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US-12625146-B2 - S100A8 as blood biomarker for the non-invasive diagnosis of Endometriosis

US12625146B2US 12625146 B2US12625146 B2US 12625146B2US-12625146-B2

Abstract

The present invention relates to methods of assessing whether a patient has endometriosis or is at risk of developing endometriosis, to methods of selecting a patient for therapy, and method of monitoring a patient suffering from endometriosis or being treated for endometriosis by determining the amount or concentration of S100A8 in a sample of the patient, and comparing the determined amount or concentration to a reference.

Inventors

  • Aikaterini GEORGOPOULOU
  • Martin Hund

Assignees

  • ROCHE DIAGNOSTICS OPERATIONS, INC.

Dates

Publication Date
20260512
Application Date
20220113
Priority Date
20190722

Claims (20)

  1. 1 . A non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100 calcium binding protein A8 (S100A8) in a sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and comparing the measured amount or concentration to a reference, wherein the patient has stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging, and administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of a drug-based therapy, a surgical therapy, and a hormonal therapy.
  2. 2 . A non-invasive method of selecting a patient for drug-based therapy or surgical therapy (laparoscopy) of endometriosis, comprising measuring the amount or concentration of S100A8 in a sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and comparing the measured amount or concentration to a reference, wherein the patient is suspected of having or has stage I endometriosis according to rASRM staging or stage II endometriosis according to rASRM staging, and administering the drug-based therapy or performing the surgical therapy on the patient selected for therapy.
  3. 3 . A non-invasive method of monitoring a patient suffering from endometriosis or being treated for endometriosis, comprising measuring the amount or concentration of S100A8 in a sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and comparing the measured amount or concentration to a reference, wherein the patient is suspected of having or has stage I endometriosis according to rASRM staging or stage II endometriosis according to rASRM staging, and administering a therapy for endometriosis to the patient based on the monitoring, wherein the therapy is selected from the group consisting of a drug-based therapy, a surgical therapy, and a hormonal therapy.
  4. 4 . The method of claim 1 , wherein the patient is a human female patient.
  5. 5 . The method of claim 1 , wherein the assessment is performed independent of the rASRM staging.
  6. 6 . The method of claim 1 , wherein endometriosis is stage I endometriosis according to rASRM staging.
  7. 7 . The method of claim 1 , wherein endometriosis is stage II endometriosis according to rASRM staging.
  8. 8 . The method of claim 1 , wherein endometriosis is selected from the group consisting of peritoneal endometriosis, endometrioma, deep infiltrating endometriosis, and adenomyosis.
  9. 9 . The method of claim 1 , wherein adenomyosis is assessed.
  10. 10 . The method of claim 1 , further comprising measuring the amount or concentration of Carbohydrate antigen 125 (CA-125) in a sample of the patient.
  11. 11 . The method of claim 1 , further comprising calculating a ratio of the amount or concentration of S100A8 and dysmenorrhea and/or of the amount or concentration of S100A8 and lower abdominal pain according to the VAS scale.
  12. 12 . The method of claim 10 , further comprising calculating a ratio of the amount or concentration of S100A8 and the amount or concentration of CA-125.
  13. 13 . A method of detecting S100A8 in a sample from a patient, the method comprising: obtaining the sample from the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and detecting whether S100A8 is present in the sample by contacting the sample with a binding agent and detecting the binding between S100A8 and the binding agent, wherein the binding agent is an antibody that specifically binds to S100A8, and wherein the patient is suspected of having or has stage I endometriosis according to rASRM staging or stage II endometriosis according to rASRM staging.
  14. 14 . A method for measuring the amount of S100A8 in a sample from a patient, the method comprising: obtaining the sample from the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, measuring the amount of S100A8 in the sample of the patient, and contacting the sample, or a portion thereof, with an agent which specifically binds S100A8, wherein the agent is an antibody and wherein the patient is suspected of having or has stage I endometriosis according to rASRM staging or stage II endometriosis according to rASRM staging.
  15. 15 . A non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, wherein the patient is suspected of having or has stage I endometriosis according to rASRM staging or stage II endometriosis according to rASRM staging, comprising measuring the amount or concentration of S100A8 in a sample of the patient, wherein the measuring comprises incubating the sample of the patient with one or more antibodies specifically binding to S100A8 thereby generating a complex between the one or more antibodies and S100A8, and quantifying the complex thereby quantifying the amount of S100A8 in the sample of the patient, comparing the measured amount or concentration to a reference, assessing whether the patient has endometriosis or is at risk of developing endometriosis, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of a drug-based therapy, a surgical therapy, and a hormonal therapy.
  16. 16 . The method of claim 15 , wherein a sandwich complex is formed comprising a first antibody to S100A8, S100A8 (analyte) and the second antibody to S100A8, wherein the second antibody is detectably labeled.
