also vital as patient monitoring tools, to enable the physician to determine whether relapse is due to worsening of the disorder, poor patient compliance or substance abuse. If pharmacological treatment is assessed to be inadequate, then therapy can be reinstated or increased; a change in therapy can be given if appropriate. As the biomarkers are sensitive to the state of the disorder, they provide an indication of the impact of drug therapy or of substance abuse.
  • PANSS Positive and Negative Syndrome Scale
  • the subjects were recruited from the Departments of Psychiatry at the
  • Serum samples were prepared randomly and blindly without pooling . 40 ⁇ of each sample was subjected to immunodepletion using MARS14 (Multiple Affinity Removal System, Agilent, Santa Clara, CA, USA) on a fast protein liquid chromatography system (AKTATM purifier UPC 10, GE Healthcare). The flow through, containing the moderate to low abundance proteins, was then
  • the samples were reduced by adding 5 mM dithiolthreitol (Sigma Aldrich, St. Louis, MI, USA) and incubated for 30 min at 60°C, and alkylated with 10 mM iodoacetemide (Sigma) with incubation in the dark for 30 min at 21°C.
  • the proteins were digested using trypsin (Promega, Madison, WI, USA) at a ratio of 1 : 50 (w/w trypsin/protein) for 16 hours at 37°C. The digestion was stopped by adding HCI to a concentration of 150mM .
  • the samples were stored in -80°C.
  • HPLC grade solvents were used for all chromatographic steps. Each sample was loaded using split-less nano-Ultra Performance Liquid Chromatography (lOkpsi nanoAcquity; Waters, Milford, MA, USA) in duplicate. Buffers used were : A) H 2 0 + 0.1% formic acid and B) acetonitrile + 0.1% formic acid. Desalting of samples was performed online using a reverse-phase C18 trapping column (180pm i.d ., 20mm length, 5pm particle size, Waters). The peptides in samples were separated using a C18 BEH nano-column (75pm i.d., 200mm length, 1.7pm particle size, Waters) at 0.3pL/minute.
  • the nanoLC was coupled online through a nanoESI emitter (7 cm length, 10 mm tip; New Objective, Woburn, MA, USA) to a quadrupole time-of-flight (Qtof) mass spectrometer (Qtof Premier, Waters).
  • Qtof time-of-flight
  • MS E also known as data independent analysis
  • positive ion mode in which the quadrupole is set to transfer all ions while the collision energy is alternated from low to high throughout the acquisition time.
  • MSI low-energy
  • mass range was set to 50 to 1990 Da.
  • Scan time was set to 0.6 seconds.
  • This mode enables accurate mass measurement of intact peptides and fragments at a high sampling rate as well as conservation of the chromatographic profile for both intact peptides and fragments.
  • a reference compound (Glu-Fibrinopeptide B; Sigma) was infused continuously for external calibration using a LockSpray and scanned every 30 seconds.
  • Protein abundance was calculated by summing peptide intensities per protein. A two tailed paired Student's T-Test was used to identify differential expression, after logarithmic transformation. Significance was set at p value of less than 0.05. Fold changes were calculated by mean intensity after treatment divided by mean intensity before treatment (after/before).
  • Phospholipid transfer protein PLTP HUMAN P55058 0.00001 1.42 1.42 1
  • Hemoglobin subunit epsilon HBE HUMAN P02100 0.00619 1.34 1.34 1
  • Zinc-alpha-2-glycoprotein ZA2G HUMAN P25311 0.02800 -1.05 0.95 40 lg lambda chain V-ll region VIL LV208_HUMAN, P01711 0.02813 1.14 1.14 1
  • Apolipoprotein A-IV APOA4 HUMAN P06727 0.00414 1.13 1.13 110
  • Apolipoprotein(a) APOA HUMAN P08519 0.01141 1.20 1.20 2
  • Angiotensinogen ANGT HUMAN P01019 0.02000 -1.05 0.95 41
  • CD5 antigen-like CD5L HUMAN 043866 0.03007 1.11 1.11 1
  • Synaptophysin-like protein 1 SYPL1 HUMAN, Q16563 0.04931 -1.10 0.91 1
  • Apolipoprotein CII as an antipsychotic-responsive biomarker Liquid chromatography mass spectrometry (LC-MS) analysis (conducted in accordance with Levin et al. Mol Psychiatry. 2010; 15 : 1088-1100) was performed on serum samples after 4 weeks treatment (T4) with
  • T4 serum apolipoprotein CII

