WO2023115171A1 - Méthode, panel et trousse pour le diagnostic et la surveillance du traitement de patientes atteintes du cancer du sein - Google Patents

Méthode, panel et trousse pour le diagnostic et la surveillance du traitement de patientes atteintes du cancer du sein Download PDF

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Publication number
WO2023115171A1
WO2023115171A1 PCT/BR2021/050561 BR2021050561W WO2023115171A1 WO 2023115171 A1 WO2023115171 A1 WO 2023115171A1 BR 2021050561 W BR2021050561 W BR 2021050561W WO 2023115171 A1 WO2023115171 A1 WO 2023115171A1
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Prior art keywords
breast cancer
diagnosis
analysis
epcam
panel
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PCT/BR2021/050561
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English (en)
Portuguese (pt)
Inventor
Paula Philbert Lajolo Canto
Donizeti William Santos
Yara Cristina de Paiva MAIA
Alinne Tatiane Faria Silva
Cláudia Mendonça Rodrigues
Juliana Carvalho Penha Pereira
Luiz Ricardo Goulart Filho
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Universidade Federal de Uberlândia
Imunoscan Engenharia Molecular Ltda
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Application filed by Universidade Federal de Uberlândia, Imunoscan Engenharia Molecular Ltda filed Critical Universidade Federal de Uberlândia
Priority to PCT/BR2021/050561 priority Critical patent/WO2023115171A1/fr
Publication of WO2023115171A1 publication Critical patent/WO2023115171A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • This patent application refers to a method of diagnosing and monitoring the treatment of patients with breast cancer, more particularly in which the method comprises the detection of subpopulations of circulating tumor cells (CTCs), based on the presence or absence of proteins analyzed by flow cytometry in peripheral blood to be used as biomarkers for breast cancer (BC).
  • CTCs circulating tumor cells
  • the present patent application refers to a panel of markers and a kit for rapid diagnostic testing of breast cancer and rapid monitoring of the treatment of patients with breast cancer.
  • the present patent application describes a method for detecting subpopulations of CTCs based on (i) the absence of CD45 and (ii) the presence of vimentin, CD44 and EpCAM.
  • the method, marker panel and detection kit based on the result of CTC analysis by flow cytometry has the potential to be used as a tool complementary to the clinical diagnosis, and can also be used to monitor the treatment. It should also be noted that the methodology proposed here comprises a fast and non-invasive technique.
  • Carcinogenesis is characterized as a multi-step process driven by changes both at the genotype and phenotype levels, and the uncontrolled growth of cells that have undergone such changes is defined as cancer (BARTOSCH et al., 2017; WEIGELT et al. ., 2014).
  • Metastatic progression is an undetermined sequence of events that involves migration of cells across the basement membrane and surrounding tissue, displacement through the bloodstream to distant sites, readaptation to the new tissue environment, and ultimately the formation of clinically detectable metastases. & MASSAGUE, 2013).
  • evidence suggests that tumor cells undergo the transition from an epithelial to mesenchymal phenotype, which will trigger the release and dissemination of these cells into the bloodstream (WERNER et al., 2017).
  • Tissue biopsy is used for diagnosis and provides histological information and allows establishing the immunohistochemical profile of hormone receptors and HER-2 receptor status.
  • it has limitations and can provide information from just one moment and only from the collected tumor tissue (TAY & TAN, 2019).
  • tumors are heterogeneous and can still undergo changes according to the type of treatment performed (GERLINGER et al. al., 2012).
  • CTCs to complement or replace tumor tissue biopsies for diagnosis and therapy makes such a methodology relevant and applicable as "real-time liquid biopsies" (PANTEL & ALIX-PANABIERES, 2010; BARDELLI & PANTEL, 2017).
  • Liquid biopsy can fill both the lack of data in relation to different times and still detect the inherent heterogeneity of the tumor tissue.
  • EDA Food and Drug Administration
  • CellSearch The only method to perform liquid biopsy approved by the Food and Drug Administration (EDA) is CellSearch. This method is based on the expression of epithelial cell adhesion molecules (EpCAM) for selection of CTCs, followed by characterization of selected cells as: i) negative for CD45 and ii) positive for cytokeratins.
  • EpCAM epithelial cell adhesion molecules
  • studies have shown that this technique does not adequately capture CTCs with low EpCAM expression.
  • CTCs that undergo the process of epithelial-mesenchymal transition (EMT) lose their epithelial antigens and are not detected by CellSearch.
  • EMT epithelial-mesenchymal transition
  • these EpCAM-negative CTCs appear to be a highly aggressive and invasive subtype (PUNNOOSE et al., 2010; GEORGES et al., 2012).