  17. 17 . The method of claim 16 , wherein the second antibody is detectably labeled with a chemiluminescent dye or an electrochemiluminescent dye.
  18. 18 . The method of claim 15 , further comprising measuring an amount or concentration of CA-125 in a sample of the patient.
  19. 19 . A non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100 calcium binding protein A8 (S100A8) in a sample of the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and comparing the measured amount or concentration to a reference, wherein the patient has stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging, and administering a therapy for endometriosis to the patient, wherein the therapy is selected from the group consisting of a drug-based therapy, a surgical therapy, and a hormonal therapy.
  20. 20 . The method of claim 19 , wherein the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to the VAS scale.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/EP2020/070427 filed Jul. 20, 2020, which claims priority to European Application 19187474.2 filed Jul. 22, 2019, the disclosures of which are hereby incorporated by reference in their entirety. The present invention relates to methods of assessing whether a patient has endometriosis or is at risk of developing endometriosis, to methods of selecting a patient for therapy, and methods of monitoring a patient suffering from endometriosis or being treated for endometriosis, by determining the amount or concentration of S100A8 in a sample of the patient, and comparing the determined amount or concentration to a reference. BACKGROUND OF THE INVENTION Endometriosis is defined as the presence of endometrial glands and stroma-like lesions outside of the uterus. The lesions can be peritoneal lesions, superficial implants or cysts on the ovary, or deep infiltrating disease. Endometriosis affects 5-8% of all women of reproductive age and 70% of women with chronic pelvic pain. The prevalence of endometriosis has been estimated at 176 million women worldwide (Adamson et al. J Endometr. 2010; 2: 3-6). For many of these women there is often a delay in diagnosis of endometriosis resulting in unnecessary suffering and reduced quality of life. In patients aged 18-45 years, there is delay of 7-10 years. As most women with endometriosis report the onset of symptoms during adolescence, early referral, diagnosis, identification of disease and treatment may mitigate pain preventing disease progression. Barriers to early diagnosis include the high cost of diagnosis and treatment in adolescent patients and presentation of confounding symptoms such as cyclic and non-cyclic pain (Parasar et al. Curr Obstet Gynecol Rep. 2017; 6: 34-41). Gold standard for the diagnosis of endometriosis is laparoscopic visualization and subsequent histological confirmation. Until now, there are no non-invasive methods for the diagnosis of endometriosis (Hsu et al. Clin Obstet Gynecol 2010: 53: 413-419). During a diagnostic laparoscopy, a gynaecologist with training and skills in laparoscopic surgery for endometriosis should perform a systematic inspection of the pelvis (NICE guideline NG73, 2017). Surgical visualization requires good expertise, training and skills for reliable diagnosis. The fact that laparoscopic surgery is needed for diagnosis, which is avoided by doctors as long as possible, leads to a delay in the diagnosis for 7-10 years. The lack of a non-invasive diagnostic test significantly contributes to the long delay between onset of the symptoms and definitive diagnosis of endometriosis (Signorile and Baldi. J Cell Physiol 2014; 229: 1731-1735). Thus there is an unmet medical need for a non-invasive test for the diagnosis of endometriosis, in particular for the diagnosis of early, minimal and mild endometriosis (revised American Society for Reproductive Medicine rASRM stages I-II). Adenomyosis is defined as infiltration of benign endometrial glands and stroma into the myometrium, the outer muscle layer of the uterus. There are 3 distinct adenomyosis sybtypes, depending on the morphology and location: internal adenomyosis, external adenomyosis and adenomyomas. Internal adenomyosis can be further classified into focal, diffuse and superficial adenomyosis (Bazot M et al. Fertil Steril. 2018; 109:389-397). Adenomyosis can also be classified based on Magnetic Resonance Imaging (MRI) findings, according to whether it is located in the outer or the inner uterine layer, into 4 subtypes I-IV. Common signs and symptoms of adenomyosis include heavy bleeding during menstruation (menorrhagia) and in-between menstrual periods (metrorrhagia), dysmenorrhea, chronic pelvic pain, dyspareunia and infertility (Chapron C et al. Hum Reprod Update. 2020; 26:392-411). Transvaginal ultrasound (TVUS) and Magnetic Resonance Imaging (MRI) are currently used to diagnose adenomyosis, with an overall sensitivity/specificity of 83.8%, 63.9% and 77.3%, 89.8% respectively. Among the different adenomyosis types, diffuse adenomyosis is more difficult to detect by imaging and requires an experienced sonographer. Also, access to imaging equipment is limited, especially among primary care healthcare professionals, and requires trained staff and specialized resources. Therefore, a non-invasive blood-based test would allow medical assessment of adenomyosis without a need for imaging device, reduce the inter-operator variability and enable a more standardized diagnosis of the condition (Chapron C et al. Hum Reprod Update. 2020; 26:392-411). Non-invasive diagnosis of endometriosis would allow earlier diagnosis and treatment, with the potential to improve quality of life and reduce the societal costs related to endometriosis, and has therefore been selected as a research priority by the World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF)