WO2017215637A1 - Marqueur du cancer de l'endomètre humain, anticorps et application de l'anticorps - Google Patents

Marqueur du cancer de l'endomètre humain, anticorps et application de l'anticorps Download PDF

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Publication number
WO2017215637A1
WO2017215637A1 PCT/CN2017/088501 CN2017088501W WO2017215637A1 WO 2017215637 A1 WO2017215637 A1 WO 2017215637A1 CN 2017088501 W CN2017088501 W CN 2017088501W WO 2017215637 A1 WO2017215637 A1 WO 2017215637A1
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endometrial cancer
antibody
em2d9
human
human endometrial
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PCT/CN2017/088501
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English (en)
Chinese (zh)
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李翀
史桂芝
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李翀
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Priority claimed from CN201610426014.9A external-priority patent/CN105859872A/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • 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
    • 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
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the invention belongs to the field of tumor immunology.
  • the present invention relates to a novel endometrial cancer tumor marker GAB31, and a monoclonal antibody EM2D9 against GAB31. Cell and histological levels demonstrate that EM2D9 specifically recognizes human endometrial cancer cells and human endometrial cancer tissues.
  • the invention also relates to a method for detecting human endometrial cancer by immunomagnetic beads.
  • the antigen detected by the detection method is the novel endometrial cancer marker GAB31 of human in the present invention, and the detection antibody is the monoclonal antibody EM2D9 against human endometrial cancer GAB31 in the present invention.
  • Endometrial cancer is one of the most common malignant tumors in the female reproductive system, and its incidence rate is the highest in the female reproductive system malignant tumors in Europe and the United States. Compared with European and American countries, the incidence of endometrial cancer in developing countries is lower, but the mortality rate is higher. As the lives and eating habits of Chinese people tend to be westernized, especially in economically developed areas, the incidence of endometrial cancer is increasing year by year. Currently, it ranks second in female reproductive system malignancies in China, second only to cervical cancer. The age of onset is getting younger. The cause of endometrial cancer is still unclear.
  • endometrial cancer Although early diagnosis of endometrial cancer includes transvaginal ultrasound, endometrial biopsy, diagnostic curettage, endometrial cytology, and many other methods, screening for endometrial cancer in asymptomatic general populations and at risk groups The method has not yet formed a unified guide or recommendation in the industry. Therefore, exploring the strategy of endometrial cancer screening is a hotspot in the research of endometrial cancer in the medical field. At present, the commonly used diagnostic methods for endometrial cancer are used for screening strategies, and all have more or less defects.
  • Transvaginal ultrasound can not determine the boundary value of endometrial thickness in endometrial lesions; endometrial biopsy is more or less uncomfortable, and a considerable proportion of subjects are missed because of insufficient tissue; diagnostic curettage It is an invasive operation. It is obviously inappropriate to include a screening strategy, and it is not suitable for non-developed areas because of the medical level. The cost of hysteroscopy is high, and the diagnostic value alone is limited.
  • the characteristics of endometrial cytology are the most Close to screening strategies, however, there is currently no uniform cytology standard. It can be seen that the screening strategy for endometrial cancer still needs further exploration.
  • CD44 is involved in the invasion and metastasis of endometrial cancer cells.
  • CD44 belongs to the cell multifunctional adhesion molecule and is a transmembrane glycoprotein encoded by a single gene, which is widely present in a variety of cells and tissues.
  • CD44 has 10 variant exons, so it can form a variety of isomers by selective shearing and splicing, and bind to the corresponding ligands on the cell surface, which can regulate various physiological and pathological processes of cells.
  • CD44 is highly expressed in a variety of tumors and is closely related to the growth, invasion and metastasis of tumor cells and the homing of hematopoietic stem cells in the tumor environment. It can be used as a marker for cancer stem cells or as a tumor screen.
  • the biological function and expression regulation mode of CD44 vary according to different conditions, such as tumor type and growth conditions. Many Factors can affect its expression, such as estrogen receptors, transcription factors and so on. Abnormal glycosylation of CD44 can lead to changes in the malignancy of tumor cells, and to explore the abnormal modification of CD44 in endometrial cancer, which can provide a new target for screening, diagnosis, prognosis and treatment of endometrial cancer. It will be of great significance for the diagnosis and treatment of endometrial cancer.
  • the present invention extracts total protein immunized mice from fresh human endometrial cancer tissues to prepare hybridoma cell lines.
  • An antibody EM2D9 capable of highly specific binding to human endometrial cancer tissues was screened by ELISA, and the antibody belongs to the IgG1 subclass. Immunohistochemistry confirmed that EM2D9 antibody had a strong positive reaction with human endometrial cancer tissue, but no cross-reaction with human normal endometrial tissue.
  • the present invention identifies by immunoprecipitation combined with mass spectrometry and sugar chip results that the antigen recognized by the EM2D9 antibody is an abnormally glycosylated CD44 which is localized on the cell membrane and has an epitope of: Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb is a new endometrial cancer marker.
  • the invention couples the EM2D9 antibody into the nano magnetic particle, prepares an anti-endometrial cancer immunomagnetic beads (EM2D9-MB), captures and enriches the detached endometrial cancer cells, and stains with the pathological smear of Wright's Giemsa. Microscopic examination under the microscope.
  • the kit is suitable for early screening, prognosis monitoring and pathological diagnosis of tumor patients.
  • the innovation of the invention lies in: (1) screening and preparing a monoclonal antibody EM2D9 against human endometrial cancer, which has a strong positive reaction with human endometrial cancer tissue, and human normal endometrial tissue No cross-reactivity; (2) revealed that the epitope recognized by EM2D9 antibody is Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb, which is a new endometrial cancer marker; (3) developed an EM2D9 based Highly sensitive antibody magnetic beads method for detecting human endometrial cancer.
  • the present invention provides a novel human endometrial cancer tumor marker, abnormally glycosylated CD44, designated GAB31.
  • GAB31 a novel human endometrial cancer tumor marker, abnormally glycosylated CD44, designated GAB31.
  • a hybridoma cell line producing a monoclonal antibody against GAB31 was obtained, and the hybridoma cell line secreted the monoclonal antibody EM2D9, and the epitope recognized by the monoclonal antibody EM2D9 was Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb. .
  • the monoclonal antibody has a strong positive reaction with human endometrial cancer tissue and no cross-reaction with human normal endometrial tissue.
  • the invention also provides an immunomagnetic beads (EM2D9-MB) diagnostic method based on monoclonal antibody EM2D9 for diagnosis of in vitro endometrial cancer.
  • the present invention provides an aberrantly glycosylated human endometrial cancer tumor marker GAB31 which is aberrantly glycosylated CD44 characterized by a glycostructure Galb1 ⁇ 3 comprising an epitope on CD44 ( Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb.
  • amino acid sequence of CD44 is set forth in SEQ ID No: 1.
  • Another object of the present invention is to provide an antibody against the human endometrial cancer marker GAB31 of the present invention which is capable of specifically recognizing the glycostructure Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 as an epitope.
  • the antibody is a polyclonal antibody or a monoclonal antibody, preferably a monoclonal antibody.
  • Another object of the present invention is to provide a kit for detecting human endometrial cancer comprising the above-described antibody EM2D9 of the present invention.
  • the antibody is monoclonal antibody EM2D9 against human endometrial cancer GAB31, which is secreted by a hybridoma cell line with accession number CGMCC No. 11796.
  • Another object of the present invention is to provide a conjugate comprising the anti-human endometrial cancer GAB31 conjugated with a substance selected from the group consisting of biomarkers, antitumor drugs, toxins and radioactive agents .
  • Another object of the present invention is to provide a kit for detecting or treating human endometrial cancer comprising the above-described antibody of the present invention.
  • the detection is carried out by coupling the nano-magnetic particles with the monoclonal antibody EM2D9, preferably by coupling the EM2D9 antibody to the nano-magnetic particles to prepare for anti-endometrial cancer immunity.
  • Magnetic beads (EM2D9 ⁇ MB).
  • the sample to be tested is a uterine scraping containing human endometrial cancer exfoliated cells.
  • Another object of the present invention is to provide a hybridoma cell line secreting monoclonal antibody EM2D9 against human endometrial cancer GAB31, which has a accession number of CGMCC No. 11796.
  • FIG. 1 Immunohistochemical map of EM2D9 mAb to human endometrial cancer tissue sections.
  • FIG. 1 Immunohistochemical map of EM2D9 mAb to human normal endometrial tissue sections.
  • mice purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • mice were immunized with fresh human endometrial cancer tissue protein homogenate at a dose of 20 ug total protein.
  • Mice were immunized by intraperitoneal injection. The mice were re-immunized two weeks later. After the serum titer of the mouse reached the requirement, the immunization was boosted once, and the spleen of the mouse was taken 3 days later to prepare a suspension of lymphocytes to prepare for cell fusion.
  • Resusciting myeloma cell Sp2/0 ATCC CRL ⁇ 1772), 8-AG (8-azaguanine) was screened to maintain cell sensitivity to HAT.
  • the lymphocyte suspension prepared in step 1) is fused with myeloma cells, and the specific method is referred to the "Guide to the Editing Immunology Experiment" ((United States) JE Science Roots (USA) DH Margulis, etc. Science Press, published in January 2009).
  • the fused cell suspension is added to a culture medium containing feeder cells.
  • HAT selection medium purchased from Invitrogen; HAT ie H: Hypoxanthine hypoxanthine, A: Aminopterin methotrexate, T: Thymidine thymidine was selectively cultured.
  • the antibody-secreting hybridoma cell strain was determined by an ELISA method. The specific method is: extracting total protein of endometrial cancer tissue, coating with 0.05 mol/L carbonate buffer (pH 9.6) at 4 ° C overnight, and adding 10% BSA at 37 ° C for 3 hours. The cells were washed 3 times with PBST, then 100 ul of the supernatant to be tested was added, and incubated at 37 ° C for 1 h. After washing 3 times, an anti-mouse horseradish peroxidase-labeled secondary antibody IgG-HRP (purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) was added and incubated at 37 ° C for 1 h.
  • IgG-HRP purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.
  • TMB purchased from Beijing Zhongshang Jinqiao Biotechnology Co., Ltd.
  • 50 ul of the stop solution was added for color development, and after standing at room temperature for 5 min, 50 ul of the stop solution was added.
  • the OD value at a wavelength of 450 nm was read with a microplate reader. An OD value greater than 2 times the OD value of the negative control was considered positive.
  • Cloning and cryopreservation of hybridomas The selected positive hybridoma cells were cloned and cultured by limiting dilution method. After three rounds of cloning culture, hybridoma cell clones with high titer monoclonal antibodies were screened for expanded culture.
  • a positive hybridoma cell line obtained in the present invention is a monoclonal hybridoma cell line against human endometrial cancer, and the hybridoma cell line is deposited on the Chinese Microbial Culture Collection Management Committee on December 23, 2015. Center (CGMCC, China, Beijing), the deposit number is CGMCC No.11796.
  • the above-described hybridoma cell strain stably stabilizing the monoclonal antibody EM2D9 (Accession No. CGMCC No. 11796) was expanded and cultured, and the cell culture supernatant was collected. Affinity chromatography of monoclonal antibody EM2D9 was performed using Protein G. The simple procedure was to first equilibrate the Protein G affinity chromatography column (purchased from "GE") with PBS; then, the cell culture containing EM2D9 monoclonal antibody was supernatantd.
  • Protein G affinity chromatography column then wash the column with PBS until the OD value of the washing solution flowing out of the column is close to zero; elute the column with 0.2 M glycine-HCL solution (pH 2.8), and collect the eluent in a separate tube. The OD value of each collection tube was measured. The eluate containing EM2D9 mAb was dialyzed against PBS and frozen at -20 °C.
  • Human endometrial cancer tissues and human normal endometrial tissues were sectioned using the EM2D9 monoclonal antibody prepared in Example 1, and the results are shown in Figs. The results showed that human endometrial cancer tissues showed a positive reaction after immunohistochemical staining by EM2D9 monoclonal antibody (Fig. 1), while human normal endometrial tissue showed a negative reaction after immunohistochemical staining with EM2D9 monoclonal antibody. figure 2).
  • Human endometrial cancer tissues, human normal endometrial tissues and other tissues were detected by immunohistochemistry using the EM2D9 monoclonal antibody prepared in Example 1, and the results are shown in Table 1. The results showed that EM2D9 antibody had a strong positive reaction with human endometrial cancer tissue, but no cross-reaction with human normal endometrial tissue and other tissues.
  • Total protein extraction 50mg human endometrial cancer tissue, after cutting and grinding into homogenate, add 1ml of three decontamination lysate, lyse at 4 °C for 5 minutes, centrifuge at 12000 rpm for 20 minutes, take the supernatant, which is human uterus Membrane cancer tissue total protein.
  • EM2D9 monoclonal antibody specifically recognizes human endometrial cancer tissue, it indicates that the antigen is abnormally glycosylated CD44, and its epitope Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb is only expressed in human uterus.
  • Membrane cancer tissue cells Since EM2D9 monoclonal antibody specifically recognizes human endometrial cancer tissue, it indicates that the antigen is abnormally glycosylated CD44, and its epitope Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb1 ⁇ 4Glcb is only expressed in human uterus.
  • Membrane cancer tissue cells since EM2D9 monoclonal antibody specifically recognizes human endometrial cancer tissue, it indicates that the antigen is abnormally glycosylated CD44, and its epitope Galb1 ⁇ 3 (Neu5Aca2 ⁇ 6) GlcNAcb1 ⁇ 4Galb
  • EM2D9-MB anti-endometrial cancer immunomagnetic beads
  • the human endometrial cancer immunodiagnostic reagent of the present invention has the following positive effects compared with the prior art: (1) high sensitivity, and the sensitivity of the method is high due to the enrichment of the conjugated monoclonal antibody EM2D9 immunomagnetic particles.
  • the conventional exfoliative cytology detection method (2) strong specificity, because the method is coupled with EM2D9 antibody that specifically binds to endometrial cancer tissue cells, it can specifically recognize endometrial cancer cells; (3 It is convenient and quick, and saves patients' medical expenses. Because of its high sensitivity and strong specificity, the detection rate of endometrial cancer patients is high, avoiding repeated diagnosis and saving of patients.

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Abstract

L'invention concerne un nouveau marqueur tumoral du cancer de l'endomètre humain, appelé GAB31. Le marqueur tumoral est un CD44 anormalement glycosylé, qui contient une structure de type saccharide d'épitope Galb1-3(Neu5Aca2-6)GlcNAcb1-4Galb1-4Glcb. L'invention concerne également un anticorps qui reconnaît spécifiquement l'antigène et on a trouvé, par l'intermédiaire d'expériences à base de billes immunomagnétiques sur des échantillons cliniques, que le taux de détection positive d'EM2D9-MB d'un procédé de détection utilisant l'anticorps pour reconnaître l'antigène GAB31 est manifestement supérieur à celui d'un procédé d'examen microscopique classique de cellules rejetées.
PCT/CN2017/088501 2016-06-15 2017-06-15 Marqueur du cancer de l'endomètre humain, anticorps et application de l'anticorps WO2017215637A1 (fr)

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CN201610426014.9A CN105859872A (zh) 2016-03-08 2016-06-15 一种人子宫内膜癌的标志物、抗体及其应用
CN201610426014.9 2016-06-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112951410A (zh) * 2021-02-08 2021-06-11 青岛大学附属医院 超声引导下的细针穿刺病理涂片快速现场评估系统

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CN1541226A (zh) * 2001-05-18 2004-10-27 ���ָ��Ӣ��ķ�������Ϲ�˾ CD44v6特异性的抗体
CN101368173A (zh) * 2008-04-09 2009-02-18 协和干细胞基因工程有限公司 抗人cd44单克隆抗体杂交瘤细胞系、单克隆抗体、工程抗体、载体、试剂盒及其用途
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CN1541226A (zh) * 2001-05-18 2004-10-27 ���ָ��Ӣ��ķ�������Ϲ�˾ CD44v6特异性的抗体
CN101368173A (zh) * 2008-04-09 2009-02-18 协和干细胞基因工程有限公司 抗人cd44单克隆抗体杂交瘤细胞系、单克隆抗体、工程抗体、载体、试剂盒及其用途
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ENGLISH, N.M. ET AL.: "Site-specific De-N-glycosylation of CD 44 Can Activate Hya-luronan Binding, and CD 44 Activation States Show Distinct Threshold Densities for Hyaluronan Binding", CANCER RESEARCH, vol. 58, no. 16, 15 August 1998 (1998-08-15), pages 3736 - 3742, XP055449582 *
STOKES, G.N. ET AL.: "Association of CD 44 Isoform Immunohistochemical Expression with Myometrial and Vascular Invasion in Endometrioid Endometrial Carcinoma", GYNECOLOGIC ONCOLOGY, vol. 84, no. 1, 15 November 2001 (2001-11-15), pages 58 - 61, XP055449579 *
WANG, JUN ET AL.: "Detection of Exon v6 of CD 44 Gene Transcript in Endometriai and its Clinical Significance", CHINESE JOURNAL OF PRACTICAL GYNECOLOGY AND OBSTETRICS, vol. 19, no. 3, 31 March 2003 (2003-03-31), pages 165 - 167 *
XIANG, DAJUN ET AL.: "Study on Expression and Significance of CD 44v6 in Endometrial Adenocarcinoma of Uterus", SUZHOU UNIVERSITY JOURNAL OF MEDICAL SCIENCE, vol. 22, no. 4, 31 December 2002 (2002-12-31), pages 373 - 376 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112951410A (zh) * 2021-02-08 2021-06-11 青岛大学附属医院 超声引导下的细针穿刺病理涂片快速现场评估系统

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