WO2020115223A1 - S100a4 utilisable en tant que marqueur de traitement par la spironolactone, la pioglitazone et la metformine - Google Patents

S100a4 utilisable en tant que marqueur de traitement par la spironolactone, la pioglitazone et la metformine Download PDF

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Publication number
WO2020115223A1
WO2020115223A1 PCT/EP2019/083848 EP2019083848W WO2020115223A1 WO 2020115223 A1 WO2020115223 A1 WO 2020115223A1 EP 2019083848 W EP2019083848 W EP 2019083848W WO 2020115223 A1 WO2020115223 A1 WO 2020115223A1
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treatment
subject
concentration
spironolactone
pioglitazone
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PCT/EP2019/083848
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English (en)
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Francis De Zegher
Lourdes IBAÑEZ
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Katholieke Universiteit Leuven
Hospital Sant Joan De Deu
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Priority claimed from GBGB1819876.2A external-priority patent/GB201819876D0/en
Application filed by Katholieke Universiteit Leuven, Hospital Sant Joan De Deu filed Critical Katholieke Universiteit Leuven
Publication of WO2020115223A1 publication Critical patent/WO2020115223A1/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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a new biomarker of hepato-visceral fat excess.
  • PCOS Polycystic ovary syndrome
  • ICD-11 code 5A80.1 Polycystic ovary syndrome
  • PCOS is a frequent cause of hirsutism and menstrual irregularity in adolescent girls and young women, is commonly accompanied by insulin resistance with compensatory hyperinsulinemia and hepato-visceral fat excess, independently of BMI, and followed by comorbidities such as subfertility and type 2 diabetes.
  • SPIOMET a treatment with low-dose spironolactone, pioglitazone and metformin
  • PCOS Polycystic ovary syndrome
  • ICD-11 code 5A80.1 Polycystic ovary syndrome
  • PCOS is a frequent cause of hirsutism and menstrual irregularity in adolescent girls and young women, is commonly accompanied by insulin resistance with compensatory hyperinsulinemia and hepato-visceral fat excess, independently of BMI, and followed by comorbidities such as subfertility and type 2 diabetes.
  • SPIOMET a treatment with low-dose spironolactone, pioglitazone and metformin
  • SPIOMET normalizes the PCOS phenotype more broadly than does treatment with an oral contraceptive (OC).
  • OC oral contraceptive
  • An in vitro method for monitoring responsiveness of a subject to treatment with spironolactone, pioglitazone and metformin comprising : determining the concentration of S100A4 in a biological fluid obtained from the subject, wherein a decrease of S100A4 compared to the concentration measured in a sample of biological fluid of the same subject prior to treatment is indicative for an effective treatment.
  • An in vitro method of selecting a polycystic ovary syndrome subject or patient for treatment by spironolactone, pioglitazone and metformin comprises: (i) performing an in vitro test of plasma level of S100A4 in the subject or patient before treatment, and (ii) deciding whether the result of the test is indicative for the treatment by spironolactone, pioglitazone and metformin when the plasma level of S100A4 is 10% or more, 20% or more, 40% or more, 60% or more or 80% or more higher than for a control subject.
  • the effect of treatment or the selection of patient suitable of treatment is assessed by the level of S100A4 and the level of fasting insulin or the level HOMA-IR or the level LDL-cholesterol or the level HMW adiponectin.
  • a method for monitoring responsiveness of a subject with ectopic hepato- visceral fat storage or excess of hepato-visceral fat storage for instance such hepato-visceral fat storage defined as sum of visceral fat (by MRI, in cm 2 ) and hepatic fat (by MRI, in %), to treatment with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof, the method comprising : determining the concentration of S100A4 in a biological fluid obtained from the subject, wherein a decrease of S100A4 compared to the concentration measured in a sample of biological fluid of the same type obtained from the subject prior to treatment with the with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof is indicative for an effective treatment.
  • hepato-visceral fat storage defined as sum of visceral fat (by MRI, in cm 2 ) and hepatic fat (
  • a method of treating a subject and determining the responsiveness of the subject to a treatment comprising : determining the level of S100A4 in a body fluid sample from the subject prior to the treatment of said subject, administering a spironolactone, pioglitazone and metformin to said subject having a disease treatable with said spironolactone, pioglitazone and metformin; determining the level of S100A4 a body fluid sample from the subject after the subject has been subjected to the method of treatment; and identifying the subject as a responder to said treatment if the level of S100A4 in a sample from the subject after the subject having been subjected to the method of treatment is decreased compared to the level of S100A4 a body fluid sample from the subject prior to the subject having being subjected to the method of treatment; and further treating the subject identified as a responder to said treatment.
