WO2016143805A1 - Procédé de détection du cancer de la vessie - Google Patents

Procédé de détection du cancer de la vessie Download PDF

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Publication number
WO2016143805A1
WO2016143805A1 PCT/JP2016/057270 JP2016057270W WO2016143805A1 WO 2016143805 A1 WO2016143805 A1 WO 2016143805A1 JP 2016057270 W JP2016057270 W JP 2016057270W WO 2016143805 A1 WO2016143805 A1 WO 2016143805A1
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WIPO (PCT)
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monoclonal antibody
antibody
bladder cancer
group
signal intensity
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PCT/JP2016/057270
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English (en)
Japanese (ja)
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孝広 落谷
祐亮 吉岡
隆之 水谷
辰也 力石
秀郎 佐々木
Original Assignee
テオリアサイエンス株式会社
国立研究開発法人国立がん研究センター
学校法人 聖マリアンナ医科大学
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Priority to JP2017505364A priority Critical patent/JPWO2016143805A1/ja
Publication of WO2016143805A1 publication Critical patent/WO2016143805A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/02—Preparation of hybrid cells by fusion of two or more cells, e.g. protoplast fusion
    • 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

  • the present invention relates to a method for detecting bladder cancer. More specifically, bladder cancer using a monoclonal antibody or an antibody fragment thereof against a specific antigen (CD9, CD63, CD55, CD82, HLA-DRB1) on the surface of an extracellular endoplasmic reticulum containing exosomes in a sample
  • a specific antigen CD9, CD63, CD55, CD82, HLA-DRB1
  • the present invention relates to a method for detecting the presence of and a kit used in the method.
  • Exosomes are a type of extracellular endoplasmic reticulum that exists in body fluids in vivo. It is known that various membrane proteins exist on the exosome surface as in the general cell surface. In addition, exosomes have been reported to be secreted from various cells, such as cells of the immune system and various cancer cells, functioning as mediators of intercellular communication in vivo and related to physiological phenomena, Relevance to diseases such as cancer is drawing attention.
  • Non-Patent Document 1 discloses that the mRNA expression levels of CD46, CD55, and CD59 are increased in the tumor tissue of bladder cancer patients.
  • CD55 is described as an example of a tumor marker characteristic of the bladder of a bladder cancer patient.
  • Non-Patent Document 2 CD82 (KAI1) mutation rarely occurs, and KAI1 down-regulation and glycosylation are considered to be important as marker information, and prostate cancer, lung cancer, pancreatic cancer It is disclosed that it is involved in the progress.
  • KAI1 is expressed at the protein level in normal bladder cells, but it is shown that expression is suppressed in 3 out of 8 bladder cancer cell lines and greatly promoted in 1 type, The association with bladder cancer is unknown.
  • Patent Document 2 describes that CD82 increases at the gene level (mRNA) in bladder cancer cells that are resistant to chemotherapy using cisplatin.
  • Patent Document 3 discloses a method for diagnosing bladder cancer by targeting a marker that shows an abnormal value compared to normal bladder cells, and HLA-DRB1 is exemplified as a marker that increases the expression level.
  • Cancer can be detected using a membrane protein present in an extracellular vesicle such as an exosome as a biomarker.
  • an extracellular vesicle such as an exosome as a biomarker.
  • it is difficult to obtain sufficient results due to large fluctuations in sensitivity and specificity, etc., and it may be false positive in conventional cancer diagnosis
  • An object of the present invention is to provide a method for detecting bladder cancer by measuring extracellular endoplasmic reticulum, particularly exosomes, and a kit used for the method.
  • the present invention relates to the following [1] to [7].
  • [1] at least one selected from the group consisting of an anti-CD9 monoclonal antibody, an anti-CD63 monoclonal antibody, and antibody fragments thereof; and (B) an anti-CD55 monoclonal antibody, an anti-CD82 monoclonal antibody, and an anti-HLA-DRB1 monoclonal antibody , And at least one selected from the group consisting of antibody fragments thereof, and at least one selected from the group consisting of CD9 and / or CD63 in body fluid samples derived from a subject, CD55, CD82, and HLA-DRB1 Measuring the signal intensity from the extracellular endoplasmic reticulum expressing The presence of bladder cancer in the case where the signal intensity in the subject is recognized to be stronger than the signal intensity in the control, comprising the step of comparing the signal intensity in the subject obtained in the step and the signal intensity in the control Method for detecting bladder cancer, which is an indicator of [2] (A) at least one
  • [4] at least one selected from the group consisting of anti-CD9 monoclonal antibody, anti-CD63 monoclonal antibody, and antibody fragments thereof; and (B) anti-CD55 monoclonal antibody, anti-CD82 monoclonal antibody, anti-HLA-DRB1 monoclonal antibody And an extracellular endoplasmic reticulum recognized by at least one selected from the group consisting of antibody fragments thereof as a marker for bladder cancer.