  • JP2018079327A, TW201920928A and US20200055048A1 use a device (microfluid chip or microfilters) to capture and/or detect CTCs. Although they also use antibodies, but immobilized on the microchip or filter, there is a need to use post-capture techniques to characterize the target cells, such as immunohistochemistry, flow cytometry, in situ hybridization, analysis of DNA mutations and immunofluorescence .
  • Patent document US20190107542A1 provides methods to detect and isolate CTCs by antibodies linked to magnetic beads and subsequent characterization of the gene expression of these cells.
  • Patent documents EP2948776B, CA2798250A1 and US20140154799A1 select CTCs based on a set of antibodies such as EpCAM, CD45, CD44, CD14, CD24, CD34, Cytokeratins like 8, 18 and 19, EGFR (epidermal growth factor receptor) , ALDH1 (aldehyde dehydrogenase 1), vimentin, among others, and then put them in culture for enrichment, with the main objective of selecting drugs for patient therapy, in addition to being able to characterize the CTCs in culture by imaging.
  • the patent document AU2016228165A1 provides methods to obtain CTCs and the possibility of analyzing a single cell. This identification is made by immunohistochemistry. with aspiration of cells by pipetting and subsequent morphological, genomic, epigenetic or proteomic analysis. Uses epithelial and mesenchymal markers.
  • the patent document JP2006509185A provides a method to detect and discriminate changes in the expression levels of molecular markers, using, among other markers, CD44.
  • the patent document WO2017180499A2 uses a method to capture CTCs from biological fluids that comprises the contact of the biological material with the lectin trapped on the magnetic surface. The separation takes place in a magnetic apparatus. The analysis of CTCs occurs a posteriori by techniques such as immunohistochemistry, genomics and metabolomics, for example. Similarly, patent document CN107428837A uses a method for enrichment and detection of CTCs based on anti-TROP2 antibody, however such analysis is valid only for tumors positive for this marker. Further analyzes include immunofluorescence, FISH and RT-PCR.
  • the patent document US20170038389A1 uses a method of detection of CTCs aiming at their differentiation from circulating endothelial cells and confirms that vimentin is expressed in these last cells, but when analyzed together with other markers (CD45 and CD144) it is possible to separate the populations.
  • the patent document CN108588018A uses an erythrocyte membrane to capture CTCs, being a more effective capture than the available methods .
  • the patent document EP3160654A2 identifies nucleic acids of CTCs using the combination of PCR and FACS (PCR-activated selection), the primers can be EpCAM, CD44 and vimentin, among others.
  • the patent document CN106868101A uses similar markers for detection of CTCs by probe and in situ hybridization, but there were no analyzes of this method for monitoring treatment or diagnosis.
  • Patent documents JP2017207516A, US20130129681A1 and EP2529223B1 use epithelial and mesenchymal markers and detection by flow cytometry, but use enrichment methods such as initial steps, magnetic beads, RosetteSep and CellSearch, respectively.
  • This patent application aimed to solve a problem in the state of the art by developing a method, panel of markers and kit for the diagnosis and monitoring of the treatment of patients with breast cancer, sensitive, specific and simple that can be implemented in the clinical routine in an optimized way.
  • FIGURE 1 a shows the percentage of mesenchymal CTCs. Mann-Whitney test with *p ⁇ 0.05;
  • FIGURE 1 b shows the percentage of intermediate CTCs. Mann-Whitney test with *p ⁇ 0.05;
  • FIGURE 1 c shows the percentage of epithelial CTCs. Mann-Whitney test with *p ⁇ 0.05.
  • the inventors of this patent application through experiments using biological samples of peripheral blood and tissues from patients with benign breast disease or breast cancer submitted or not to chemotherapy, were able to identify that the expression of only four specific markers would be useful in the development of a method, panel of markers and diagnostic and monitoring kit for simplified breast cancer treatment. More particularly, the analysis of the referred markers within the developed method is capable of indicating, through a cut-off defined specifically for the separation of groups, whether the patient has: benign breast disease (BMD), breast cancer not treated by chemotherapy ( BC without CT) or breast cancer with chemotherapy treatment (CM with CT).
  • BMD benign breast disease
  • BC without CT breast cancer not treated by chemotherapy
  • CM with CT breast cancer with chemotherapy treatment
  • the panel of markers proposed by the present invention encompasses the detection of: CD45, a marker for negative selection, defined as a pan-leukocyte marker; Vimentin, a typical marker of the mesenchymal phenotype and with studies demonstrating that higher levels of this protein are associated with greater invasive power of tumor cells in vitro and, consequently, its silencing reduces the formation of metastases (ZELENKO et al., 2017); CD44, established marker for stem cells, being an adhesion molecule, related to cell-to-cell and cell-matrix interactions (KLINGREIL et al., 2010).
  • CD44 promotes the invasion and migration of CTCs (SENBANJO et al., 2017); EpCAM, a transmembrane glycoprotein, which has an adhesion function and is related to cell signaling, proliferation, differentiation and migration (OSTA et al., 2004).
  • the present patent application proposes the use of a panel of markers, comprising labeled antibodies anti-CD45 (for negative selection), anti-CD44, anti-vimentin and anti-EpCAM.
  • This panel of markers is capable of identifying subpopulations of breast cancer (BC) CTCs, selected from biological samples, such as peripheral blood, from patients with BC or DBM through a simplified and error-free diagnostic method. enrichment step using flow cytometry.
  • the analysis of the expression of the selected markers allows the identification and separation of populations of CTCs with mesenchymal (CD45-, EpCAM-, CD44+ and vimentin+), intermediate (CD45-, EpCAM+, CD44+ and vimentin+) and epithelial profile (CD45-, EpCAM+, CD44- and vimentin-).
  • mesenchymal CD45-, EpCAM-, CD44+ and vimentin+
  • intermediate CD45-, EpCAM+, CD44+ and vimentin+
  • epithelial profile CD45-, EpCAM+, CD44- and vimentin-
  • the present invention proposes the use of a simplified method for detecting populations of CTCs, exempt from the need for a previous enrichment step of the CTCs, based on: (i) the selection of CTCs absent from CD45 (CD45-) and (ii) in the identification of the profile of CTCs through the presence or absence of vimentin, CD44 and EpCAM, the identification of these populations composes a simplified panel for diagnosis and treatment monitoring.
  • the present patent application proposes more particularly the use of a diagnostic method and monitoring of breast cancer treatment, based on the detection, identification and analysis of populations of CTCs, preferably by flow cytometry, which comprises the steps of: obtaining a biological sample, preferably blood, more preferably peripheral blood;
  • CD45- selection of CTCs absent from CD45
  • the step of identifying the profiles of the CTCs includes identifying the profiles:
  • mesenchymal CD45-, EpCAM-, CD44+ and vimentin4.
  • the CTC profile analysis stage comprises the use of defined cut offs in relation to the percentage of CTC populations in each of the identified profiles, for the diagnosis of benign disease (BMD) or breast cancer (CM), or monitoring of breast cancer with chemotherapy (CM with CT) and breast cancer without chemotherapy (CM without CT).
  • BMD benign disease
  • CM breast cancer
  • CM with CT breast cancer without chemotherapy
  • the present patent application further describes a panel of markers for the diagnosis and monitoring of the treatment of patients with breast cancer comprising fluorochrome-labeled anti-CD45 antibody, fluorochrome-labeled anti-CD44 antibody, fluorochrome-labelled antibody anti-vimentin and anti-EpCAM fluorochrome-labelled antibody for detection of CTC populations, where the panel allows the identification of CTC profiles:
  • mesenchymal CD45-, EpCAM-, CD44+ and vimentin+
  • epithelial CD45-, EpCAM+, CD44- and vimentin-).
  • the Panel further comprises a diagnostic panel and a monitoring panel based on the analysis of the CTC profiles, in which the diagnostic panel comprises:
  • the monitoring panel comprises:
  • This patent application further describes a kit for the diagnosis and monitoring of breast cancer treatment comprising, combined or separated in one or more containers: antibody labeled with an anti-CD45 fluorochrome, antibody labeled with a fluorochrome anti-CD44, anti-vimentin fluorochrome-labeled antibody, and anti-EpCAM fluorochrome-labeled antibody; in which it still understands instructions for use.
  • Said kit may further comprise, in another embodiment, said panel of markers described in the present patent application, as well as may comprise instructions for use in said method described in the present patent application.
  • This example refers to the characteristics of the study subjects, who are grouped into patients with breast cancer who have or have not undergone chemotherapy (CM with CT or CM without CT group), patients with benign breast disease (CM group DBM).
  • Table 1 presents the clinical, hormonal, diagnostic and therapeutic characteristics of patients with breast cancer.
  • Table 1 presents the clinical, hormonal, diagnostic and therapeutic characteristics of patients with breast cancer.
  • This example refers to the RT-qPCR analysis of the transcriptional levels of the breast cancer and benign breast disease groups.
  • Table 2 shows the comparison of transcriptional levels between breast cancer (CM) and benign breast disease (BMD).
  • Table 3 shows the comparison of levels between breast cancer with chemotherapy (CM with CT), breast cancer without chemotherapy (CM without CT) and benign breast disease (BMD).
  • FIG. 1 shows the percentages of CTCs with mesenchymal, intermediate and epithelial profile in the blood of patients with benign breast disease (BMD), breast cancer with chemotherapy (CM with CT) and breast cancer without chemotherapy (CM without CT).