  • a method of treating a subject and determining the responsiveness of the subject to treatment of polycystic ovary syndrome with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof comprising : determining the level of S100A4 in a body fluid sample from the subject prior to the treatment of said subject, administering a polycystic ovary syndrome subject with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof to said subject having a disease treatable with said polycystic ovary syndrome with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof; determining the level of S100A4 a body fluid sample from the subject after the subject has been subjected to the method of treatment; and identifying the subject as a responder to said treatment with said spironolactone, pioglitazone and metformin if the
  • a method of treating a subject and determining the responsiveness of the subject to treatment of non-alcoholic fatty liver disease [NAFLD] with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof comprising : determining the level of S100A4 in a body fluid sample from the subject prior to the treatment of said subject, administering a non-alcoholic fatty liver disease [NAFLD] subject with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof to said subject having a disease treatable with said non-alcoholic fatty liver disease [NAFLD] with spironolactone, pioglitazone and metformin or with a contraceptive or a combination thereof; determining the level of S100A4 a body fluid sample from the subject after the subject has been subjected to the method of treatment; and identifying the subject as a responder to said treatment with said spironolactone, pioglit
  • a method of selecting a polycystic ovary syndrome subject or patient for treatment by spironolactone, pioglitazone and metformin or by an oral contraceptive comprises: (i) performing an in vitro test of plasma level of S100A4 in the subject or patient before treatment, and (ii) deciding whether the result of the test is indicative for the treatment by spironolactone, pioglitazone and metformin or with a contraceptive , wherein the result of the test is indicative for the treatment by spironolactone, pioglitazone and metformin or with a contraceptive when the plasma level of S100A4 is 10% or more, 20% or more, 40% or more, 60% or more or 80% or more higher than for a control subject.
  • the effect of treatment or the selection of patient suitable of treatment is assessed by the level of S100A4 and the level HOMA-IR.
  • the effect of treatment or the selection of patient suitable of treatment is assessed by the level of S100A4 and the level HMW adiponectin.
  • the effect of treatment or the selection of patient suitable of treatment is assessed by the level of S100A4 and the level of at least two of fasting insulin, HOMA-IR, LDL- cholesterol and HMW adiponectin.
  • An in vitro method for monitoring responsiveness of a subject to a treatment with spironolactone, pioglitazone and metformin comprising :
  • the effect of treatment or the selection of patient suitable of treatment is assessed by determining the level of S100A4 and determining the level of one or more of fasting insulin, HOMA-IR, LDL-cholesterol, and HMW adiponectin.
  • the disclosure of the present invention allows to investigate whether a combination of spironolactone, pioglitazone without metformin, can be used as a medicament for the above mentioned indications, and whether S100A can be used as a marker for identifying responders, and predicting the outcome of such treatment.
  • the complete cDNA sequence for human S100A4 has the Genbank accession number M80563 (31 October 1994).
  • the complete cDNA sequence for murine S100A4 has the Genbank accession number D00208 (5 December 1997).
  • the complete protein sequence for human S100A4 has the UniProt accession number P26447 (August 1 , 1992).
  • S100 calcium-binding protein A4 (S100A4) is a member of the S100 calcium binding protein family and was first identified and categorized as a metastasis- associated protein. In humans it is encoded by the S100A4 gene [Stoler & Bouck (1985) Proc. Natl. Acad. Sci. USA 82, 570-574] and the S100A4 gene itself was originally isolated [Ebralidze et at. (1989) Genes Dev. 3, 1086-1093].
  • S100A4 is defined in the "Definitions" section. The term also includes all the physiologically relevant posttranslational chemical modifications forms, for example, glycosylation, phosphorylation or acetylation, etc., provided that the functionality of the protein is maintained.
  • Said term encompasses the S100A4 of any mammal species, including but not being limited to domestic and farm animals (cows, horses, pigs, sheep, goats, dogs, cats or rodents), primates and humans.
  • the S100A4 is human.
  • the complete protein sequence for murine S100A4 has the UniProt accession number P07091 (April 1 , 1988).
  • an antibody or fragment thereof that specifically binds a S100A4 polypeptide preferably the human S100A4 polypeptide can be used to assay to measure circulating S100A4 polypeptide.
  • the term "antibody” relates to a monomeric or multimeric protein which comprises at least one polypeptide having the capacity for binding to a determined antigen and comprising all or part of the light or heavy chain variable region of an immunoglobulin molecule.
  • the term antibody includes any type of known antibody, such as, for example, polyclonal antibodies, monoclonal antibodies and genetically engineered antibodies, such as chimeric antibodies, humanized antibodies, primatized antibodies, human antibodies and bispecific antibodies.
  • the invention also comprises the use of fragments of the different types of antibodies mentioned above which substantially preserve the anti-angiogenic activity of the antibody.
  • antibody fragment includes antibody fragments such as Fab, F(ab')2, Fab', single chain Fv fragments (scFv), diabodies and nanobodies.
  • Papain digestion of antibodies produces two identical antigen binding fragments referred to as "Fab” fragments, each with a single antigen binding site, and a residual "Fc” fragment, the name of which reflects its capacity for readily crystallizing.
  • Pepsin treatment yields an F(ab')2 fragment which has two antigen binding sites and which is still capable of crosslinking to the antigen.
  • Fv is the minimal antibody fragment containing a complete antigen binding and antigen recognition site.
  • This region consists of a variable domain of a variable light chain and heavy chain dimer in a strong noncovalent association.
  • the three hypervariable regions of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer.
  • the six hypervariable regions confer antigen-antibody specificity to the antibody.
  • a single variable domain or half an Fv, which comprises only three hypervariable regions specific for an antigen
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain.
  • Fab' fragments differ from Fab fragments in the addition of a few residues at the carboxy terminus of the domain CHI of the heavy chain, including one or more cysteines of the antibody hinge region.
  • the "single chain Fv” or “scFv” antibody fragments comprise the VH and VL domains of an antibody, in which these domains are present in a single polypeptide chain.
  • the Fv polypeptide additionally comprises a linker polypeptide between the VH and VL domains which allows the scFv to form the desired structure for antigen binding.
  • nanobodies designates small sized entities (15 kDa) formed solely by the antigen binding region of the heavy chain (VH fragment) of immunoglobulins. Said nanobodies are mainly produced after immunizing animals of the Camelidae family, such as camels, llamas and dromedaries, mainly llamas; and also of the shark family, which have the particularity of having antibodies which naturally lack the light chain and recognize the antigen by the heavy chain variable domain.
  • antibody that recognizes an epitope of S100A4 indicates that the antibody is capable of showing specific binding to the epitope without showing substantial binding to other epitopes not comprising this sequence.
  • substantially higher affinity refers to an affinity level for a particular amino acid sequence which is distinguishable from a level of other amino acid sequence when detected with an intended measurement device or method.
  • the affinity of the binding between the antibody and peptide comprising the epitope is at least one order of magnitude higher, at least two orders of magnitude, at least three orders of magnitude higher, at least four orders of magnitude, at least five orders of magnitude higher, at least six orders of magnitude higher than the affinity of the binding between the antibody and a peptide which does not comprising the sequence of the epitope.
  • the association constant (Ka) of binding with substantially high affinity is, for example, at least 107M-1, preferably at least 108M-1, and more preferably at least 109M-1 or lower.
  • antibody is used herein in the broadest sense and covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g.
  • bispecific antibodies include bispecific antibodies, and antibody fragments so long as they exhibit the desired biological activity.
  • An intact "antibody” includes heteromultimeric glycoproteins comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond while the number of disulfide linkages between the heavy chains of different immunoglobulin isotypes varies. Each heavy and light chain also has intrachain disulfide bridges. Each heavy chain has at one end a heavy chain variable region (abbreviated herein as HCVR or VH) followed by a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI , CH2, and CH3.
  • HCVR heavy chain variable region
  • Each light chain has a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region at its other end.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino -terminus to carboxyl-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions are not directly involved in the binding of the antibody to the antigen but exhibit various effector functions such as participation in antibody dependent cell-mediated cytotoxicity (ADCC), phagocytosis via binding to Fey receptor, half- life/clearance rate via neonatal Fc receptor (FcRn) and complement dependent cytotoxicity via the Clq component of the complement cascade.
  • ADCC antibody dependent cell-mediated cytotoxicity
  • FcRn neonatal Fc receptor
  • complement dependent cytotoxicity via the Clq component of the complement cascade.
  • fragment when referring to an antibody, means antigen binding fragments of an antibody comprising a partial heavy or light chain variable sequence, which retain capacity to bind human or murine S 100A4.
  • fragments include, without being limited to, (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment (Ward et at. (1989) Nature 341, 544-546], which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL, and CHI domains
  • F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • Fragments can be prepared by recombinant techniques or enzymatic or chemical cleavage of intact antibodies, e.g. papain digestion (see for example, W094/29348).
  • VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); See, e.g., Bird et al. (1988) Science 242, 423-426 and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85, 5879-5883).
  • scFv single chain Fv
  • Such single chain antibodies are included by reference to the term "antibody”.
  • the term "monoclonal antibody” refers to a preparation of antibody molecules of homogeneous molecular composition i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope or antigenic binding site.