  • [5] at least one selected from the group consisting of an anti-CD9 monoclonal antibody, an anti-CD63 monoclonal antibody, and antibody fragments thereof; and (B) an anti-CD55 monoclonal antibody, an anti-CD82 monoclonal antibody, and an anti-HLA-DRB1 monoclonal antibody. And an exosome recognized by at least one selected from the group consisting of antibody fragments thereof as a marker for bladder cancer.
  • bladder cancer can be detected by measuring extracellular vesicles such as exosomes without worrying about false positives, thereby determining the presence or degree of progression of bladder cancer. can do.
  • FIG. 1 is a diagram showing detection results of various markers in urine derived from urine of a bladder cancer patient using an exoscreen method.
  • FIG. 2 is a diagram showing relative results based on the amount of creatinine for the expression of various markers in urinary exosomes of bladder cancer patients using the exoscreen method.
  • FIG. 3 is a graph comparing the detection results (creatinine amount standard) of exosome-derived CD55 and CD82.
  • the present invention is a method for detecting bladder cancer in a subject, wherein a signal intensity derived from an extracellular endoplasmic reticulum in a body fluid sample is measured using a specific monoclonal antibody, and the value is higher than that of a healthy person
  • a large feature is that it is judged that there is a possibility of having bladder cancer when it is large.
  • a step of measuring the signal intensity derived from an extracellular endoplasmic reticulum expressing the antigen in a body fluid sample derived from a subject using a monoclonal antibody or antibody fragment thereof against a specific antigen hereinafter also referred to as step A).
  • step B the step of comparing the signal intensity in the subject obtained in the step with the signal intensity in the control (hereinafter also referred to as step B), wherein the signal intensity in the subject is If it is recognized that it is stronger than the signal intensity, it is an indicator of the presence of bladder cancer.
  • detecting bladder cancer includes detecting the presence or absence of development of bladder cancer and the degree of progression of a disease state.
  • the present inventors focused on membrane proteins present in urinary exosomes, and examined those that are detected in urinary exosomes of bladder cancer patients but difficult to detect in healthy individuals.
  • CEACAM7, DUOX2, HLA-DRB1, ABCB1, ELANE, IFITM2, CD55, and CD82 as antigens specific to exosomes in the urine of patients.
  • the present inventors have previously found that exosomes can be specifically captured using anti-CD9 antibody and anti-CD63 antibody. By combining these with an antibody against the antigen, the measurement value of a healthy person is It was found that good results were obtained that there was little variation and no false positives were detected and that signals were detected only from bladder cancer patients, and the present invention was completed.
  • Step A is a step of measuring a signal derived from an extracellular endoplasmic reticulum expressing the antigen in a body fluid sample derived from a subject using a monoclonal antibody or an antibody fragment thereof against the specific antigen.
  • the extracellular vesicle is an vesicle secreted outside the cell, and examples thereof include exosomes.
  • Examples of the monoclonal antibody or antibody fragment thereof used in Step A include monoclonal antibodies or fragments thereof consisting of two groups. Specifically, an antibody group (A) that specifically captures extracellular vesicles and an antibody group (B) against an antigen specific to the extracellular vesicle secreted from bladder cancer cells.
  • the antibody group (A) may be any antibody that can specifically capture extracellular vesicles, specifically, an anti-CD9 monoclonal antibody or an antibody fragment thereof, an anti-CD63 monoclonal antibody or an antibody fragment thereof. It is sufficient that at least one of these can be used.
  • the antibody group (B) may be any antibody that can specifically capture extracellular vesicles secreted from bladder cancer cells, specifically, an anti-CEACAM7 monoclonal antibody or an antibody fragment thereof, an anti-DUOX2 monoclonal antibody Or an antibody fragment thereof, anti-HLA-DRB1 monoclonal antibody or antibody fragment thereof, anti-ABCB1 monoclonal antibody or antibody fragment thereof, anti-ELANE monoclonal antibody or antibody fragment thereof, anti-IFITM2 monoclonal antibody or antibody fragment thereof, anti-CD55 monoclonal antibody or antibody thereof Fragment, anti-CD82 monoclonal antibody or antibody fragment thereof. It is sufficient that at least one of these can be used.
  • the monoclonal antibody or antibody fragment thereof used in the present invention may be any one that recognizes a specific antigen, and can be prepared according to a known method. That is, an anti-CD9 monoclonal antibody or an antibody fragment thereof recognizes CD9, an anti-CD63 monoclonal antibody or an antibody fragment thereof recognizes CD63, an anti-CEACAM7 monoclonal antibody or an antibody fragment thereof recognizes CEACAM7, and an anti-DUOX2 monoclonal antibody or an antibody thereof
  • the antibody fragment recognizes DUOX2, the anti-HLA-DRB1 monoclonal antibody or an antibody fragment thereof recognizes HLA-DRB1, the anti-ABCB1 monoclonal antibody or an antibody fragment thereof recognizes ABCB1, and the anti-ELANE monoclonal antibody or an antibody fragment thereof is ELANE Anti-IFITM2 monoclonal antibody or antibody fragment thereof recognizes IFITM2, anti-CD55 monoclonal antibody or antibody fragment thereof recognizes CD55, and anti-CD82 monoclonal antibody
  • the anti-CD9 monoclonal antibody, the anti-CD63 monoclonal antibody, and their antibody fragments are hybridomas that produce the monoclonal antibodies.
  • 1-1-1 A cell obtained from a cell deposited under the following deposit number in the center of Tsukuba Center 6) can also be used.
  • FERM BP-11519 (monoclonal antibody produced is CD9-12A12 antibody, designated CD9: 12A12, date of acceptance November 8, 2011)
  • FERM BP-11520 (monoclonal antibody produced is CD63-8A12 antibody, designated CD63: 8A12, date of acceptance November 8, 2011)
  • FERM BP-11521 (the monoclonal antibody produced is the CD63-13C8 antibody, designated CD63: 13C8, date of commissioning November 8, 2011)
  • the “monoclonal antibody fragment” is a part of the monoclonal antibody described above, and similarly to the monoclonal antibody, CD9, CD63, CEACAM7, DUOX2, HLA-DRB1, ABCB1, ELANE, IFITM2, CD55, CD82.
  • the fragment having specific binding to the antigen includes Fab, F (ab ′) 2, Fab ′, single chain antibody (scFv), disulfide stabilized antibody (dsFv), dimerization Examples include body V region fragments (Diabodies), CDR-containing peptides, etc. (Expert Opinion on Therapeutic Patents, Vol. 6, No. 5, pp. 441-456, 1996).
  • antibody group (A) and antibody group (B) are not particularly limited as long as monoclonal antibodies belonging to the respective groups or antibody fragments thereof are used in appropriate combinations, and examples include the following combinations. .
  • Aspect 1 An aspect in which an anti-CD9 monoclonal antibody and its antibody fragment are used in combination with an anti-CD55 monoclonal antibody or a fragment thereof
  • Aspect 2 An aspect in which an anti-CD9 monoclonal antibody and its antibody fragment are combined with an anti-CD82 monoclonal antibody or a fragment thereof
  • Aspect 3 An aspect in which an anti-CD63 monoclonal antibody and an antibody fragment thereof are combined with an anti-HLA-DRB1 monoclonal antibody or a fragment thereof
  • an extracellular endoplasmic reticulum is recognized by any one of the monoclonal antibodies or antibody fragments thereof, and the corresponding antigen is obtained by the other monoclonal antibody or the antibody fragment thereof.
  • the signal derived from the extracellular endoplasmic reticulum in which is expressed can be quantified.
  • CD9 and CD55 on the extracellular endoplasmic reticulum are recognized by these monoclonal antibodies or fragments thereof, and signals derived from the extracellular endoplasmic reticulum in which CD9 and CD55 are expressed. Can be quantified. The same applies to other aspects.
  • any one monoclonal antibody or antibody fragment thereof may be used as a solid phase antibody, and the other monoclonal antibody or antibody fragment thereof may be used as a labeled antibody.
  • the solid phase antibody and the labeled antibody may be either the antibody group (A) or the antibody group (B), but are derived from an antigen specific to the extracellular endoplasmic reticulum in a body fluid sample derived from a bladder cancer patient. From the viewpoint of detecting a signal, it is preferable to use the antibody group (A) as a solid phase antibody and the antibody group (B) as a labeled antibody.
  • the preparation of the solid phase antibody and the labeled antibody is not particularly limited, and can be performed according to a known method. Such a combined monoclonal antibody or antibody fragment thereof is suitably used in the sandwich ELISA method and exoscreen method described below.
  • the sample used for measuring the signal intensity derived from the extracellular endoplasmic reticulum is not limited as long as it is a body fluid sample.
  • a body fluid sample For example, blood, serum, plasma, urine, saliva, milk, nasal discharge, cerebral spinal cord Those selected from the group consisting of liquids are exemplified. Of these, urine is preferable.
  • the signal intensity derived from the extracellular endoplasmic reticulum may be measured by any method using the monoclonal antibody or antibody fragment thereof, and can be performed, for example, according to the sandwich ELISA method or the exoscreen method.
  • the sandwich ELISA method first, one type of monoclonal antibody or an antibody fragment thereof is used as a solid phase antibody, and a complex is formed by contacting with a sample containing extracellular vesicles. Thereafter, another monoclonal antibody or an antibody fragment thereof is added thereto after labeling to form a further complex, and the label is detected to derive from the extracellular endoplasmic reticulum expressing the antigen recognized by both antibodies. Signal intensity can be measured.
  • the exoscreen method is an application of AlphaLISA developed by PerkinElmer.
  • two types of antibodies having different epitopes are used.
  • One antibody is biotinylated, and the other is reacted with a sample using an antibody to which Alpha LISA acceptor beads are bound.
  • the biotinylated antibody and donor beads are bound via streptavidin, and the acceptor beads and donor beads are adjacent to each other.
  • the adjacent state within 200 nm
  • singlet oxygen is generated from the donor bead by excitation at 680 nm, and when singlet oxygen reaches the acceptor bead, light of 615 nm can be emitted and detected as a signal.
  • exosomes having a size of about 100 nm can be measured as a sample.
  • the signal intensity derived from the extracellular endoplasmic reticulum containing the target protein in the body fluid sample can be measured.
  • the following step B is performed.
  • Step B is a step of comparing the signal intensity derived from the extracellular endoplasmic reticulum in the subject obtained in Step A and the signal strength in the control, and it is recognized that the signal strength in the subject is stronger than the signal strength in the control. Is an indicator of the presence of bladder cancer.
  • the control person may be any person who does not develop bladder cancer, and includes a healthy person.
  • the signal intensity in the control person is the signal intensity derived from the extracellular endoplasmic reticulum in the body fluid sample derived from the control person, and is measured together with the measurement of the signal intensity derived from the extracellular endoplasmic reticulum of the subject in Step A. Alternatively, it may be measured separately. Alternatively, the signal intensity derived from the extracellular vesicles of a plurality of controls may be measured, and the signal intensity derived from the extracellular vesicles of the controls may be set from the statistics.
  • the body fluid sample derived from the control is preferably the same type of sample as the body fluid sample derived from the subject.
  • the body fluid sample derived from the control is also urine.
  • the method is not particularly limited, and known methods (Steel method, t-test, Wilcoxon test, etc.) can be used. If the analysis shows that the signal intensity from the subject's extracellular endoplasmic reticulum is greater than the signal intensity from the control's extracellular endoplasmic reticulum, the subject has bladder cancer. It is judged that there is a high possibility.
  • the presence or absence of bladder cancer can be determined by detecting extracellular vesicles present in a body fluid sample using the antibody, as one embodiment of the present invention, (A) At least one selected from the group consisting of an anti-CD9 monoclonal antibody, an anti-CD63 monoclonal antibody, and an antibody fragment thereof; and (B) an anti-CD55 monoclonal antibody, an anti-CD82 monoclonal antibody, an anti-HLA-DRB1 monoclonal antibody, and an antibody fragment thereof
  • a method for providing bladder cancer or information on a suspicion of bladder cancer comprising detecting an extracellular vesicle recognized by at least one selected from the group consisting of a body fluid sample derived from a subject. Can be mentioned.