  • Trizol reagent Invitrogen, Life Technologies, Carlsbad, CA, USA
  • the solution was incubated in a PTC-100 thermocycler (MJ Research) at 37°C for 1 hour and heated to 95°C for 5 minutes. Control reactions (without RNA) were performed to verify possible exogenous contaminants.
  • the cDNA was stored at -20°C for further amplification.
  • Ep-CAM, MMP-2, MMP-9, N-cadherin and vimentin) in relation to the endogenous gene (B2M) were estimated using real-time PCR from the cDNA obtained.
  • the samples were amplified in duplicate and the detection was based on the fluorescence emission of the SYBRGreen dye according to the use of the Master Mix SYBR®Green PCR Core Reagents kit (Applied Biosystems).
  • the monolayer was incubated with AB serum to block the FC portions, preventing unspecific binding, and then labeled with fluorochrome-labeled monoclonal antibodies anti-CD45 (304008, PE) (Biolegend, San Diego, CA, USA), anti-CD44 (338816 , PE/Cy7) (Biolegend, San Diego, CA, USA) and anti-EpCAM (324208, APC) (Biolegend, San Diego, CA, USA). Then, erythrocytes were lysed with BD lysis solution FACS (Becton, Dickinson, and Company (BD), Franklin Lakes
  • washing solution (1x Phosphate Buffer Saline, 1% Bolvin Serum Albumin and 0.1% Sodium Azide).
  • Cells were resuspended in 150pL of washing solution.
  • BD FACS permeabilization solution Becton, Dickinson, and Company (BD), Franklin Lakes, FL, USA).
  • the Kolmogorov-Smirnov normality test was performed. Depending on the behavior of the variables, parametric tests were performed for variables with normal distribution or non-parametric tests for variables without normal distribution. To compare the expression (mRNA and protein) of the target genes between the established groups the Mann-Whitney test or t test for independent samples was used. The 95% confidence interval was considered and p values ⁇ 0.05 were considered significant. Statistical analyzes were performed using GraphPad Prism 5 (GraphPad Software, La Jolla, CA, USA) and SPSS version 21.0 (SPSS, IBM, Chicago, IL, USA).
  • KRUSPE S.
  • DICKEY D.D.
  • URAK K. T. et al. Rapid and sensitive detection of breast cancer cells in patient blood with nuclease-activated probe technology. Mol Ther Nucleic Acids., v.8, p.542-557, 2017.
  • KLINGBEIL P.; NATRAJAN. R.; EVERITT, G.; VATCHEVA, R.; MARCHIO, C.; PALACIOS, J.; BUERGER, H.; REIS-FILHO, JS;
  • ISACKE, C.M. CD44 is overexpressed in basal-like breast cancers but is not a driver of llplS amplification.

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Abstract

L'invention concerne une méthode pour la détection de sous-populations de CTC basée sur (i) l'absence de CD45 et (ii) la présence de vimentine, de CD44 et d'EpCAM, analysées par cytométrie de flux dans des échantillons biologiques, par exemple de sang périphérique, à utiliser comme biomarqueurs du cancer du sein (CM). L'analyse de ces marqueurs a été réalisée sans étape d'enrichissement préalable des CTC, ce qui optimise le procédé. Par ailleurs, la présente invention concerne un panel de marqueurs et une trousse pour le test diagnostique rapide du cancer du sein et la surveillance rapide du traitement de patientes atteintes du cancer du sein, et présente le potentiel d'être utilisée comme outil complémentaire de diagnostic clinique et de surveillance du traitement.
PCT/BR2021/050561 2021-12-20 2021-12-20 Méthode, panel et trousse pour le diagnostic et la surveillance du traitement de patientes atteintes du cancer du sein WO2023115171A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180059114A1 (en) * 2016-08-24 2018-03-01 National Cancer Center Magnetic nanostructure for detecting and isolating circulating tumor cells comprising antibody- and magnetic nanoparticle-conjugated conductive polymer
WO2020227574A2 (fr) * 2019-05-07 2020-11-12 Board Of Regents, The University Of Texas System Procédés de prédiction de la réactivité d'un médicament dans des échantillons de sujets atteints d'un cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180059114A1 (en) * 2016-08-24 2018-03-01 National Cancer Center Magnetic nanostructure for detecting and isolating circulating tumor cells comprising antibody- and magnetic nanoparticle-conjugated conductive polymer
WO2020227574A2 (fr) * 2019-05-07 2020-11-12 Board Of Regents, The University Of Texas System Procédés de prédiction de la réactivité d'un médicament dans des échantillons de sujets atteints d'un cancer

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