  • the monoclonal antibodies are produced by a hybrid cell product of the fusion of a B-cell clone descendent of a single unique parent cell and a tumor plasma cell.
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • the term “diclonal antibody” refers to a preparation of at least two antibodies to murine or human S100A4. Typically, the different antibodies bind different epitopes.
  • oligoclonal antibody refers to a preparation of 3 to 100 different antibodies to murine or human S100A4. Typically, the antibodies in such a preparation bind to a range of different epitopes.
  • polyclonal antibody refers to a preparation of more than 1 (two or more) different antibodies to murine or human S 100A4 derived from different B- cell lines, i.e., antibodies which are a mixture of immunoglobulins, secreted against a specific antigen (S100A4). Such a preparation includes antibodies binding to a range of different epitopes.
  • bispecific antibody refers to that antibody having two different binding specificities, see. e.g., U.S. Patents. 5,922,845 and 5,837,243; Zeilder (1999) J. Immunol. 163, 1246-1252; Somasundaram (1999) Hum. Antibodies 9, 47-54; Keler (1997) Cancer Res. 57, 4008-4014.
  • a bispecific antibody may have one binding site for a cell surface antigen, and a second binding site for an Fc receptor on the surface of an effector cell.
  • the exemplary bispecific antibodies can bind to two different epitopes of the B-cell surface marker.
  • a binding arm of an anti- B cell marker can be combined with an arm which binds to a triggering molecule in a leukocyte, such as a T-cell receptor molecule (for example, CD2 or CD3), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD 16), such that the mechanisms of cell defence are concentrated in the B-cell.
  • Bispecific antibodies can also be used to locate cytotoxic agents against the B-cell.
  • bispecific antibodies have a binding arm to the marker of the lymphocyte and an arm which binds to the cytotoxic agent (for example, saporin, anti-interferon-a, vinca alkaloid, ricin A-chain, methotrexate or a radioactive hapten isotope).
  • cytotoxic agent for example, saporin, anti-interferon-a, vinca alkaloid, ricin A-chain, methotrexate or a radioactive hapten isotope.
  • Bispecific antibodies can be prepared as whole antibodies or as antibody fragments (for example, F(ab)2 bispecific antibodies).
  • Bispecific antibodies further include diabodies.
  • Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (See, e.g., Holliger, P. et al. (1993) Proc. Natl. Acad. Sci. USA 90, 6444-6448; Poljak et al. (1994) Structure 2, 121 -1123).
  • the term "multispecific antibody” refers to that antibody having at least three binding sites or specificities.
  • epitope refers to a protein determinant capable of specific binding to an antibody, or the place where an antibody binds its Ag, or by extension to the peptide presented in an MHC molecule to which a T-cell receptor binds.
  • Epitopes consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non- conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • central fat means the hepato-visceral adipose tissue (VAT) and/or ectopic hepato-visceral fat storage. Central fat was defined sum of visceral fat (by MRI, in cm 2 ) and hepatic fat (by MRI, in %).
  • isolated means identified and separated or removed from its natural environment.
  • a polynucleotide or a polypeptide naturally present in a living organism is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is “isolated,” including but not limited to when such polynucleotide or polypeptide is introduced back into a cell, even if the cell is of the same species or type as that from which the polynucleotide or polypeptide was separated.
  • an agent effective to induce an immune response against an antigen refers to a different substance than the monoclonal antibody of the present invention that acts as a stimulator of immune responses thereby increasing the response to the vaccine, without having any specific antigenic effect in itself.
  • This agent is also known in the art as an adjuvant.
  • Examples include lipid A, Bordetella pertussis or Mycobacterium tuberculosis derived proteins, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.); aluminium salts such as aluminium hydroxide gel (alum) or aluminium phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes biodegradable microspheres; monophosphoryl lipid A and quil A.
  • aluminium salts such as aluminium hydroxide gel (alum) or aluminium phosphate
  • salts of calcium, iron or zinc an insoluble suspension of acylated tyrosine acylated sugars
  • cationically or anionically derivatized polysaccharides polyphosphazene
  • Cytokines such as GM CSF or interleukin-2, - 7, or-12, may also be used as adjuvants.
  • the phrase "specifically binds" when referring to antibodies and antigen binding fragments thereof means that the antibody binds murine or human S100A4 with no or insignificant binding to other murine or human proteins. The term however does not exclude the fact that antibodies of the invention may also be cross-reactive with other forms of S100A4.
  • the antibody binds with an association constant (Ka) of at least about 1 x 106 M"1 or 107 M"l, or about 108 M”1 to 109 M” l, or about 1010 M"1 to 1011 M”1 or higher, and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • Ka association constant
  • telomere binding reaction that is determinative of the presence of a target protein in the presence of a heterogeneous population of proteins and other biologies.