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Abstract

L'invention concerne une méthode de diagnostic ou de surveillance de la schizophrénie ou d'autres troubles psychotiques.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104704365A (zh) * 2012-10-15 2015-06-10 国立大学法人名古屋大学 精神分裂症标记物组及其利用
CN108752422A (zh) * 2018-05-25 2018-11-06 吉林大学 一种微小隐孢子虫检测用tsp4多肽序列及用途
WO2020206454A1 (fr) * 2019-04-04 2020-10-08 Sapphire Biotech, Inc. Systèmes et méthodes de diagnostic rapide de divers cancers
US10955420B2 (en) 2016-09-07 2021-03-23 Mayo Foundation For Medical Education And Research Identification and monitoring of cleaved immunoglobulins by molecular mass
WO2021130310A1 (fr) * 2019-12-23 2021-07-01 The Royal College Of Surgeons In Ireland Marqueurs prédictifs de trouble psychotique
US11209439B2 (en) 2015-09-24 2021-12-28 Mayo Foundation For Medical Education And Research Identification of immunoglobulin free light chains by mass spectrometry
US11604196B2 (en) 2014-04-04 2023-03-14 Mayo Foundation For Medical Education And Research Isotyping immunoglobulins using accurate molecular mass
US11946937B2 (en) 2017-09-13 2024-04-02 Mayo Foundation For Medical Education And Research Identification and monitoring of apoptosis inhibitor of macrophage

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"DSM-IV Diagnostic and Statistical Manual of Mental Disorders", 2000, AMERICAN PSYCHIATRIC ASSOC
DAN MA ET AL: "Antipsychotic Treatment Alters Protein Expression Associated with Presynaptic Function and Nervous System Development in Rat Frontal Cortex", JOURNAL OF PROTEOME RESEARCH, vol. 8, no. 7, 6 July 2009 (2009-07-06), pages 3284 - 3297, XP055013405, ISSN: 1535-3893, DOI: 10.1021/pr800983p *
HUARD K ET AL: "Apolipoproteins C-II and C-III inhibit selective uptake of low- and high-density lipoprotein cholesteryl esters in HepG2 cells", INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, EXETER, GB, vol. 37, no. 6, 1 June 2005 (2005-06-01), pages 1308 - 1318, XP004997021, ISSN: 1357-2725, DOI: 10.1016/J.BIOCEL.2005.01.005 *
LEVIN ET AL., MOL PSYCHIATRY, vol. 15, 2010, pages 1088 - 1100
SCHWARZ EMANUEL ET AL: "Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia.", BIOMARKER INSIGHTS 2010 LNKD- PUBMED:20520744, vol. 5, 1 May 2010 (2010-05-01), pages 39 - 47, XP002664762, ISSN: 1177-2719 *
Y LEVIN ET AL: "Global proteomic profiling reveals altered proteomic signature in schizophrenia serum", MOLECULAR PSYCHIATRY, vol. 15, no. 11, 23 June 2009 (2009-06-23), pages 1088 - 1100, XP055011584, ISSN: 1359-4184, DOI: 10.1038/mp.2009.54 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104704365A (zh) * 2012-10-15 2015-06-10 国立大学法人名古屋大学 精神分裂症标记物组及其利用
US11604196B2 (en) 2014-04-04 2023-03-14 Mayo Foundation For Medical Education And Research Isotyping immunoglobulins using accurate molecular mass
US11209439B2 (en) 2015-09-24 2021-12-28 Mayo Foundation For Medical Education And Research Identification of immunoglobulin free light chains by mass spectrometry
US10955420B2 (en) 2016-09-07 2021-03-23 Mayo Foundation For Medical Education And Research Identification and monitoring of cleaved immunoglobulins by molecular mass
US11946937B2 (en) 2017-09-13 2024-04-02 Mayo Foundation For Medical Education And Research Identification and monitoring of apoptosis inhibitor of macrophage
CN108752422A (zh) * 2018-05-25 2018-11-06 吉林大学 一种微小隐孢子虫检测用tsp4多肽序列及用途
CN108752422B (zh) * 2018-05-25 2019-12-24 吉林大学 一种微小隐孢子虫检测用tsp4多肽序列及用途
WO2020206454A1 (fr) * 2019-04-04 2020-10-08 Sapphire Biotech, Inc. Systèmes et méthodes de diagnostic rapide de divers cancers
WO2021130310A1 (fr) * 2019-12-23 2021-07-01 The Royal College Of Surgeons In Ireland Marqueurs prédictifs de trouble psychotique

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