US20200190172A1 - Method for diagnosing/determining the effectiveness of treatment for depression - Google Patents

Method for diagnosing/determining the effectiveness of treatment for depression Download PDF

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US20200190172A1
US20200190172A1 US16/341,158 US201716341158A US2020190172A1 US 20200190172 A1 US20200190172 A1 US 20200190172A1 US 201716341158 A US201716341158 A US 201716341158A US 2020190172 A1 US2020190172 A1 US 2020190172A1
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depression
peptide
concentration
treatment
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Jean Mazella
Marc Borsotto
Catherine Heurteaux
Morgane Roulot
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Centre National de la Recherche Scientifique CNRS
Universite de Nice Sophia Antipolis UNSA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/723—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • 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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates in particular to polyclonal antibodies directed against peptides, particularly derived from the propeptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) hereinafter called PE.
  • the present invention also relates to polyclonal antibodies directed against peptides, particularly those derived from the propeptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) with the exception of fragment 12-18 of said propeptide, hereinafter called Mini-Spadin.
  • the present invention also relates to a method for detecting depression and a method for monitoring the effectiveness of an antidepressant therapy.
  • the present invention enables peptide assay to be used to diagnose the response to antidepressant therapy in major depression without being affected by treatment with mature mini-spadin or with its modified extremities.
  • the present invention is applicable particularly in the pharmaceutical industry and particularly in the development of diagnostic tools used in the prevention and/or surveillance of psychiatric illnesses, in particular of patients suffering or having suffered from depression.
  • brackets ([ ]) refer to the list of references provided at the end of the text.
  • Psychiatric illnesses represent a real problem for Public Health.
  • the most recent works have confirmed the high prevalence of depression: throughout their lives, 20% of women and 10% of men have experienced, are experiencing or will experience a depressive episode [1].
  • These figures are clearly significant; they are even more so when considering the major complication of depression, suicide, which accounts for 12,000 deaths per year in a country like France [2].
  • Depression is a very common and often disabling illness. It can affect up to 20% of the population in industrialized countries. Its origins are numerous and varied. This pathology affects both the psyche and the behavior and physiology of patients. Treatments for depression are also numerous and the mechanisms of action of the drugs used are not clearly established.
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRI serotonin reuptake inhibitors
  • SNRI selective noradrenalin reuptake inhibitors
  • glucocorticoids are generally associated with a negative effect on mood, as well as structural alterations of the hippocampus, through a reduction in the synthesis of BDNF (Brain-Derivated Neurotrophic Factor), an excessive secretion of glutamic acid and/or a reduction in glucose uptake [6].
  • BDNF Brain-Derivated Neurotrophic Factor
  • inhibitors of the synthesis of glucocorticoids and antagonists of glucocorticoid receptors produce AD type effects [7].
  • Antagonists acting on substance P receptors, particularly NK1, or the CRF receptor (Corticotropin-Releasing Factor), as well as antagonists of NMDA receptors have been developed with a certain degree of effectiveness [8-10].
  • antidepressants modulate the expression of different factors involved in the survival and growth of cells, such as CREB, Bcl2 or MAP-kinases.
  • CREB CREB
  • Bcl2 MAP-kinases
  • the antidepressant drugs used today produce a range of adverse effects, including dryness of the mouth, blurred vision and changes in intestinal function (diarrhea or constipation). Although many side effects are temporary (such as nausea), some appear to be constant over time (such as sexual effects) and risk affecting assiduity to treatment over the long term. This is the reason why research into new molecules acting on newly identified receptors or channels in depression is crucial.
  • NTRS3 Neurotensin Receptor 3
  • sortilin the inactivation of which in mice produces a depression-resistant phenotype, similar to that observed in invalided mice for the TREK-1 background potassium channel.
  • TREK-1 a gene involved in the antidepressive response in humans. This study also suggests the use of an animal model to research antidepressant treatments in the identification of candidate genes for a study on humans. TREK1 channel blockers therefore represent a new concept in the field of design of antidepressant drugs.
  • MDD Major Depressive Disorder
  • TRD treatment-resistant depression
  • treatments are still based soled on the relatively subjective evaluation of symptoms. Due to the low rate of remission, the identification of reliable biological markers predicting the clinical development of major depressive disorder and characterizing the extent of the result of treatment thus appears to be mandatory [3].
  • Clinical and preclinical trials have identified a certain number of factors that can serve as putative biomarkers for the diagnosis and treatment of major depressive disorder. However, the usefulness of any given marker to serve as clinically useful biomarker of MDD is limited by a lack of sensitivity and specificity [18-19].
  • BDNF Brain Derived Neurotrophic Factor
  • Sortilin is known to control the regulation of the intracellular traffic on the secretory pathway of BDNF [22]. Furthermore, increased serum levels of sortilin have been indicated as being associated with MDDs and correlated with BDNF [23-24].
  • Spadin is a partial peptide (12-28) of the propeptide of 44 amino acids (PE) generated from the maturation of sortilin [25], also called neurotensin receptor-3 [26].
  • PEG propeptide of 44 amino acids
  • spadin and propeptide When injected intravenously or intraperitoneally into mice, spadin and propeptide have shown powerful antidepressant (AD) activities by inhibiting the activity of the TREK-1 potassium channel [27], which is one of the goals in the treatment of depression [28].
  • AD antidepressant
  • spadin and propeptide are effective biological markers of depression, particularly of major depressive disorder.
  • the present invention precisely resolves and overcomes the above-mentioned obstacles and drawbacks of the prior art, in particular the absence of reliable markers of depression and its treatment, by providing AB1 polyclonal antibodies bound particularly to spadin and its propeptide but not to mini-spadin.
  • the present invention also relates to an anti-peptide polyclonal antibody derived from PE with the exception of fragment 12-18 and an antibody directed against the 12-18 sequence of PE.
  • the inventors are the first to have developed antibodies enabling the measurement of the concentration of spadin and propeptide and its fragments in a biological sample.
  • the inventors have shown, thanks to the antibodies of the invention, that two human peptides, namely Propeptide and/or Spadin and Mini-Spadin, can be independently measured on the basis of samples of human serums.
  • the subject matter of the present invention relates to polyclonal antibodies (AB1) directed against the peptide of sequence APLPRWSGPIGVSWGLR (SEQ ID NO 2) (Spadin).
  • the present invention also relates to polyclonal antibodies (AB2) directed against peptides comprising the sequence GVSWGLR (Mini-Spadin).
  • the inventors have shown that the AB1 polyclonal antibody binds to the peptides chosen from the group comprising: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2), APLPRWSGPIGVSWGL (SEQ ID NO 3), LPRWSGPIGVSW (SEQ ID NO 4) and WSGPI (SEQ ID NO 5), with the sole exception of the peptide GVSWGLR (SEQ ID NO 6).
  • the peptides chosen from the group comprising: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2), APLPRWSGPIGVSWGL (SEQ ID NO 3), LPRWSGPIGVSW (SEQ ID NO 4) and WSGPI (SEQ ID NO 5), with the sole exception of the peptide GVSWGLR (SEQ ID
  • the present invention relates to polyclonal antibodies (AB1) directed against the peptides in the group comprising: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2), APLPRWSGPIGVSWGL (SEQ ID NO 3), LPRWSGPIGVSW (SEQ ID NO 4) and WSGPI (SEQ ID NO 5) with the sole exception of the peptide GVSWGLR (SEQ ID NO 6).
  • polyclonal antibody (AB1) is directed against the peptides in the group consisting of: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2), APLPRWSGPIGVSWGL (SEQ ID NO 3), LPRWSGPIGVSW (SEQ ID NO 4) and WSGPI (SEQ ID NO 5).
  • the inventors have also shown that the AB2 polyclonal antibody is bound to the peptides chosen from the group comprising: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2) and GVSWGLR (SEQ ID NO 6).
  • the present invention relates to polyclonal antibodies (AB2) directed against the peptides in the group comprising QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2) and GVSWGLR (SEQ ID NO 6).
  • polyclonal antibody is directed against the peptides in the group consisting of: QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1), APLPRWSGPIGVSWGLR (SEQ ID NO 2) and GVSWGLR (SEQ ID NO 6).
  • the inventors are the first to have developed antibodies that enable measurement of the concentration of spadin and propeptide and its fragments in a biological sample.
  • the inventors have shown that two human peptides, namely propeptide and/or spadin and mini-spadin can be independently measured from samples of human serum.
  • propeptide or PE means the peptide of sequence:
  • 12-28 PE or spadin means the peptide fragment of the 12 to 28 propeptide amino acid sequence, namely APLPRWSGPIGVSWGLR (SEQ ID NO 2).
