WO2024017988A1 - Rapport entre fgfbp1 et metrnl dans l'évaluation du syndrome des ovaires polykystiques - Google Patents
Rapport entre fgfbp1 et metrnl dans l'évaluation du syndrome des ovaires polykystiques Download PDFInfo
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- 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
- G01N33/689—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 pregnancy or the gonads
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
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- G01N2333/52—Assays involving cytokines
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- 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 method for diagnosing PCOS in a subject, said method comprising the steps of a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), d) comparing the calculated score with a reference score, and e) diagnosing PCOS in a subject.
- a method of selecting a patient for therapy of PCOS comprising a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), d) comparing the calculated score with a reference score, and e) selecting the patient for PCOS therapy.
- the present invention relates to a method for monitoring PCOS progression in a subject having PCOS or for monitoring response to treatment in a subject having PCOS, said method comprising a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), d) comparing the calculated score with a reference score, and e) monitoring progression in the subject suffering from PCOS or being treated for PCOS.
- the present invention relates to a computer-implemented method for the diagnosis of PCOS in a subject.
- PCOS Polycystic ovarian syndrome
- Patients with PCOS can have a range of clinical presentations, which can be of reproductive and/or of metabolic type.
- Reproductive presentations include irregular menstrual cycle, infertility, pregnancy complications and hirsutism
- metabolic presentations include obesity, insulin resistance, metabolic syndrome, prediabetes, type-2 diabetes and cardiovascular factors.
- These clinical presentations are also associated with psychological disorders, such as anxiety and depression (Escobar-Morreale, H. F. 2018; International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018).
- PCOS non-classical adrenal hyperplasia
- NCAH non-classical adrenal hyperplasia
- Congenital Adrenal Hyperplasia androgen secreting tumors
- Cushing syndrome thyroid disorders
- hyperprolactinemia Escobar-Morreale HF.
- Polycystic ovary syndrome definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018 ;14(5):270-284; Teede HJ, Misso ME, Costello MF, et al. International PCOS Network. Recommendations from the international evidencebased guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602-1618). Diagnostic tests which may be used to exclude other diseases are e.g.
- Thyroid Stimulating Hormone Thyroid Stimulating Hormone
- PCOS may be caused by a combination of genetic, epigenetic and environmental factors, such as inheritance.
- PCOS is one of the most common endocrine disorders in women, affecting 10% of the women during their reproductive years, up to 70% of the affected women remain undiagnosed (March WA, Moore VM, Willson KJ, et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-51).
- PCOS The mostly widely used criteria for PCOS diagnosis are the so-called Rotterdam Criteria.
- PCOS is indicated, if at least 2 of the following criteria apply: (i) irregular cycles (oligomenorrhea) and/or ovulatory dysfunction (oligo-anovulation, OA), (ii) clinical and/or biochemical hyperandrogenism (HA) and (iii) polycystic ovarian morphology (PCOM) (PCOS Consensus Workshop Group, Fertil Steril 2004; 81:19-25).
- the first criterion is defined as menstrual cycles with a cycle length of less than 21 days or more than 35 days or less than 8 cycles per year.
- Clinical and/or biochemical signs of hyperandrogenism where clinical hyperandrogenism is defined as hirsutism (excess and male-pattern hair growth) and/or acne, and biochemical hyperandrogenism is defined as higher levels of free androgens compared to healthy controls.
- Clinical hyperandrogenism is also defined as a modified Ferriman-Gallwey score of > 8.
- Biochemical hyperandrogenism may be assessed using free testosterone or the free androgen index (FAI) which can be calculated measuring total testosterone and sex hormone binding globuline (SHBG).
- FAI free androgen index
- SHBG free androgen index
- PCOM is usually determined according to the “International Evidence-based Guideline for PCOS 2018” using endovaginal ultrasound transducers with a frequency bandwidth that includes 8 MHz.
- the threshold for PCOM is considered to be on either ovary: a follicle number per ovary of > 20 and/or an ovarian volume >10 ml, ensuring no corpora lutea, cysts or dominant follicles are present. If older ultrasound technology is used, the threshold for PCOM could be an ovarian volume >10 ml or a follicle count of > 12 on either ovary.
- AMH Anti-Mullerian Hormone
- AMH is a glycoprotein hormone whose expression is critical to sex differentiation at a specific time during fetal development. Further, AMH produced by granulosa cells of growing follicles usually correlates with the number of antral follicles within the ovary. Therefore, serum levels of AMH may be a surrogate biomarker for the antral follicle count/number (AFC) determined by transvaginal ultrasound.
- AFC antral follicle count/number
- oligomenorrhea defined as mean menstrual cycle length > 35 days
- AMH above threshold oligomenorrhea
- hyperandrogenism defined as either testosterone above threshold and/or the presence of hirsutism (mFG score > 5).
- AMH was suggested in combination with hyperandrogenism and oligomenorrhea (Sahmay et al., 2014) or in combination with SHBG (Calzada et al.,
- Another method for detecting PCOS is to measure other hormones, such as e.g. luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- LH luteinizing hormone
- FSH follicle-stimulating hormone
- Testosterone is the most abundant measured androgen, in its total, bound and free form.
- the practice of measuring free testosterone has its limitations. Direct measurement of free testosterone using radioimmunoassay is highly inaccurate, and does not reflect the true values.
- the assays have high intra- and interassay variability. Alternatively, a greater degree of accuracy, particularly for clinical research, will be obtained by measuring total testosterone concentration using extraction and chromatography, or gas (GC-MS) or liquid (LC-MS) chromatography-mass spectrometry.
- the diagnostic performance of measuring serum testosterone may be enhanced by the concomitant measurement of SHBG, such that the calculation of free T concentration from the total testosterone and SHBG levels only requires solving a second-degree equation (Azziz R, Carmina E, Dewailly D, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009 ;91(2):456-88).
- the definition of HA may differ depending on ethnicity.
- the mFG score of >8 to diagnose hirsutism in women with PCOS may not be appropriate for the diagnosis in all ethnicities.
- East-Asian women have a lower prevalence of hirsutism compared to Caucasians, and a score of >5 has been proposed for defining hirsutism in Chinese women.
- the level of androgens in blood differs between ethnicities, where the Japanese population has a lower prevalence of raised androgens and testosterone is only recommended as a complementary factor in the diagnosis of PCOS in this population (Huang Z, Yong EL. Ethnic differences: Is there an Asian phenotype for polycystic ovarian syndrome? Best Pract Res Clin Obstet Gynaecol. 2016;37:46-55; Kubota T. Update in polycystic ovary syndrome: new criteria of diagnosis and treatment in Japan. Reprod Med Biol. 2013;12(3):71-77).
- Phenotype A is characteristic for patients showing hyperandrogenism, ovulatory dysfunction and/or irregular cycles and polycystic ovarian morphology.
- Phenotype B is characterized by hyperandrogenism, ovulatory dysfunction and/or irregular cycles.
- Phenotype C is characterized by hyperandrogenism and polycystic ovarian morphology.
- Phenotype D is characterized by ovulatory dysfunction and/or irregular cycles and polycystic ovarian morphology.
- PCOS medication available. Treatment is symptom- oriented and adapted to personal needs.
- Therapeutic approaches target hyperandrogenism, irregular cycles and/or ovulatory dysfunction and associated metabolic disorders, such as diabetes.
- the International evidence-based guideline for the assessment and management of polycystic ovary syndrome of 2018 provides information to support clinical decision making and patient management.
- PCOS An area of particular interest in the diagnosis of PCOS is in women of young age, namely adolescents and young women under the age of 25, when the features of normal pubertal development overlap with adult diagnostic criteria. This makes diagnosis controversial and challenging. Many of the manifestations that are used for diagnosing PCOS may evolve over time and change during the first years after menarche. Normal pubertal physiological changes such as irregular menstrual cycles, acne and PCOM, overlap with adult PCOS diagnostic criteria. In adolescent and young adult women, PCOS is diagnosed when both the OA and HA criteria are fulfilled.
- the pelvic ultrasound is not recommended to be done in adolescents ⁇ 8 years from menarche, due to the high incidence of multifollicular ovaries in this life stage (Pena AS, Witchel SF, Hoeger KM, Oberfield SE, Vogiatzi MG, Misso M, Garad R, Dabadghao P, Teede H. Adolescent polycystic ovary syndrome according to the international evidence-based guideline. BMC Med. 2020;18(l):72).
- the assessment of an irregular menstrual cycle in adolescents can be difficult. Menstrual cycles are often irregular during adolescence.
- the present invention relates to a method for diagnosing PCOS in a subject, said method comprising the steps of a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), and d) comparing the calculated score with a reference score. e) diagnosing PCOS in a subject.
- step e) is based on the results of the comparison step d). Accordingly, step e) may be as follows: e) diagnosing PCOS in a subject based on the results of the comparison in step d).
- the present invention relates to a method of selecting a patient for therapy of PCOS, comprising: a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), d) comparing the calculated score with a reference score, and e) selecting the patient for PCOS therapy.
- step e) is based on the results of the comparison step d). Accordingly, step e) may be as follows: e) selecting the patient for PCOS therapy based on the results of the comparison in step d).
- the present invention relates to a method for monitoring PCOS progression in a subject having PCOS or for monitoring response to treatment in a subject having PCOS, said method comprising a) determining the amount or concentration of FGFBP1 in sample from the subject, b) determining the amount or concentration of METRNL in a sample from the subject, c) calculating a score of the amounts or concentrations determined in steps a) and b), d) comparing the calculated score with a reference score, and e) monitoring progression in the subject suffering from PCOS or being treated for PCOS.
- step e) is based on the results of the comparison step d). Accordingly, step e) may be as follows: e) monitoring progression in the subject suffering from PCOS or being treated for PCOS, based on the results of step d).
- the present invention relates to a computer-implemented method for diagnosing PCOS in a subject, said method comprising
- step (b) processing the values received in step (a) with the processing unit, wherein said processing comprises
- step (c) optionally providing the diagnosis via an output device, wherein said diagnosis is based on the results of step b).
- the present invention relates to the use of FGFBP1 and METRNL as biomarkers for the diagnosis of PCOS. Further, the invention relates to the use of at least one agent which specifically binds to METRNL and of at least one agent which specifically binds to FGFBP1 for the diagnosis of PCOS.
- the present invention relates to a kit comprising at least one agent that specifically binds to METRNL and at least one agent that specifically binds to FGFBP1.
- FIG. 1 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for PCOS cases when all phenotypes were combined (phenotypes A-D). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 2 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in controls versus PCOS cases when all phenotypes were combined (phenotypes A-D). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 3 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for PCOS phenotypes A-D when compared to controls. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 4 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in healthy controls and in PCOS phenotypes A-D. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 6 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in young controls versus young PCOS cases (age ⁇ 25) combined phenotypes A-D. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 7 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for young PCOS cases (age ⁇ 25) separated by phenotypes A-D versus young healthy controls (age ⁇ 25). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 8 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in young healthy controls (age ⁇ 25) and in PCOS phenotypes A-D (age ⁇ 25). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 9 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for PCOS cases when all phenotypes were combined (phenotypes A-D). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 10 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in controls versus PCOS cases when all phenotypes were combined (phenotypes A-D). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 11 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNE for PCOS phenotypes A-D when compared to controls. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 12 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in healthy controls and in PCOS phenotypes A-D. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 13 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for different PCOS age groups (15-20, 20-25, 25-45) when compared to controls. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 14 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in healthy controls and in PCOS age groups (15-20, 20-25, 25-45). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 15 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for young PCOS cases (age 15-25) when all phenotypes A- D were combined. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 16 Values of the ratio between the two serum biomarkers FGFBP1 and METRNL in young healthy controls versus young PCOS cases (age 15-25), combined phenotypes A-D. The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- FIG. 17 ROC curve analysis for the ratio between the two serum biomarkers FGFBP1 and METRNL for young PCOS cases (age 15-25) separated by phenotypes A-D versus young healthy controls (age 15-25). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- Figure 18 Values of the ratio between the two serum biomarkers FGFBP1 and METRNE in young healthy controls (age 15-25) and in PCOS phenotypes A-D (age 15-25). The ratio was performed between the biomarker concentrations obtained by ELISA immunoassays.
- the methods as referred to in accordance with the first, the second or the third aspects of the present invention include methods which essentially consist of the aforementioned steps or methods which include further steps.
- the methods of the present invention preferably, are ex vivo, and more preferably in vitro methods.
- the methods according to the first, the second or the third aspects of the present invention may comprise steps in addition to those explicitly mentioned above.
- further steps may relate to the determination of further markers and/or to sample pre-treatments or evaluation of the results obtained by the method.
- the methods may be carried out manually or assisted by automation.
- step (a), (b), (c), (d) and/or (e) may in total or in part be assisted by automation, e.g., by a suitable robotic and sensory equipment for the determination in step (a) and (b) or a computer-implemented calculation in step (c) or a computer-implemented comparison in step (d).
- a suitable robotic and sensory equipment for the determination in step (a) and (b) or a computer-implemented calculation in step (c) or a computer-implemented comparison in step (d).
- the methods of the present invention may be computer- implemented.
- Fibroblast growth factor binding protein 1 (FGFBP1, alias FGF-BP, FGFBP1, FGFBP, FGFBP-1 or HBP17) is a 26.2kDa protein belonging to the fibroblast growth factor binding protein family.
- FGFBP1 binds FGF1, FGF2, FGF7, FGF10, FGF22 and HSPG2 (perlecan) in a reversible non-covalent manner (Wu DQ, Kan MK, Sato GH, et al. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. J Biol Chem.
- the fibroblast growth factor binding protein is a novel interaction partner of FGF-7, FGF-10 and FGF-22 and regulates FGF activity: implications for epithelial repair. Oncogene. 2005 Aug l l;24(34):5269-77; Abuharbeid S, Czubayko F, Aigner A. The fibroblast growth factor-binding protein FGF-BP. Int J Biochem Cell Biol. 2006;38(9): 1463-8).
- FGFBPs shuttle FGFs from their storage sites to their receptors (Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010, 10:116-129).
- Biochemical studies revealed that FGFBP1 binds to FGF2 in a dose-dependent and specific manner and that this binding is inhibited by FGF1, heparansulphate and heparinoids (Tassi E, Al-Attar A, Aigner A, et al.
- FGF fibroblast growth factor
- FGFBP1 can contribute to embryonic development, angiogenesis, wound healing, tumor growth, and malignant progression as well as to the maintenance and reinnervation of the neuromuscular junction and blood-brain barrier development (Czubayko F, Smith RV, Chung HC, Wellstein A. Tumor growth and angiogenesis induced by a secreted binding protein for fibroblast growth factors. J Biol Chem 1994, 269:28243-28248; Mongiat M, Otto J, Oldershaw R, et al. Fibroblast growth factor-binding protein is a novel partner for perlecan protein core.
- FGFBP1 mRNA is expressed in mouse normal skin, lung, intestine, ovaries, placenta, stomach and eye (Fon Tacer K, Bookout AL, Ding X, et al. Research resource: comprehensive expression atlas of the Fibroblast Growth Factor system in adult mouse. Mol Endocrinol 2010, 24:2050-2064; Kurtz A, Wang HL, Darwiche N, et al.
- FGFBP1 binding protein for FGF
- a genetic polymorphism in the human FGFBP1 gene was associated with higher gene and protein expression in the human kidney and an increased risk of familial hypertension (Tomaszewski M, Charchar FJ, Nelson CP, et al. Pathway analysis shows association between FGFBP1 and hypertension. J Am Soc Nephrol. 2011 May;22(5):947-55). It has been shown that modulation of FGF signaling by FGFBP1 can regulate vascular sensitivity to endogenous angiotensin II and hence control steady-state blood pressure (Tassi E, Lai EY, Li L, et al.
- FGFBP1 Fibroblast Growth Factor- Binding Protein
- FGF2 mRNA expression is high in preovulatory follicles and in the early luteal phase, it then decreases in the late luteal phase and remains at low levels during pregnancy (Berisha B, Schams D, Rodler D, Pfaffl MW. Angiogenesis in The Ovary - The Most Important Regulatory Event for Follicle and Corpus Luteum Development and Function in Cow - An Overview. Anat Histol Embryol. 2016 Apr;45(2): 124-30).
- Intraperitoneal injection of FGF2 in a mouse model of estradiol valerate induced PCOS, had protective and ameliorative effects (Moayeri A, Rostamzadeh A, Raoofi A, et al.
- FGF2- signaling While the role of FGF2- signaling is unclear in PCOS, its metabolic function has been investigated in recent years. FGF2, depending on concentration, can function as either a positive or a negative factor of in vitro adipogenesis (Kim S, Ahn C, Bong N, et al. Biphasic effects of FGF2 on adipogenesis. PEoS One. 2015 Mar 19;10(3):e0120073. doi: 10.1371/journal.pone.0120073). Mathes and colleagues showed that FGF2- dependent signaling enhances the differentiation of fibro/adipogenic progenitors promoting the formation of intramuscular adipose tissue (Mathes S, Fahrner A, Ghoshdastider U, et al.
- FGF-2-dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis. Proc Natl Acad Sci U S A. 2021 Sep 14; 118(37):e2021013118. doi: 10.1073/pnas.2021013118).
- the appearance of adipose tissue between skeletal muscle fibers is a unique feature of aging, obesity and type 2 diabetes, demonstrating association with insulin resistance.
- FGF2 has been shown to be a negative regulator of thermogenesis in both brown and beige fat. Disruption of FGF2 strongly enhanced the thermogenic action of brown and beige fat, leading to increased energy expenditure and improved lipid homeostasis.
- Meteorin-like protein is a hormone (28KDa secreted protein) that is induced after exercise and cold exposure in the skeletal muscle and adipose tissue, respectively. Increased expression of METRNL in the circulation or in adipose tissue resulted in 'browning' of the white adipose tissue (WAT). Intraperitoneal injection with Metml-Fc protein in mice for 7 days induced significant body weight reduction, increased 02 consumption and glucose tolerance. Metml did not show direct effect on the thermogenesis of white adipocytes in vitro, which indicated the involvement of a non-adipose cell type in the induction of beige fat.
- Metml seemed to rather stimulate several immune cell subtypes to enter the adipose tissue and to activate their prothermogenic actions.
- METRNL-treated mice had increased macrophage and eosinophils numbers in WAT and increased expression of genes that are associated with alternative macrophage activation (Rao RR, Long JZ, White JP, et al. Meteorinlike is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014 Jun 5;157(6):1279-1291).
- METRNL has been associated with innate and possibly acquired immunity. High expression of METRNL was identified in activated monocytes (M2-polarized macrophages), skin and mucosal tissues.
- METRNL is expressed by resting fibroblasts and TFNy-treated keratinocytes. Over-expression of METRNL was described in several human skin diseases including psoriasis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis (Ushach I, Burkhardt AM, Martinez C, et al. METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages. Clin Immunol. 2015 Feb; 156(2): 119-27). Recently, Baht and colleagues described a role for METRNL in coordinating skeletal muscle repair through macrophage accretion and phenotypical switch.
- METRNL in response to local injury METRNL would be secreted predominantly from macrophages. Furthermore, METRNL promoted an anti-inflammatory function through a STAT3-dependent auto-/paracrine mechanism inducing insulin-like growth factor 1 (IGF-1), which activated muscle progenitors to help myogenesis. Finally, METRNL has been shown to be a critical regulator of muscle regeneration acting directly on immune cells to promote an anti-inflammatory/pro-regenerative environment and myogenesis (Baht GS, Bareja A, Lee DE, et al. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat Metab. 2020 Mar;2(3):278-289. Erratum in: Nat Metab.
- METRNL has been suggested to act as a neurotrophic factor with therapeutic potential in neural development.
- METRNL is indeed able to cross the blood brain barrier (BBB) and an increasing blood-brain barrier dysfunction caused increasing cerebrospinal fluid METRNL concentrations (Berghoff M, Hbpfinger A, Rajendran R, et al. Evidence of a Muscle-Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum. Journal of Clinical Medicine. 2021; 10(15):3271).
- Serum METRNL levels have been studied in association with type 2 diabetes (T2DM) producing conflicting results (Lee JH, Kang YE, Kim JM, et al. Serum Meteorin-like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Res Clin Pract. 2018 Jan;135:7-10; Chung HS, Hwang SY, Choi JH, et al. Implications of circulating Meteorin-like (Metrnl) level in human subjects with type 2 diabetes. Diabetes Res Clin Pract. 2018 Feb; 136: 100- 107; Wang K, Li F, et al.
- Serum Levels of Meteorin-Like are Increased in Patients with Newly Diagnosed Type 2 Diabetes Mellitus and Are Associated with Insulin Resistance. Med Sci Monit. 2019 Mar 31;25:2337-2343; El-Ashmawy HM, Selim FO, Hosny TAM, Almassry HN. Association of low serum Meteorin like (Metrnl) concentrations with worsening of glucose tolerance, impaired endothelial function and atherosclerosis. Diabetes Res Clin Pract. 2019 Apr; 150:57-63; Wang C, Pan Y, Song J, et al. Serum Metrnl Level is Correlated with Insulin Resistance, But Not with P-Cell Function in Type 2 Diabetics.
- METRNL illustrated a negative correlation with IL-6 and TNF-a in both CAD patients and also with BMI, insulin resistance, IL-6 and TNF-a in T2DM patients (Dadmanesh M, Aghajani H, Fadaei R, Ghorban K. Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines. PLoS One. 2018 Sep 13;13(9):e0204180). Furthermore, a case-control study for CAD patients showed significant associations of serum METRNL with the presence and severity of CAD (Liu ZX, Ji HH, Yao MP, et al.
- Serum Metrnl is associated with the presence and severity of coronary artery disease. J Cell Mol Med. 2019 Jan;23(l):271-280). Obese patients undergoing bariatric surgery showed decreased circulating levels of METRLN and improvement in glucose and lipid homeostasis compared to normalweight controls (Pellitero S, Piquer-Garcia I, Ferrer-Curriu G, et al. Opposite changes in meteorin-like and oncostatin m levels are associated with metabolic improvements after bariatric surgery. Int J Obes (Lond). 2018 Apr;42(4):919-922). Recently two studies have investigated circulating levels of METRNL in PCOS patients compared to controls. Fouani et al.
- PCOS-RPL PCOS-recurrent pregnancy loss
- PCOS-RPL PCOS-recurrent pregnancy loss
- PCOS-RPL infertile PCOS
- Women’s age was from 20 to 40 years (average of controls’ age: 30.02 ⁇ 4.60; average of PCOS cases’ age: 29.88 ⁇ 4.22).
- the authors found lower serum METRNL levels in PCOS patients when compared to controls.
- serum METRNL correlated with BMI, adiponectin, and homocysteine in controls, and inversely correlated with FBG, fasting insulin, and HOMA-IR in PCOS group and subgroups.
- IBD In Inflammatory Bowel Disease
- METRNL serum levels were decreased and a negative correlation was identified with TNF-a, IL-6 and BMI levels (Gholamrezayi A, Mohamadinarab M, Rahbarinejad P, et al. Characterization of the serum levels of Meteorin-like in patients with inflammatory bowel disease and its association with inflammatory cytokines. Lipids Health Dis. 2020 Oct 30;19(l):230).
- measurements of the ratio between FGFBP1 and METRNL in a sample have the advantage to identify if the patient responds to therapy.
- An additional advantage of measurements of the ratio between FGFBP1 and METRNL in a sample of a patient is to monitor the progression of PCOS.
- a computer-implemented method for assessing a subject suffering from PCOS by measuring the ratio between FGFBP1 and METRNL levels in a sample and, optionally, with further criteria such as a value for oligo- anovulation and/or irregular cycles, hyperandrogenism and/or polycystic ovarian morphology or with further biomarkers or hormones, for assessing said subject based on the comparison and/or the calculation of the data described above.
- PCOS cardiovascular disease
- the metabolic type of PCOS include obesity, insulin resistance, metabolic syndrome, pre-diabetes, type-2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular factors.
- NAFLD nonalcoholic fatty liver disease
- the term “phenotypical” can be used instead of “reproductive”.
- the term “reproductive” (or “phenotypical”) describes any feature of the phenotype of a female known to be indicative of PCOS.
- reproductive characteristics comprise polycystic ovarian morphology (PCOM) and/or clinical hyperandrogenism, such as acne, seborrhea, alopecia, and/or hirsutism.
- PCOM polycystic ovarian morphology
- clinical hyperandrogenism such as acne, seborrhea, alopecia, and/or hirsutism.
- these reproductive characteristics comprise polycystic ovarian morphology (PCOM) and/or clinical hyperandrogenism, more preferably acne, seborrhea, alopecia, deepening of voice and/or hirsutism.
- PCOM polycystic ovarian morphology
- clinical hyperandrogenism more preferably acne, seborrhea, alopecia, deepening of voice and/or hirsutism.
- These reproductive characteristics of clinical hyperandrogenism may be simply diagnosed by asking the female or are apparent after a short physical examination of the female’s body.
- a reference population does not show any or not more than one of these phenotypical characteristics known to be indicative of PCOS.
- PCOS is assessed from the group consisting of metabolic or phenotypical PCOS. In further embodiments, PCOS is assessed from the group consisting of phenotype A, phenotype B, phenotype C and phenotype D PCOS.
- the methods according to the present invention are an in vitro methods.
- diagnosis means assessing whether a subject as referred to in accordance with the method of the present invention suffers from PCOS or not.
- diagnosis PCOS shall be understood as “aiding” or “assisting” in the diagnosis of PCOS.
- a physician may be assisted in the diagnosis of PCOS by additional information and/or devices.
- the actual diagnosis might be carried out by a physician.
- diagnosis of the present invention is usually not intended to be correct for 100% of the subjects to be tested.
- diagnosis preferably, requires that a correct diagnosis can be made for a statistically significant portion of subjects. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p- value determination, Student's t-test, Mann-Whitney test etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983.
- Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%.
- the p-values are, preferably, 0.4, 0.1, 0.05, 0.01, 0.005, or 0.0001.
- sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
- Samples of body fluids can be obtained by well-known techniques and include, preferably, samples of blood, plasma, serum, capillary blood, interstitial fluid, peritoneal fluid, menstrual fluid, more preferably, samples of blood, plasma or serum.
- Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
- Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting.
- cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
- the sample is blood sample (i.e. a whole blood sample), a serum sample, or a plasma sample.
- the term “subject” as referred to herein is, preferably, a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
- the subject is a human.
- the subject can be male or female.
- patient and “subject” are used interchangeably herein.
- the patient is a female human patient of less than 25 years old.
- the patient is a female human patient of less than 20 years old.
- the patient is a female human patient of 15 to less than 25 years old.
- the patient is a female human patient of 15 to less than 20 years old. In particular embodiments, the patient is a female human patient of less than 25 years old and three years after menarche. In particular embodiments, the patient is a female human patient of less than 20 years old and three years after menarche. In particular embodiments, the patient is a female human patient of 15 to less than 25 years old and three years after menarche. In particular embodiments, the patient is a female human patient of 15 to less than 20 years old and three years after menarche.
- step a) of the methods of the present invention the amount or concentration of FGFBP1 is determined, i.e. measured, in a sample from the subject.
- step b) the amount or concentration of METRNL is determined in a sample, from the subject. It is to be understood that steps a) and b) can be carried out in any order. Further, the steps may be carried out simultaneously.
- the amounts or concentrations of FGFBP1 and METRNL are determined using antibodies, in particular using monoclonal antibodies.
- steps a) and b) of determining the amounts or concentrations of FGFBP1 and METRNL in a sample of the patient comprises performing an immunoassay.
- the immunoassay is performed either in a direct or indirect format.
- such immunoassay is selected from the group consisting of enzyme linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), radioimmunoassay (RIA), or immuno assay based on detection of luminescence, fluorescence, chemiluminescence or electrochemiluminescence.
- steps a) and b) of determining the amounts or concentrations of FGFBP1 and METRNL in a sample of the patient comprises the steps of: i) incubating the sample of the patient with one or more antibodies specifically binding to FGFBP1, thereby generating a complex between the antibody and FGFBP1, and ii) incubating the sample of the patient with one or more antibodies specifically binding to METRNL, thereby generating a complex between the antibody and METRNL, and iii) quantifying the complexes formed in steps i) and ii), thereby quantifying the amount or concentration of FGFBP1 and METRNL in the sample of the patient.
- the sample in step i) is incubated with two antibodies, specifically binding to FGFBP1.
- the sample can be contacted with the first and the second antibody in any desired order, i.g. First antibody first and then the second antibody or second antibody first and then the first antibody, or simultaneously, for a time and under conditions sufficient to form a first anti-FGFBPl antibody / FGFBP1 / second anti-FGFBPl antibody complex.
- the detection of the anti-FGFBPl antibody / FGFBP1 complex can be performed by any appropriate means.
- the detection of the first anti-FGFBPl antibody / FGFBP1 / second anti-FGFBPl antibody complex can be performed by any appropriate means. The person skilled in the art is absolutely familiar with such means / methods.
- a sandwich will be formed comprising a first antibody to FGFBP1, FGFBP1 (analyte) and the second antibody to FGFBP1, wherein the second antibody is detectably labeled.
- a sandwich will be formed comprising a first antibody to FGFBP1, FGFBP1 (analyte) and the second antibody to FGFBP1, wherein the second antibody is detectably labeled and wherein the first anti-FGFBPl antibody is capable of binding to a solid phase or is bound to a solid phase.
- the sample in step ii) is incubated with two antibodies, specifically binding to METRNL.
- the sample can be contacted with the first and the second antibody in any desired order, i.g. First antibody first and then the second antibody or second antibody first and then the first antibody, or simultaneously, for a time and under conditions sufficient to form a first anti-METRNL antibody / METRNL / second anti-METRNL antibody complex.
- the detection of the anti-METRNL antibody / METRNL complex can be performed by any appropriate means.
- the detection of the first anti-METRNL antibody / METRNL / second anti-METRNL antibody complex can be performed by any appropriate means. The person skilled in the art is absolutely familiar with such means / methods.
- a sandwich will be formed comprising a first antibody to METRNL, METRNL (analyte) and the second antibody to METRNL, wherein the second antibody is detectably labeled.
- a sandwich will be formed comprising a first antibody to METRNL, METRNL (analyte) and the second antibody to METRNL, wherein the second antibody is detectably labeled and wherein the first anti-METRNL antibody is capable of binding to a solid phase or is bound to a solid phase.
- the second antibody is directly or indirectly detectably labeled.
- the second antibody is detectably labeled with a luminescent dye, in particular a chemiluminescent dye or an electrochemiluminescent dye.
- steps i) and ii) can be performed simultaneously or sequentially in any order.
- antibody is known in the art. As used herein, the term refers to any immunoglobulin (Ig) molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains. As used herein, the term “antibody” also includes an antigen-binding fragment of the antibody. As used herein, an antigen-binding fragment of an antibody shall be capable of specifically binding to the antigen. Thus, antigen binding fragments of antibodies are fragments retaining the ability of the (full-length) antibody to specifically bind to the antigen (such as METRNL or FGFBP1). Antibody fragments preferably comprise a portion of a full length antibody, preferably the variable domain thereof, or at least the antigen binding site thereof.
- the antigen-binding fragment is selected from the group consisting of a Fab fragment, a Fab' fragment, a Facb fragment, a F(ab')2 fragment, a scFv fragment, an a Fv fragment.
- the antigen-binding fragment is a F(ab')2 fragment.
- the fragments can be produced by enzymatic cleavage of an antibody of the present invention.
- the fragments can be generated by synthetic or recombinant techniques.
- Fab fragments are preferably generated by papain digestion of an antibody, Fab' fragments by pepsin digestion and partial reduction, F(ab')2 fragments by pepsin digestion), and facb fragments by plasmin digestion.
- Fv or scFv fragments are preferably produced by molecular biology techniques.
- the antibody in accordance with the methods of the present invention can be a polyclonal or monoclonal antibody.
- the antibody is a monoclonal antibody.