  • the specified binding moieties bind preferentially to a particular target protein and do not bind in a significant amount to other components present in a test sample. Specific binding to a target protein under such conditions may require a binding moiety that is selected for its specificity for a particular target antigen.
  • a variety of assay formats may be used to select ligands that are specifically reactive with a particular protein.
  • solid-phase ELISA immunoassays, immunoprecipitation, Biacore, and Western blot are used to identify peptides that specifically react with human or murine S100A4.
  • a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background. It is to be understood that that affinity interactions between and aptamer and an analyte or target or antibody and an analyte or target are a matter of degree.
  • the "specific binding affinity" of an aptamer or antibody for its target means that the aptamer or antibody binds to its target generally with a much higher degree of affinity than such aptamer or antibody may binds to other, non-target, components in a mixture or sample.
  • blocks as used throughout the present specification in relation to antibodies and antigen binding fragments thereof of the invention means that the biological activity of human or murine S100A4 is reduced in the presence of the antibodies and antigen binding fragments thereof of the present invention in comparison to the activity of human or murine S100A4 in the absence of such antibodies and antigen binding fragments thereof. Blocking may be due to but not limited to one or more of neutralizing ligand binding, preventing the ligand activating the receptor, down regulating the human or murine S100A4 or affecting effector functionality. Levels of blockade can be measured in several ways, for example by use of the assays as set out in the examples below, proteolytic activity, cell migration, tumour development, tumour angiogenesis and tumour dissemination (metastasis).
  • Nucleic acid means either DNA, RNA, single-stranded or double- stranded and any chemical modifications thereof, provided only that the modification does not interfere with amplification of selected nucleic acids. Such modifications include, but are not limited to, modifications at cytosine exocyclic amines, substitution of 5-bromo-uracil, backbone modifications, methylations, unusual base-pairing combinations and the like.
  • nucleic acid refers to a polymer of nucleotides of any length, and such nucleotides may include deoxyribonucleotides, ribonucleotides, and/or analogs or chemically modified deoxyribonucleotides or ribonucleotides.
  • polynucleotide include double- or single-stranded molecules as well as triple-helical molecules.
  • Ligand or "ligand of a given target” means a nuclei acid that binds another molecule (target).
  • a ligand In a population of candidate nucleic acids, a ligand is one which binds with greater affinity than that of the bulk population. In a candidate mixture there can exist more than one ligand for a given target. The ligands can differ from one another in their binding affinities for the target molecule.
  • the term "about” represents an insignificant modification or variation of the numerical values such that the basic function of the item to which the numerical value relates is unchanged.
  • the terms “comprises,” “comprising,” “includes,” “including,” “contains,” “containing,” and any variations thereof, are intended to cover a non exclusive inclusion, such that a process, method, product-by-process, or composition of matter that comprises, includes, or contains an element or list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, product-by-process, or composition of matter.
  • aptamers indicates oligonucleic acid or peptide molecules that are capable to bind a specific target entity.
  • aptamers are artificial oligonucleotides which can serve as antibody mimics because of their high affinity and selectivity for various target compounds ranging from small molecules, such as drugs and dyes, to complex biological molecules such as enzymes, peptides, and proteins.
  • Custom aptamers can be identified from random oligonucleotide libraries for specific target compounds by an in vitro iterative process called Systematic Evolution of Ligands by Exponential Amplification (SELEX).
  • SELEX Systematic Evolution of Ligands by Exponential Amplification
  • Aptamers can form a 3D structure serving as receptors specific to their target compounds similar to antibodies. Aptamers also have a number of advantages over antibodies such as a tolerance to wide ranges of pH and salt concentrations, heat stability, ease of synthesis, and cost efficiency. The specificity and affinity of aptamers are comparable, if not higher, to antibodies. Aptamers are also capable of being reversibly denatured for the release of target compounds, which makes the aptamers especially useful receptors for biosensing applications.
  • aptamers can be comprised of single-stranded (ss) oligonucleotides and/or be chemically synthesized peptides that have been engineered through repeated rounds of in vitro selection, or equivalent techniques identifiable by a skilled person, to bind to various targets.
  • ss single-stranded
  • an “aptamer” or “nucleic acid ligand” is a set of copies of one type or species of nucleic acid molecule that has a particular nucleotide sequence.
  • An aptamer can include any suitable number of nucleotides.
  • “Aptamers” refer to more than one such set of molecules. Different aptamers may have either the same number or a different number of nucleotides. Aptamers may be DNA or RNA and may be single stranded, double stranded, or contain double stranded regions.