  • 12-27 PE means the peptide fragment of peptides 12 to 27 of the propeptide, namely:
  • 14-25 PE means the peptide fragment of the 14 to 25 propeptide amino acid sequence, namely: LPRWSGPIGVSW (SEQ ID NO 4).
  • 1-16 PE or pro-spadin means the peptide fragment of the 1 to 16 propeptide amino acid sequence, namely:
  • 22-28 PE or spadin (12-18) or mini-spadin means the peptide fragment of the 22 to 28 propeptide amino acid sequence or the peptide fragment of the 12 to 18 spadin peptides, namely: GVSWGLR (SEQ ID NO 6).
  • the present invention relates in particular to a method for the production of the polyclonal antibodies of the invention.
  • the method for the production of the polyclonal antibodies of the invention can comprise the following steps:
  • the composition comprising a peptide of sequence APLPRWSGPIGVSWGLR (SEQ ID NO 2) or a peptide of sequence GVSWGLR (SEQ ID NO 6) for administration to an animal can be an immunogenic composition.
  • This may include, for example, any immunogenic composition known to a person skilled in the art.
  • This may include, for example, a composition comprising at least one adjuvant.
  • an adjuvant means any immunogenic adjuvant known to a person skilled in the art. This may include, for example, a Freund or Alun adjuvant.
  • the animal can be any animal known to a person skilled in the art suitable for the production of antibodies; including, for example, a mouse, rat, rabbit, chicken, goat, sheep, donkey or horse.
  • administration can be achieved using any means and/or method known to a person skilled in the art. This may include, for example, an administration by injection, for example via a syringe. Administration can be achieved by any pathway known to a person skilled in the art; including, for example, an administration by a subcutaneous, intradermal, intramuscular and/or intravenous pathway.
  • the peptide can be administered at step a) at a concentration of 1 to 4 mg per animal, for example from 1.5 mg to 3 mg per animal, for example at a concentration of 2 mg per animal.
  • the recovery of the antibody can be achieved by any method known to a person skilled in the art. This may include, for example, a collection of serum from the animal, a bleeding and/or any means/method enabling serum to be recovered from the animal.
  • the isolation of the antibody can be achieved by any method known to a person skilled in the art.
  • This may include, for example, a filtration, for example through a membrane.
  • the filtration of the solution can be performed via a membrane comprising pores with a pore diameter ranging from 0.2 to 0.45 ⁇ m.
  • This may include, for example, a sterile membrane.
  • the membrane may be, for example, a cellulose, polyethersulfone, polycarbonate or nylon membrane.
  • a method may also be included that comprises a step of coagulation of the blood, for example for 1 to 3 hours at a temperature ranging from 15 to 25° C., elimination of the clot formed, filtration of the solution, centrifugation and recovery of the supernatant containing the polyclonal antibodies.
  • Centrifugation can be performed for a time ranging from 5 to 20 minutes, for example from 10 to 17 minutes, for example 15 minutes.
  • Centrifugation can be performed, for example, at a speed of 5,000 to 25,000 rpm, for example from 10,000 to 20,000 rpm, for example equal to 15,000 rpm.
  • the antibodies of the invention can be produced by any suitable method, for example the method described in Lee, B. S., Huang, J. S., Jayathilaka, L. P., Lee, J., Gupta, S. 2016. Antibody production with synthetic peptides. High resolution imaging of cellular proteins, vol 1474 of the series Methods in Molecular Biology, 25-47. [29].
  • the inventors have also shown that the antibodies according to the invention allow the concentration of spadin and the propeptide and its fragments to be measured in a biological sample.
  • the inventors have shown that two human peptides, namely propetide or spadin and mini-spadin, can be measured independently from samples of human serum.
  • the present invention thus also relates to the in vitro use of the antibodies of the invention for the detection/assay of a peptide chosen from propeptide, spadin and mini-spadin in a biological sample.
  • the antibodies suitable for the detection and/or assay of propeptide, spadin and mini-spadin are those defined above. They may include, for example, the polyclonal antibodies AB1 or AB2.
  • the antibodies according to the invention allow the concentration of mini-spadin to be detected and/or measured in a biological sample.
  • the antibodies according to the invention advantageously allow the concentration of mini-spadin that has been injected into a mammal, for example an animal or a human being, to be detected and/or measured in a sample.
  • propeptide or spadin can be independently measured from samples of human serum.
  • mini-spadin two human peptides, namely propeptide or spadin and mini-spadin can be independently measured from samples of human serum.
  • the inventors have also shown that the antibodies according to the invention advantageously allow, with the antibody AB1, the detection/measurement of the PE concentration, spadin but not mini-spadin, and, with the antibody AB2, the detection/measurement of the PE concentration, spadin and mini-spadin, the absolute value of the difference in concentration between the measurement with antibodies AB2 and AB1 corresponding to the mini-spadin concentration.
  • the present invention also therefore relates to the in vitro use of the antibodies according to the invention for the detection and/or measurement of the concentration of mini-spadin in a biological sample.
  • a “biological sample” means any sample obtained from mammals, for example a mammal chosen from the group comprising the order of Monotremata, Didelphimorphia, Paucituberculata, Microbiotheria, Notoryctemorphia, Dasyuromorphia, Peramelemorphia, Diprotodontia, Tubulidentata, Sirenia, Afrosoricida, Macroscelidea, Hyracoidea, Proboscidea, Cingulata, Pilosa, Scandentia, Dermoptera, Primates, Rodentia, Lagomorpha, Erinaceomorpha, Soricomorpha, Chiroptera, Pholidota, Carnivora, Perissodactyla, Artiodactyla and Cetacea. These may include, for example, a human or an animal.
  • the biological sample may be any biological fluid, for example, this may include a sample of blood, plasma, serum, cerebrospinal fluid (CSF), vaginal mucus, nasal mucus, saliva, urine and/or milk.
  • the biological sample is a sample of blood or a sample of serum.
  • the antibodies of the invention can be used in any suitable assay/detection method known to a person skilled in the art.
  • This may include an immunoassay method, for example an ELISA or AlphaLISA assay.
  • This may include, for example, an assay method described in the document Immunoanalysis: De la often aux mm de securities en biologie legal [Immunoanalysis: From theory to the selection criteria in clinical biology], Catherine Massart, EPD science 2009.
  • the inventors are also the first to have shown that the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) is reduced in an individual in a depressive state.
  • the inventors have also shown that the antibodies according to the invention allow the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) to be determined in a biological sample of a healthy control individual and also of a depressive individual.
  • the present invention thus also relates to the in vitro use of the antibodies of the invention for the detection of a depressive state from a biological sample of an individual.
  • depressive state or “depressive individual” mean an individual suffering from a mood disorder accompanied by sadness and mental anguish. This may include, for example, any depressive state known to a person skilled in the art, for example a major depressive disorder (MDD), neurotic depression/psychotic depression, psychogenic depression/endogenic depression and/or reactive depression/autonomous depression.
  • MDD major depressive disorder
  • neurotic depression/psychotic depression neurotic depression/psychotic depression
  • psychogenic depression/endogenic depression and/or reactive depression/autonomous depression.
  • “healthy control individual” means an individual, for example a human being, not presenting a depressive state, for example a mood disorder accompanied by sadness and mental anguish, and/or not having presented a depressive state and/or not presenting a major depressive disorder and/or not having presented a major depressive disorder.
  • “individual” means a mammal chosen from the group comprising the order of Monotremata, Didelphimorphia, Paucituberculata, Microbiotheria, Notoryctemorphia, Dasyuromorphia, Peramelemorphia, Diprotodontia, Tubulidentata, Sirenia, Afrosoricida, Macroscelidea, Hyracoidea, Proboscidea, Cingulata, Pilosa , Scandentia, Dermoptera, Primates, Rodentia, Lagomorpha, Erinaceomorpha, Soricomorpha, Chiroptera, Pholidota, Carnivora, Perissodactyla, Artiodactyla and Cetacea. This may include, for example, a human or an animal.
  • biological sample means any sample obtained from mammals, for example a mammal chosen from the group comprising the order of Monotremata, Didelphimorphia, Paucituberculata, Microbiotheria, Notoryctemorphia, Dasyuromorphia, Peramelemorphia, Diprotodontia, Tubulidentata, Sirenia, Afrosoricida, Macroscelidea, Hyracoidea, Proboscidea, Cingulata, Pilosa, Scandentia, Dermoptera, Primates, Rodentia, Lagomorpha, Erinaceomorpha, Soricomorpha, Chiroptera, Pholidota, Carnivora, Perissodactyla, Artiodactyla and Cetacea. This may include, for example, a human or an animal.
  • the in vitro detection method can be any in vitro method known to a person skilled in the art suitable for the use of antibodies. This may include, for example, an immunochemical method such as a western blot, ELISA, an immunocytochemical method such as confocal microscopy, immunoelectron microscopy and/or an immunohistochemical method.
  • an immunochemical method such as a western blot, ELISA
  • an immunocytochemical method such as confocal microscopy, immunoelectron microscopy and/or an immunohistochemical method.
  • the present invention also relates to an in vitro method for detecting/determining depression in a patient comprising the following steps:
  • the measurement of the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR can be achieved according to the method described in Mazella, J. et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.
  • “reference healthy subject” means a mammal, for example a human being, not presenting a depressive state and/or not having presented a depressive state and/or not presenting a major depressive disorder and/or not having presented a major depressive disorder.
  • a “group of reference subjects” means a group allowing a reliable reference value to be defined. This may include, for example, a group comprising at least 2 reference subjects as defined above, for example at least 40 reference subjects. This may include, for example, a group comprising 40 to 200 reference subjects.
  • the reference concentration of the peptide (Cref) preferably corresponds to a measured concentration from a biological sample of a reference healthy subject or group of healthy subjects with similar physiological characteristics, for example chosen from the group comprising the age, weight, sex, body mass and drug, tobacco and alcohol abuse.
  • the “peptide reference concentration” can be the concentration of said peptide in a reference healthy subject and/or reference group of healthy subjects.
  • the peptide reference concentration can range from 20 to 30 nM, for example from 22 to 28 nM.
  • the inventors have also shown that the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) changes during a pharmacological treatment of a depressive state in an individual.
  • an effective pharmacological treatment makes it possible to “restore” the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) and to increase its concentration or even to return to a reference concentration.
  • the inventors have also shown that the antibodies according to the invention make it possible to monitor the effectiveness of a treatment for depression by monitoring the concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR (SEQ ID NO 1) in a biological sample of an individual.
  • treatment means, for example, a medical treatment, for example an allopathic treatment, involving taking molecules, for example chemical molecules, for example molecules obtained by organic synthesis, molecules of biological origin, for example proteins, molecules coming from living organisms, for example mammals, microorganisms, plants and/or synthesized by living organisms, for example proteins, nucleic acid molecules, or any other non-chemical treatment, for example re-education, or any other treatment based on cell therapy, for example the injection of stem cells.
  • molecules for example chemical molecules, for example molecules obtained by organic synthesis
  • molecules of biological origin for example proteins, molecules coming from living organisms, for example mammals, microorganisms, plants and/or synthesized by living organisms, for example proteins, nucleic acid molecules, or any other non-chemical treatment, for example re-education, or any other treatment based on cell therapy, for example the injection of stem cells.
  • the treatment can be any antidepressant treatment known to a person skilled in the art.
  • This may, for example, include treatment using SSRIs (Selective Serotonin Reuptake Inhibitors), for example fluoxetine (Prozac (registered trademark)), paroxetine (Deroxat, Divarius, Paxil (registered trademark)), sertraline (Zoloft (registered trademark)); citalopram (Seropram, Celexa (registered trademark)), Escitalopram Oxalate (Seroplex, Cipralex (registered trademark)), indalpine, zimelidine, dapoxetine (Priligy (registered trademark)), the maleate of fluvoxamine maleate (Floxyfral (registered trademark)); SNRIs (Serotonin Norepinephrine Reuptake Inhibitors), for example venlafaxine (Effexor (registered trademark)), milnacipran (Ixel)
  • the biological sample is as defined above.
  • the individual is as defined above.
  • the measurement of the concentration can be performed using any method suitable and known to a person skilled in the art. This may include a method as defined above.
  • the present invention makes it possible to measure the quantity of sortilin-derived peptides in a biological sample, for example a blood sample from an individual, in particular a mammal, while differentiating it from the assay of mini-spadin that can correspond to the active molecule used in an antidepressant treatment.
  • a biological sample for example a blood sample from an individual, in particular a mammal
  • the present invention advantageously makes it possible, if mini-spadin (12-18) is used as an antidepressant drug, to monitor and control the effective doses in each individual/patient.
  • the antibodies of the invention advantageously make it possible to differentiate the sortilin-derived endogenous peptides from exogenous peptides, mini-spadin (12-18), present in the human serum.
  • antibodies in the methods for measuring concentrations according to the invention and/or for monitoring the effectiveness of an antidepressant treatment advantageously make it possible with AB1 to measure the serum levels of sortilin-derived peptides of healthy controls/individuals and depressive individuals/patients even if they are treated with mini-spadin (12-18), and to measure the effectiveness of mini-spadin (12-18) bioavailability with the difference obtained between the peptides measured with AB2 and the peptides measured with AB1 as described in FIG. 1A .
  • the present invention makes it possible to detect a depressive state in an individual, for example a patient, with a greater sensitivity and specificity than known methods. Furthermore, the present invention advantageously makes it possible to monitor the effectiveness of a treatment for depression whatever the treatment used.
  • the method of the invention particularly by the advantageous use of the antibody AB1, makes it possible to monitor the effectiveness of a treatment for depression even if the individual and/or the patient is treated with a peptide, for example an exogenous peptide, for example a peptide of sequence SEQ ID NO 6.
  • the present invention makes it possible, by using the antibodies AB1 and AB2, for example to monitor the change in concentration, for example of the peptide of sequence SEQ ID NO 6.
  • FIG. 1A is a diagram representing the structure/recognition relationships of the antibodies AB1 and AB2 according to the different fragments.
  • + means that the antibody recognizes the fragment and ⁇ means that it is not recognized, n.t. means not tested.
  • FIGS. 1B and 1C represent the relative affinities for spadin, PE and analogs assayed by the detection method.
  • FIG. 1D represents the results of the Porsolt Forced Swim Test (FST), currently used in the screening of antidepressants. Mice treated with spadin or partial peptides had a shorter immobility time than those obtained with a saline solution.
  • FST Porsolt Forced Swim Test
  • FIG. 2 represents the PE concentrations in the serums of healthy patients, untreated MDDs (T0) and MDD patients (T1) treated for 12 weeks.
  • FIG. 2 also represents the average ⁇ SEM of the Montgomery-Asberg Depression Rating Scale (MADRS) for MDD patients before (T0) and after (T1) a treatment of 12 weeks (bars). *** P ⁇ 0.001.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • Example 1 Method for the Detection of Spadin and the Detection of Major Depressive Disorder (MDD)
  • room temperature means a temperature of between 19 and 25° C., for example equal to 22° C.
  • the peptides were synthesized by GeneCust (Dudelange, Germany).
  • the rabbit polyclonal antibodies against spadin (YAPLPRWSGPIGVSWGLR (SEQ ID NO 8)) were prepared by Eurogentec (Seraing, Belgium).
  • the antibody used was the AB1 antibody, as mentioned above.
  • the spadin (5.4 mg; 2.7 mmol) was dissolved in 1.5 ml of 25 nM pH 6.7 phosphate buffer.
  • Some biotin N-hydroxysuccinimide (13.5 mmol) resuspended in 700 ⁇ l 70% acetonitrile/30% of dimethylformamide was added to the spadin solution and incubated for one night at room temperature.
  • the biotinylated spadin was purified by High Performance Liquid Chromatography (HPLC) using a Waters system equipped with a semi-preparative Lichrosorb RP18 column.
  • HPLC High Performance Liquid Chromatography
  • the biotinylated spadin (elution at 27 min), identified by mass spectroscopy, was collected, quantified by its absorption at 280 nm and lyophilized in aliquots.
  • streptavidin donor microbeads were recognized by biotinylated spadin, while acceptor microbeads with rabbit anti-IgG were bound by anti-spadin antibodies.
  • acceptors and donors were in close proximity, the signal was produced by a molecular interaction between the binding partners on the beads.
  • the propeptide present in the serum sample was able to interfere with this interaction leading to competition.
  • Calibration curves were obtained by incubation, in 96-well plates, of 10 nM of biotinylated spadin with the anti-spadin antibody (1:1000) in the AlphaLisa (registered trademark) buffer in the absence or presence of increasing concentrations of spadin (10 ⁇ 11 to 10 ⁇ 6 M) for 1 hour at room temperature. After the addition of donor and acceptor beads and an additional incubation for 2 hours at room temperature, the plates were read using an Enspire reader (Perkin). For the serum measurements, the same volume of serum was added instead of the unlabeled spadin. The quantity of propeptide was determined from its signal percent inhibition and calculated using the standard curve.