- the term “monoclonal antibody” is well known in the art.
- the term preferably refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts.
- a monoclonal antibody of the present invention can be made by the well-known hybridoma method described by Kohler and Milstein, Nature, 256:495 (1975), or can be made by recombinant DNA methods.
- the monoclonal antibody is selected from a group consisting of a sheep monoclonal antibody, a mouse monoclonal antibody, a rabbit monoclonal antibody, a goat monoclonal antibody, a horse monoclonal antibody, a chicken monoclonal antibody.
- the monoclonal antibody is a mouse monoclonal antibody.
- the antibodies (or fragments) that are used in steps a) and b) of the methods of the present invention can be used in a sandwich assay as capture antibody in combination with at least one other antibody binding to a different epitope.
- the antibodies can be used in sandwich assays.
- Sandwich assays are among the most useful and commonly used assays encompassing a number of variations of the sandwich assay technique.
- an unlabeled (capture) binding agent is immobilized or can be immobilized on a solid substrate, and the sample to be tested is brought into contact with the capture binding agent.
- a second (detection) binding agent labeled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of binding agent-biomarker-labeled binding agent.
- any unreacted material may be washed away, and the presence of the biomarker is determined by observation of a signal produced by the reporter molecule bound to the detection binding agent.
- the results may either be qualitative, by simple observation of a visible signal, or may be quantitated by comparison with a control sample containing e.g. known amounts of the biomarker to be determined (as standard or calibrator as described elsewhere herein).
- the incubation steps of a typical sandwich assay can be varied as required and appropriate. Such variations include for example simultaneous incubations, in which two or more binding agents and biomarkers are co-incubated. For example, both the sample to be analyzed and a labeled binding agent are added simultaneously to an immobilized capture binding agent. It is also possible to first incubate the sample to be analyzed and a labeled binding agent and to thereafter add an antibody bound to a solid phase or capable of binding to a solid phase.
- the formed complex between a specific binding agent and the biomarker shall be proportional to the amount or concentration of the biomarker present in the sample. It will be understood that the specificity and/or sensitivity of the binding agent to be applied defines the degree of proportion of at least one marker comprised in the sample, which is capable of being specifically bound. Further details, on how the measurement can be carried out, are also found elsewhere herein.
- the amount or concentration of formed complex shall be transformed into an amount or concentration of the biomarker reflecting the amount indeed present in the sample.
- amount encompasses the absolute amount of FGFBP1 or of METRNL, the relative amount or concentration of the said FGFBP1 or METRNL, as well as any value or parameter which correlates thereto or can be derived therefrom.
- values or parameters comprise intensity signal values from all specific physical or chemical properties obtained from the said peptides by direct measurements, e.g., intensity values in mass spectra or NMR spectra.
- values or parameters which are obtained by indirect measurements specified elsewhere in this description, e.g., response levels determined from biological read out systems in response to the peptides or intensity signals obtained from specifically bound ligands.
- values correlating to the aforementioned amounts or parameters can also be obtained by all standard mathematical operations.
- the determination of an “amount” is performed by the disclosed system, whereby a computing device determines the “amount” based on contacting and measuring steps performed by one or more analyzer units of said system.
- step c) of the methods according to the first, or the second or the third aspects of the present invention a score of the amounts or concentrations determined in steps a) and b), i.e. the amount or concentration of FGFBP1 and the amount or concentration of METRNL is calculated.
- calculating refers to assessing a score, which is based on the amount of FGFBP1 and the amount or concentration of METRNL determined in the sample(s) of the subject. For example, it is envisaged to calculate a score based on the amount or concentration of FGFBP1 and the amount or concentration of METRNL, i.e. a single score, and to compare this score to a reference score. The calculated score combines information on the amount or concentration of FGFBP1 and the amount or concentration of METRNL. Moreover, the biomarkers may be weighted in the score in accordance with their contribution to the establishment of the diagnosis. The score can be regarded as a classifier parameter for diagnosing PCOS.
- the score shall enable the diagnosis of PCOS based on the comparison with a reference score.
- the reference score is preferably a value, in particular a cut-off value, which allows for differentiating between a subject who suffers from PCOS and a subject who does not suffer from PCOS.
- the score is a ratio, i.e. a ratio of the amount or concentration of FGFBP1 and the amount or concentration of METRNL.
- the ratio calculated in step c) according to the first, or the second, or the third aspects of the present invention is compared to a reference ratio.
- the ratio is the ratio of the amount or concentration of FGFBP1 to the amount or concentration of METRNL.
- the ratio is the ratio of the amount or concentration of METRNL to the amount or concentration of FGFBP1.
- step d) the score calculated in step c) shall be compared with a reference score.
- a calculated ratio shall be compared to a reference ratio.
- comparing encompasses comparing the score calculated for a sample from a test subject, which a suitable reference source specified elsewhere in this description.
- the comparison is, preferably, assisted by automation.
- a suitable computer program comprising algorithms for the comparison of subject’s calculated score and the reference score may be used.
- Such computer programs and algorithms are well known in the art.
- a comparison can also be carried out manually.
- the computer program may further evaluate the result of the comparison, i.e. automatically provides the desired assessment in a suitable output format, i.e. the diagnostic result.
- the said diagnostic result may, preferably, serve as an aid for establishing the final diagnosis of PCOS by, e.g., a medical practitioner.
- the calculation step and/or the comparison step may be carried out by using a computer comprising a processing unit.
- the reference score to be chosen so that either a difference or an identity of the calculated score to the calculated score allows for identifying those test subjects which belong into the group of subjects which suffer from PCOS, or not.
- the method allows either excluding (rule-out) or identifying (rule-in) a subject who is suffering from PCOS. Differences in the score, i.e. increases or decreases, as used herein, preferably, are differences which are statistically significant.
- the method may also use other diagnostic criteria such as oligo-anovulation or hyperandrogenism to assess whether a patient suffers from PCOS.
- the reference score such as the reference ratio, shall allow for differentiating whether a subject suffers from PCOS, or not.
- the diagnosis is made by assessing whether the score of the test subject is above or below the reference score. It is not necessary to provide an exact reference score.
- a relevant reference score can be obtained by correlating the sensitivity and specificity and the sensitivity/specificity for any score. A reference score resulting in a high sensitivity results in a lower specificity and vice versa.
- the reference score is derived from a sample from a subject (or from samples group of subjects) known to suffer from PCOS.
- the reference score is derived from a sample from a subject (or from samples group of subjects) known not to suffer from PCOS.
- the score calculated in step c) according to the first, or the second, or the third aspects of the present invention may be a ratio.
- the ratio is the ratio of the amount or concentration of FGFBP1 to the amount or concentration of METRNL.
- a ratio i.e. a calculated ratio
- the calculated ratio is the ratio of the amount or concentration of METRNL to the amount or concentration of FGFBP1.
- a ratio i.e. a calculated ratio
- a ratio which is lower than the reference ratio is indicative for a subject who suffers from PCOS.
- a ratio which is larger than the reference ratio is indicative for a subject who does not suffer from PCOS.
- the methods of the present invention further comprises the step of recommending a suitable therapy, if PCOS has been diagnosed.
- the methods further comprises the step of initiating a suitable therapy, if PCOS has been diagnosed.
- the term “recommending” as used herein means establishing a proposal for a therapy which could be applied to the subject. However, it is to be understood that applying the actual therapy whatsoever is not comprised by the term.
- the therapy to be recommended depends on the out-come of the diagnosis provided by the method of the present invention.
- the recommendation step referred to above can also, preferably, be automated.
- the diagnosis obtained by the method of the present invention i.e. the diagnostic result of the method, will be used to search a database comprising recommendations of therapeutic measures for the individual possible diagnostic results.
- the therapy to be recommended or initiated is selected between a drug-based therapy of PCOS or for lifestyle changes to control metabolic symptoms.
- drug-based therapy of PCOS is selected from the group consisting of drugs for regulating periods, in particular oral contraceptives or progestin therapy, drugs for preventing or controlling diabetes, in particular type 2 diabetes, drugs for preventing or controlling high cholesterol, hormones or drugs to increase fertility, drugs, hormones or procedures to remove excess hair, drugs or procedure to control acne.
- the methods of the present invention may be also carried out as computer- implemented inventions.
- one or more steps, such as the comparison step and/or the calculation step are carried out by a computer comprising a processing unit (i.e. a computer).
- all steps are carried by a computer comprising a processing unit.
- the fourth aspect of the present invention relates to a computer- implemented method for diagnosing PCOS in subject, comprising
- step (b) processing the values received in step (a) with the processing unit, wherein said processing comprises
- step (c) optionally providing the diagnosis via an output device, wherein said diagnosis is based on the results of step b).
- the processing unit is comprised by a computer.
- step b) according to the fourth aspect of the present invention further comprises retrieving, at the processing unit, from a memory a reference score, i.e. a reference score which is suitable for the diagnosis of PCOS.
- information on the diagnosis is provided via a display, configured for presenting the assessment. Accordingly, information may be provided whether the subject suffers from PCOS, or not, as described elsewhere herein. Further, recommendations for suitable therapeutic can be displayed. As described elsewhere herein, various therapeutic measures may be recommended. In this case, the treatment option or treatment option(s) may be shown in the display.
- the methods may comprise the further step of transferring the information on the assessment of the methods of the present invention to the subject’s electronic medical records.
- the assessment made in the last step of the methods of the present invention can be printed by a printer.
- the print-out shall contain information on whether the patient is at risk, or not at risk and/or a recommendation of a suitable therapeutic measure.
- the present invention further relates to i) the use of FGFBP1 and METRNL as biomarkers, or to ii) the use of at least one agent which specifically binds to METRNL and of at least one agent which specifically binds to FGFBP1, for diagnosing PCOS.
- said use in an in vitro use i.e. is carried out in sample from the subject.
- the one agent which specifically binds to FGFBP1 is an antibody or an antigen-binding fragment.
- the one agent which specifically binds to METRNL is an antibody or an antigen-binding fragment.
- the present invention relates to a kit comprising at least one agent which specifically binds to METRNL and at least one agent which specifically binds to FGFBP1.
- kits refers to a collection of the aforementioned means, for example, provided in separately or within a single container.
- the container may comprise instructions for carrying out the method of the present invention.
- the kit comprises reagents for the diagnosis of PCOS.
- the reagents of the kit may comprise antibodies or antibody fragments.
- the antibodies or antibody fragments recognize epitopes or antigens of FGFBP1 and/or METRLN.
- the kit may further contain other reagents which recognize other bio markers. Therefore, the kit may also comprise a combination of at least three reagents.
- a biomarker can also comprise hormones, such as Anti-Mullerian Hormone, AMH.
- the kit can be used in any diagnostic assay.
- Example 1 Diagnostic performance of the ratio between the two biomarkers FGFBP1 and METRNL in women with PCOS (phenotypes A, B, C and D) and controls determined by ELISA technology Performance validation has been performed in a sample collective of 85 cases (serum samples from women with PCOS) and 44 controls (serum samples from healthy women).
- the concentration of the two analytes, FGFBP1 and METRNL was determined by ELISA (enzyme-linked immunosorbent assay).
- the case group is composed of patients diagnosed with PCOS (26 phenotype A, 19 phenotype B, 20 phenotype C and 20 phenotype D) according to the Rotterdam criteria.
- the control group includes healthy women without PCOS.
- the concentration of FGFBP1 in human serum was determined using the Human FGFBP1 ELISA kit from Sigma- Aldrich (catalog number: RAB1460).
- the concentration of METRNL in human serum was determined using the Human METRNL ELISA kits from R&D Systems (catalog number: DY7867-05).
- the kits are a solid-phase sandwich Enzyme-Linked Immunosorbent Assay (ELISA) designed to detect and quantify respectively the levels of human FGFBP1 and METRNL in cell culture supernatants, plasma, and serum. The two analytes were measured in separate plates, only one analyte was measured at a time.
- FGFBP1 antibody pre-coated plates were provided with the kit. Samples were measured in 75-fold dilution. After bringing all reagents to room temperature 100 pL of each sample and standard were added to the plate. Samples and standards were measured in duplicates. During 2.5 hours incubation at room temperature with gentle shaking, any FGFBP1 present was bound to the immobilized capture antibody on the microtiter plate. During the washing step (4 x 300 pL), unbound substances were removed from the plate before 100 pL of the diluted Detection Antibody was added to the wells.
- the capture antibody for METRNL was diluted to the working concentration in PBS without carrier protein.
- a 96-well microplate was incubated with 100 pL per well of the diluted Capture Antibody. The plate was sealed and incubated overnight at room temperature. The plate was then washed 3 times with 400 pL of Wash Buffer per well each time. After the last wash the Wash Buffer was completely removed, the plate was blocked by adding 300 pL of Regent Diluent to each well and incubated at room temperature for a minimum of 1 hour. The plate was washed 3 times with 400 pL of Wash Buffer per well each time and was made ready to use. Samples were measured in 4-fold dilution.