  • a sensor indicates a device that measures a physical quantity and converts it into a signal which can be read by an observer or by an instrument. As is understood, a sensor is calibrated against known standards. Accordingly, a sensor can be used to capture a target entity by exploiting the affinity of aptamer to the target entity, and can be detected using techniques identifiable by a skilled person upon reading of the present disclosure.
  • detect indicates the determination of the existence, presence or fact of a target or signal in a limited portion of space, including but not limited to a sample, a reaction mixture, a molecular complex and a substrate including a platform and an array.
  • Detection is "quantitative” when it refers, relates to, or involves the measurement of quantity or amount of the target or signal (also referred as quantitation), which includes but is not limited to any analysis designed to determine the amounts or proportions of the target or signal.
  • Detection is “qualitative” when it refers, relates to, or involves identification of a quality or kind of the target or signal in terms of relative abundance to another target or signal, which is not quantified.
  • An “optical detection” indicates detection performed through visually detectable signals: spectra or images from a target of interest or a probe attached to the target.
  • labeling agent refers to one or more reagents that can be used to detect a target molecule/aptamer complex.
  • a detectable moiety or label is capable of being detected directly or indirectly.
  • target may be used herein interchangeably, and generally refer to a substance, compound or component whose presence or absence in a sample has to be detected.
  • Analytes include but are not limited to biomolecules and in particular biomarkers.
  • biomolecule indicates a substance compound or component associated to a biological environment including but not limited to sugars, amino acids, peptides proteins, oligonucleotides, polynucleotides, polypeptides, organic molecules, haptens, epitopes, biological cells, parts of biological cells, vitamins, hormones and the like.
  • biomarker indicates a biomolecule that is associated with a specific state of a biological environment including but not limited to a phase of cellular cycle, health and disease state. The presence, absence, reduction, upregulation of the biomarker is associated with and is indicative of a particular state.
  • polypeptides polypeptides
  • solid support means any substrate having a surface to which molecules may be attached, directly or indirectly, through either covalent or non-covalent bonds.
  • the substrate materials may be naturally occurring, synthetic, or a modification of a naturally occurring material.
  • Solid support materials may include magnetic beads, or any other materials that are capable of having one or more functional groups, such as any of an amino, carboxyl, thiol, or hydroxyl functional group, for example, incorporated on its surface.
  • the solid support may take any of a variety of configurations ranging from simple to complex and can have any one of a number of shapes, including beads, disks, particles, plates, rods, strips, tubes, wells, and the like.
  • the surface may be relatively planar (e.g., a slide), spherical (e.g., a bead), cylindrical (e.g., a column), or grooved.
  • separating means any process whereby one or more components of a mixture are separated from other components of the mixture.
  • aptamers bound to target molecules can be separated from other nucleic acids that are not bound to target molecules and from non-target molecules. That is, a separation process or step allows for the separation of all the nucleic acids in a candidate mixture into at least two pools based on their relative affinity and/or dissociation rate to the target molecule.
  • the separation process can be accomplished by various methods. For example, magnetic beads upon which target molecules are conjugated can also be used to separate aptamers in a mixture.
  • SPR surface plasmon resonance
  • sample refers to a mixture, gas, or substance that may or may not comprise a target or analyte.
  • Samples include but are not limited to biological samples, such as blood, sputum, breath, urine, semen, saliva, amniotic fluid, meningeal fluid, glandular fluid, nipple aspirate, lymph fluid, bronchial aspirate, joint aspirate, synovial fluid, cellular extract, cerebrospinal fluid, homogenized solid material from stool or tissue samples, bacterial culture, viral culture, or experimentally-separated fractions thereof.
  • biological samples such as blood, sputum, breath, urine, semen, saliva, amniotic fluid, meningeal fluid, glandular fluid, nipple aspirate, lymph fluid, bronchial aspirate, joint aspirate, synovial fluid, cellular extract, cerebrospinal fluid, homogenized solid material from stool or tissue samples, bacterial culture, viral culture, or experimentally-separated fractions thereof
  • non-target refers to molecules in a sample that form a non-specific complex with an aptamer. It will be appreciated that a molecule that is a non target for a first aptamer may be a target for a second aptamer. Similarly, a molecule that is a target for a first aptamer may be a non-target for a second aptamer.
  • PCOS Polycystic ovary syndrome
  • childbearing age preferably refers to an age between 20 and 45 years old, more preferably to an age between 20 and 35 years old.
  • Oligo-ovulatory androgen excess in adolescent girls or women is a major cause of subfertility and relates to hepatic steatosis, independently of obesity.
  • PCOS may result in enlarged ovaries, and physically manifest as excess hair growth, acne, obesity or infrequent, prolonged menstrual cycles, hirsutism, seborrhoea and menstrual irregularity. It is unknown whether early interventions influence the post-treatment rates of spontaneous ovulations.
  • PCOS is typically diagnosed via one of two methods: clinical or biochemical hyperandrogenism.
  • Clinical hyperandrogenism is defined as moderate to severe hirsutism with a Ferriman-Gallway score of > 9 AND a free testosterone level that is equal to or > 50% above the ULN( upper limit of normal), while biochemical hyperandrogenism is defined as free testosterone level that is equal to or > 75% above the ULN.
  • the term "contraceptive” refers to the following.
  • hormonal contraceptive formulations There are two main types of hormonal contraceptive formulations: combined methods which contain both an oestrogen and a progestin, and progestogen-only methods which contain only progesterone or one of its synthetic analogues (progestins).
  • COCP oral contraceptive pill
  • the combined oral contraceptive pill (COCP) often referred to as the birth control pill or colloquially as “the pill”
  • COCP often referred to as the birth control pill or colloquially as “the pill”
  • COCP often referred to as the birth control pill or colloquially as “the pill”
  • the pill is a type of birth control that is designed to be taken orally by women. It includes a combination of an oestrogen (usually ethinylestradiol) and a progestogen (specifically a progestin). When taken correctly, it alters the menstrual cycle to eliminate ovulation
  • Non-alcoholic fatty liver disease refers to a disorder characterized by an abnormal accumulation of fat in the liver, due to causes other than excessive alcohol use.
  • NAFLD is a continuum of liver abnormalities, from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis).
  • a liver can remain fatty without disturbing liver function (NAFL), but by various mechanisms and possible insults to the liver, it may also progress into a non-alcoholic steatohepatitis (NASH), a state in which steatosis is combined with inflammation and sometimes fibrosis (steatohepatitis).
  • NASH non-alcoholic steatohepatitis
  • Alescence refers to the age range between 10 and 24 years more typically between 10 and 19 years.
  • Non-obese refers to a body mass index below 30, typically below 27,5 and more typically below 25.
  • the present invention discloses that circulating S100A4 concentrations relate to central fat excess, are elevated in adolescents with PCOS and can be normalized more with SPIOMET treatment than OC.
  • Adolescent PCOS appears to be essentially driven by an exhaustion of the capacity to expand subcutaneous VAT in a metabolically safe way, resulting in a lipotoxic state and in lipid deposition in central/ectopic depots (liver and viscera).
  • high presence of S100A4 has been associated with subcutaneous VAT dysfunction, inflammation and insulin resistance, and with adipocyte hypertrophy, independently of BMI.
  • S100A4 could be exerting a protective role in mice experiencing obesity and inflammation induced by a high-fat diet.
  • serum S100A4 was found to be linked to central fat; circulating S100A4 levels in girls with PCOS and central-fat excess were increased as compared to healthy controls, and dropped to near normal levels after insulin sensitization with low-dose SPIOMET, paralleling the fall in hepato-visceral fat, and the improvement of the markers of insulin resistance and adipose tissue inflammation and dysfunction. S100A4 could become a marker of central (hepato-visceral) fat excess, independently of whether the major origin of circulating S100A4 is subcutaneous or non-subcutaneous adipose tissue.
  • An inflammatory subset of macrophages in the liver may be an alternative or an additional source of circulating S100A4 in girls with hepatic fat excess; a partially hepatic origin of circulating S100A4 in girls with PCOS would contribute to explain the fall of circulating S100A4 levels after SPIOMET-enhanced reduction of liver fatness, as well as the absence of such a fall after OC treatment which fails to reduce liver fatness.
  • the present findings establish adolescent PCOS as condition combining central fat excess (even in the absence of obesity) with high circulating concentrations of S100A4, a protein that is long known to enhance the metastatic progression of a variety of cancers. These findings may be relevant in view of the evidence that young women with PCOS are at high risk (up to 18-fold) for developing endometrial carcinoma, which happens to be the most BMI-dependent among human cancers.
  • Study limitations include the relatively low number of participants, which may have prevented the detection of smaller differences between subgroups, and the absence of an untreated subgroup.
  • Study strengths include the strict inclusion and exclusion criteria, and the availability of a broad spectrum of advanced outcomes allowing to identify associations between circulating S100A4 and surrogates of adipose-tissue dysfunction.
  • S100A4 is a circulating marker of hepato- visceral fat excess, at least in adolescent girls with PCOS.