  • the cohort of control individuals was made up of 49 healthy unrelated volunteers who were selected for diagnosis of DSM-IV Axis I disorders by expert psychologists using the Mini-International Neuropsychiatric Interview (MINI) [30]. Only healthy volunteers with no history of drug or alcohol abuse or dependency and no personal or first-degree relative family history of psychiatric disorders were enrolled in the trial. Furthermore, the absence of pertinent neurological illnesses, namely epilepsy and Parkinson's syndrome, was compulsory for enrolment in the trial. Lastly, subjects who obtained a score of less than 27/30 in the Mini Mental State Examination (MMSE) were excluded from the trial.
  • MMSE Mini Mental State Examination
  • the cohort of patients was made up of 37 patients, having a Major Depressive Disorder (MDD) with moderate to severe depression, who met the criteria of the classification system in the Diagnostic and Statistical Manual IV (DSM-IV) of mental disorders.
  • MDD Major Depressive Disorder
  • DSM-IV Diagnostic and Statistical Manual IV
  • the diagnosis of unipolar depression was confirmed by a structured clinical interview for DSM-IV Axis I disorders (SCID-I).
  • the exclusion criteria were as follows: a) a mental retardation or cognitive disorder; b) life history of schizophrenia, schizoaffective disorder or a bipolar disorder; c) personality disorder, addiction, alcohol abuse or dependency, obsessive-compulsive disorder or post-traumatic stress as a primary diagnosis; and d) comorbidity with an eating disorder.
  • Axis I Generalized Anxiety Disorder (GAD)
  • GAD Generalized Anxiety Disorder
  • NOS anxiety disorders Not Otherwise Specified
  • 2 5.4%) showed symptoms of Axis II disorders (dependent personality disorder) and no alcohol abuse, as a secondary diagnosis (the total number exceeded the number of subjects due to the presence of comorbidities).
  • SSRI serotonin reuptake inhibitors
  • SNRI serotonin-noradrenalin reuptake inhibitors
  • TCA tricyclic antidepressants
  • NSSA noradrenergic and specific serotonergic antidepressants
  • MADRS Montgomery and Asberg Depression Rating Scale
  • venous blood samples were taken in the morning between 8:00 a.m. and 9:00 a.m. in tubes without anticoagulant.
  • the serum was separated by centrifugation (1620 g for 15 minutes). Blood samples for the PE measurements were collected at each time point.
  • the specificity of the antibodies used was studied. In particular, the specificity of the antibodies used in the assay method was studied.
  • a series of partial sequences of human PE was prepared in order to characterize the specificity of the antibodies used ( FIG. 1A ).
  • Neurotensin (NT, black squares) and somatostatin-14 (SS14, white squares) were not recognized by the antibodies.
  • the 14-25 PE fragment was bound to the antibodies with an IC50 of 1.73 nM, while the IC50 of the 12-27 PE fragment was 3.44 nM.
  • the 22-28 PE fragment (mini-spadin, white squares) and 1-16 PE fragment (black squares) were not recognized by the antibodies. Each point corresponds to the average ⁇ SEM of 3 to 6 independent experiments.
  • a polyclonal composition making it possible specifically to measure the propeptide and spadin concentration was obtained.
  • FIG. 1D shows the results of the Posolt Forced Swim Test (FST).
  • FST Posolt Forced Swim Test
  • FIG. 3 is a histogram representing the stability of PE in human serum.
  • the PE concentration for each incubation period was determined using an AlphaLISA assay method.
  • the average concentrations at the different time points are expressed as an average ⁇ SEM.
  • the determination of the ANOVA was carried out and revealed no difference between the EDTA-free serum group and serum with EDTA.
  • the unpaired t test for the PE concentration between serum and EDTA-serum indicated no significant difference for each time. Consequently, the stability of the SLI measurement for 24 hours at room temperature ( FIG. 3 ) validated the subsequent measurements on mice and humans.
  • the antibody used recognized only one series of peptides derived from human PE, as well as PE itself, and not unrelated peptides like neurotensin or somatostatin.
  • the peptides recognized by the antibody have antidepressant activities as shown by the mouse forced swim test ( FIG. 1D ).
  • This example thus clearly shows that the PE concentration in the serum is downregulated. i.e. it is less in patients with a major depressive disorder (MDD) compared to healthy subjects.
  • MDD major depressive disorder
  • This example also clearly shows that the PE concentration varies with an antidepressant treatment and, particularly in patients presenting a propeptide concentration below normal, enables a return to the normal in correlation with the clinical development of the treatment for depression.