- lyophilized, recombinant METRNL delivered with the kit was reconstituted and diluted in the Reagent Diluent.
- the calibration range of the METRNL assay is 15.6 pg/mL to 1000 pg/mL.
- a seven point standard curve was obtained using 2-fold serial dilutions of the recombinant METRNL in the Reagent Diluent.
- the calibration curve was fitted using a four parameter logistic (4-PL, Newton/Raphson) curve-fit.
- the ratio FGFBP I :METRNL was calculated for each sample.
- Receiver Operating Characteristic (ROC) curves were generated for the ratio FGFBPI :METRNL (Fig. 1). The model performance is determined by looking at the area under the curve (AUC). The best possible AUC is 1 while the lowest possible is 0.5.
- the data obtained by performing the ratio between the concentrations of FGFBPI and METRNL were used to generate box and whisker plots for control and PCOS cases when all phenotypes were combined (phenotypes A-D).
- the FGFBPI :METRNL ratio is increased in women with PCOS when compared to healthy controls (Fig. 2).
- Table 2 shows the diagnostic performance of the FGFBPI :METRNL ratio to distinguish between women with PCOS when separated by the different phenotypes A, B, C and D versus healthy control subjects. AUC for each phenotype is reported in the table.
- ROC curve analysis for the FGFBP1:METRNL ratio for PCOS cases separated by the different phenotypes versus healthy controls showed an AUC of 0.95 (95% CI 0.87-1.00), 0.99 (95% CI 0.97-1.00), 1.00 (95% CI 0.99-1.00) and 0.99 (95% CI 0.98-1.00), respectively for the phenotypes from A to D (Fig. 3).
- the results confirm the high diagnostic accuracy of the FGFBPEMETRNL ratio for PCOS.
- the FGFBPEMETRNL ratio in all the different PCOS phenotypes (Phenotype A-D) showed increased levels compared to healthy controls (Fig. 4).
- Table 3 shows the diagnostic performance of the FGFBPEMETRNL ratio in young women (age ⁇ 25), to distinguish young women with PCOS from young healthy control subjects when all phenotypes were combined (phenotypes A-D).
- the ROC curve analysis for the FGFBP1 :METRNL ratio for young PCOS cases illustrated an AUC of 1.00 (95% CI 1-1), 0.93 (95% CI 0.75- 1), 1.00 (95% CI 1-1), 1.00 (95% CI 1-1) for each phenotype respectively, confirming high diagnostic accuracy of the FGFBPEMETRNL ratio for PCOS, in the subgroup of women of age 25 or younger (Fig. 7).
- the FGFBPEMETRNL ratio was increased in all the different PCOS phenotypes (Phenotype A-D, age ⁇ 25) when compared to the FGFBPEMETRNL ratio in young healthy controls (age ⁇ 25, Fig. 8).
- Example 2 Diagnostic performance of the ratio between the two biomarkers FGFBP1 and METRNL in women with PCOS (phenotypes A, B, C and D) and controls determined by ELISA technology, in different age groups
- Performance validation has been performed in an additional sample collective of 240 cases (serum samples from women with PCOS) and 48 controls (serum samples from healthy women).
- the concentration of the two analytes, FGFBP1 and METRNL was determined by ELISA (enzyme-linked immunosorbent assay).
- the control group includes healthy women without PCOS (age 20-40).
- the concentration of FGFBP1 in human serum was determined using the Human FGFBP1 ELISA kit from Sigma- Aldrich (catalog number: RAB1460).
- the concentration of METRNL in human serum was determined using the Human METRNL ELISA kits from R&D Systems (catalog number: DY7867-05). Measurements were performed as described in example 1.
- Receiver Operating Characteristic (ROC) curves were generated for the ratio FGFBPI :METRNL (Fig. 9). The model performance is determined by looking at the area under the curve (AUC).
- AUC area under the curve
- the data obtained by ELISA immunoassay were used to generate box and whisker plots for control and PCOS cases when all phenotypes were combined (phenotypes A-D).
- the FGFBPI :METRNL ratio is increased in women with PCOS when compared to healthy controls (Fig. 10).
- Table 6 shows the diagnostic performance of FGFBPI :METRNL ratio to distinguish between women with PCOS when separated by the different phenotypes A, B, C and D versus healthy control subjects. AUC for each phenotype is reported in the table. Table 6
- ROC curve analysis for FGFBP1:METRNL ratio for PCOS cases separated by the different phenotypes versus healthy controls showed an AUC of 0.95 (95% CI 0.92- 0.98), 1.00 (95% CI 1.00-1.00), 1.00 (95% CI 1.00-1.00) and 0.94 (95% CI 0.90- 0.99), respectively for the phenotypes from A to D (Fig. 11).
- the results confirm the high diagnostic accuracy of FGFBPEMETRNL ratio for PCOS.
- Table 7 shows the diagnostic performance of FGFBPEMETRNL ratio in different age groups (15-20, 20-25, 25-40), to distinguish women with PCOS from healthy control subjects when all phenotypes were combined (phenotypes A-D).
- ROC curve analysis for FGFBPEMETRNL ratio for PCOS cases separated by the different age groups versus healthy controls showed an AUC of 0.91 (95% CI 0.85- 0.97), 0.96 (95% CI 0.93-0.99) and 0.98 (95% CI 0.95-1.00), respectively for the age groups 15-20, 20-25, 25-40 (Fig. 13).
- the results confirm the high diagnostic accuracy of FGFBPEMETRNL ratio for PCOS in all the different age groups.
- Table 8 shows the diagnostic performance of FGFBP1:METRNL ratio in young women (15 ⁇ age ⁇ 25), to distinguish young women with PCOS from young healthy control subjects when all phenotypes were combined (phenotypes A-D).
- the FGFBP I :METRNL ratio was increased in all the different PCOS phenotypes (Phenotype A-D, 15 ⁇ age ⁇ 25), when compared to the FGFBPI :METRNL ratio in young healthy controls (15 ⁇ age ⁇ 25, Fig. 18).
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Abstract
La présente invention concerne un procédé de diagnostic du syndrome des ovaires polykystiques (PCOS) chez un sujet, ledit procédé comprenant les étapes consistant à a) déterminer la quantité ou la concentration du FGFBP1 total dans l'échantillon provenant du sujet, b) déterminer la quantité ou la concentration de METRNL dans un échantillon provenant du sujet, c) calculer un score des quantités ou des concentrations déterminées dans les étapes a) et b), d) comparer le score calculé à un score de référence, et e) diagnostiquer le PCOS chez un sujet.
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