  • Example 1 Subjects and Methods
  • Circulating S100A4 was measured in spare serum samples available from 22 (of 36) girls in the first trial, and from 29 (of 29) girls in the second trial (Figure 2), for a total population of 51 girls (average age 15.8 yr; BMI 24.5 Kg/m 2 ). Both trials were initiated in the Adolescent Endocrinology Unit of Sant Joan de Deu University Hospital, Barcelona, Spain. The inclusion criteria were: 1) hirsutism (score >8 on Ferriman 8i Gallwey scale), oligomenorrhea (menstrual intervals >45 days), gynecological age >2.0 years, and absence of sexual activity (no need for contraception).
  • Exclusion criteria were 21 -hydroxylase deficiency; glucose intolerance or diabetes mellitus; evidence of thyroid, liver, or kidney dysfunction; hyperprolactinemia; prior use of medications affecting gonadal or adrenal function, or carbohydrate or lipid metabolism [Ibanez et at. (2017) J Adolesc Health 61, 446-453].
  • OC treatment for 1 year consisted of 20 pg of ethinylestradiol plus 100 mg of levonorgestrel for 21/28 days, and placebo for 7/28 days; SPIOMET treatment for 1 year consisted of a low-dose combination of spironolactone 50 mg/d, pioglitazone 7.5 mg/d, and metformin 850 mg/d [Ibanez et al. (2017) J Adolesc Health 61, 446-453].
  • HOMA-insulin resistance (HOMA- IR) was calculated as [fasting insulin in mU/L] x [fasting glucose in mg/dl_]/405.
  • Serum S100A4 was measured using a Human Protein S100A4 ELISA kit (CSB- EL02032HU, Cusabio Biotech, Wuhan, China) with a lower detection limit of 0.2 ng/ml, and with intra- and inter-assay variation coefficients of ⁇ 0.8% and ⁇ 10%, respectively.
  • Body composition was assessed by dual X-ray absorptiometry with a Lunar Prodigy and Lunar software (version 3.4/3.5, Lunar Corp, WI); abdominal fat (subcutaneous and visceral) and hepatic fat were assessed by magnetic resonance imaging (MRI) using a multiple- slice MRI 1.5 Tesla scan (Signa LX Echo Speed Plus Excite, General Electric, Milwaukee, WI) [Ibanez et al. (2017) J Adolesc Health 61, 446-453].
  • Central fat was arbitrarily defined here as the sum of visceral fat (in cm 2 ) and hepatic fat (in %).
  • BMI body mass index
  • SHBG sex hormone-binding globulin
  • FAI free androgen index
  • HOMA-IR homeostasis model assessment insulin resistance
  • HDL high- density lipoprotein
  • LDL low-density lipoprotein
  • HMW high molecular weight
  • usCRP ultra-sensitive C-reactive protein
  • DXA dual X-ray absorptiometry
  • MRI magnetic resonance imaging.
  • One-year changes in circulating S100A4 correlated also with those in fasting insulin, HOMA-IR, LDL-cholesterol and HMW adiponectin (Table 2).
  • Results are Pearson correlation coefficients and p values adjusted for changes in body mass index (BMI) in multiple regression analysis.
  • SHBG sex hormone binding globulin
  • FAI free androgen index
  • HOMA-IR homeostasis model assessment insulin resistance
  • HDL high-density lipoprotein
  • LDL low-density lipoprotein
  • HMW high molecular weight
  • usCRP ultra-sensitive C-reactive protein
  • DXA dual X-ray absorptiometry
  • MRI magnetic resonance imaging.

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Abstract

L'invention se rapporte à l'utilisation in vitro d'un ligand se liant de manière spécifique à S100A4, par exemple un anticorps pour identifier la réponse au traitement par la spironolactone, la pioglitazone et la metformine, par exemple chez des patientes souffrant d'un syndrome ovarien polykystique (SOP). L'invention concerne en outre un procédé in vitro de surveillance de la réactivité d'un sujet à un traitement par la spironolactone, la pioglitazone et la metformine, le procédé comprenant les étapes consistant à : déterminer la concentration en S100A4 d'un échantillon corporel prélevé chez le sujet avant le traitement ou au tout début de celui-ci, déterminer la concentration en S100A4 dudit échantillon corporel prélevé chez le sujet au cours dudit traitement, une baisse de la concentration en S100A4 par rapport à la concentration avant le traitement ou au tout début de celui-ci indiquant que le traitement est efficace.
PCT/EP2019/083848 2018-12-05 2019-12-05 S100a4 utilisable en tant que marqueur de traitement par la spironolactone, la pioglitazone et la metformine WO2020115223A1 (fr)

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GBGB1819876.2A GB201819876D0 (en) 2018-12-05 2018-12-05 Hepato-visceral fat excess
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