  • the propeptide concentration is a marker of the depressive state and can be used to detect/determine a depressive state, for example a major depressive disorder, and also to determine/monitor the effectiveness of an antidepressant treatment.
  • the serum PE concentration is an additional marker to the known serum level marker, for example BDNF [31].
  • the serum PE concentration is significant lower in patients with MDD and, taking into account the fact that the peptides measured in the present example have been generated from sortilin, a study of the possible correlation with the level and/or expression of sortilin has been carried out.
  • the variation of the expression of sortilin in the blood has previously been observed in patients suffering from MDD.
  • the gene expression of sortilin decreases with clinical improvement [23]
  • sortilin is overexpressed in patients suffering from MDD, particularly in non-responders [32].
  • the increase in the level of sortilin is associated with the state of depression [24].
  • Example 2 Method for Obtaining Antibodies AB1 and AB2 and Determining their Specificities
  • the two antibodies were prepared from rabbit and the volumes obtained were approximately 200 ml of each. In the experimental protocols, these antibodies were used at dilutions of 1/1000 and 1/5000. The techniques used to measure the level of propeptide in the blood were multiple, immunological or fluorescence. The peptide assay can be achieved with 100 ⁇ I of blood and is reproducible.
  • FIG. 1 shows the specificities of the bonds for each antibody.
  • antibodies AB1 and AB2 were obtained by injecting into two rabbits, namely Oryctolagus cuniculus , spadin coupled to KLH (Keyhole limpet hemocyanin protein) (AB1) or mini-spadin (22-28 PE) coupled to KLH (AB2) on day 0, DO (1 mg), day 7, D7 (1 mg), day 14, D14 (1 mg) and day 29, D29 (1 mg).
  • Blood samples namely 20 ml, were taken on day 27 (D27) and day 42 (D42).
  • the polyclonal serum was obtained by centrifuging at 1200 ⁇ g for 10 min.
  • the polyclonal serum corresponding to the supernatant was recovered.
  • the immune response was checked by ELISA for each antibody.
  • the antibodies contained in the serum were kept at ⁇ 20° C.
  • the cohort of control individuals was made up of 49 healthy unrelated volunteers who were selected for diagnosis of DSM-IV Axis I disorders by expert psychologists using the Mini-International Neuropsychiatric Interview (MINI) [30]. Only healthy volunteers with no history of drug or alcohol abuse or dependency and no personal or first-degree relative family history of psychiatric disorders were enrolled in the trial. Furthermore, the absence of pertinent neurological illnesses, namely epilepsy and Parkinson's syndrome, was compulsory for enrolment in the trial. Lastly, subjects who obtained a score of less than 27/30 in the Mini Mental State Examination (MMSE) were excluded from the trial.
  • MMSE Mini Mental State Examination
  • the cohort of patients was made up of patients having a Major Depressive Disorder (MDD) with moderate to severe depression who met the criteria of the classification system of Diagnostic and Statistical Manual IV (DSM-IV) of mental disorders.
  • MDD Major Depressive Disorder
  • DSM-IV Diagnostic and Statistical Manual IV
  • the diagnosis of unipolar depression was confirmed by a structured clinical interview for DSM-IV Axis I disorders (SCID-I).
  • the exclusion criteria were as follows: a) a mental retardation or cognitive disorder; b) life history of schizophrenia, schizoaffective disorder or a bipolar disorder; c) personality disorder, addiction, alcohol abuse or dependency, obsessive-compulsive disorder or post-traumatic stress as a primary diagnosis; and d) comorbidity with an eating disorder.
  • a measurement of the serum concentration of the peptide of sequence QDRLDAPPPPAAPLPRWSGPIGVSWGLRAAAAGGAFPRGGRWRR was made according to the method described in Example 1 prior to the administration of any antidepressant treatment.
  • the measurement of the concentration was made from a blood sample. The concentration was measured independently for each patient prior to any treatment. The concentration measured was 19 nM.
  • SSRI selective serotonin reuptake inhibitors
  • SNRI selective serotonin-noradrenalin inhibitors
  • TCA tricyclic antidepressants
  • NSSA noradrenergic and specific serotonergic antidepressants
  • S2 C2/C1 (C1, concentration before treatment, C2, concentration after treatment). If the value of S2 was more than 1.2, the treatment administered was an effective antidepressant.

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