  • the signal intensity derived from the extracellular vesicle of the control person is set to the signal intensity derived from the extracellular vesicle before the operation of the subject, and the signal intensity derived from the extracellular vesicle after the operation is set to the cell of the subject. If the signal intensity derived from the outer endoplasmic reticulum is compared with the signal intensity derived from the outer endoplasmic reticulum, the bladder cancer may be reduced or decreased. It can be judged that it is expensive.
  • the signal intensity derived from the extracellular ER of the control person is set to the signal intensity derived from the extracellular ER before treatment of the subject.
  • the signal intensity derived from the extracellular vesicle after treatment decreased. In this case, it can be determined that there is a high possibility that the treatment is effective for treating bladder cancer.
  • the present invention also measures the signal intensity derived from the extracellular endoplasmic reticulum using the monoclonal antibody or antibody fragment thereof before and after receiving treatment for bladder cancer, and the value after treatment is the value before treatment.
  • the evaluation method characterized by judging that the said treatment has an effect when it is smaller than the above can be provided.
  • a kit for detecting bladder cancer is provided.
  • the kit of the present invention includes any kit capable of detecting extracellular vesicles in a body fluid sample. Specifically, at least one selected from the group consisting of an antibody capable of recognizing an antigen present on the surface of the extracellular endoplasmic reticulum, (A) an anti-CD9 monoclonal antibody, an anti-CD63 monoclonal antibody, and an antibody fragment thereof; And a kit containing at least one selected from the group consisting of anti-CD55 monoclonal antibody, anti-CD82 monoclonal antibody, anti-HLA-DRB1 monoclonal antibody, and antibody fragments thereof.
  • kits can be used as long as they are detection methods using an antibody when detecting extracellular vesicles in a body fluid sample (for example, ELISA method, exoscreen method, etc.). If extracellular vesicles are detected, proteins other than extracellular vesicles may be detected simultaneously by the antibody.
  • kits of the present invention for example, when a signal derived from an extracellular endoplasmic reticulum present in a blood sample of a healthy person and a subject is measured, and there is a significant difference in the signal intensity between the two, the bladder in the subject A determination and / or diagnosis of the onset of cancer can be made.
  • Example 1 Detection of bladder cancer marker protein
  • proteomic analysis of the exosomes derived from the urination of 3 bladder cancer patients and the urine of 2 healthy persons was detected in 2 or more patients with bladder cancer and detected in healthy persons Proteins that were not selected were selected. Selected results are shown in Table 1.
  • Example 2 (Detection of bladder cancer) From the results obtained in Example 1, bladder cancer was detected using CD55, CD82, or HLA-DRB1 as an index.
  • Example 3 (Detection of bladder cancer using CD55 and CD82 as an index) Taking the measurement signal of CD9 and CD55 positive exosomes on the horizontal axis and the measurement signal of CD9 and CD82 positive exosomes on the vertical axis, and setting the cut-off value so that all 7 healthy subjects are negative, 8 out of 14 cases An example bladder cancer patient was shown to be positive for at least either exosome (FIG. 3). That is, it was shown that a combination of CD55 and CD82 can be a bladder cancer marker with higher accuracy.
  • the method of the present invention makes it possible to determine whether or not the sample provider has a high possibility of developing bladder cancer. This is useful because the sample provider can take measures to prevent the progression of cancer.

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Abstract

L'invention concerne un procédé pour détecter le cancer de la vessie, comprenant une étape consistant à mesurer l'intensité d'un signal provenant d'une vésicule extracellulaire à l'aide de (A) au moins un composé choisi dans le groupe constitué d'un anticorps monoclonal anti-CD9, d'un anticorps monoclonal anti-CD63 et de fragments des anticorps et (B) au moins un composé choisi dans le groupe constitué d'un anticorps monoclonal anti-CD55, d'un anticorps monoclonal anti-CD82, d'un anticorps monoclonal anti-HLA-DRB1 et de fragments des anticorps. Selon le procédé de la présente invention, il est possible de déterminer si une probabilité élevée que le cancer de la vessie soit développé chez un donneur d'échantillon es présente. En conséquence, il devient possible pour le donneur d'échantillon de prendre une mesure pour empêcher la progression du cancer. Par conséquent, le procédé de la présente invention est utile.
PCT/JP2016/057270 2015-03-10 2016-03-09 Procédé de détection du cancer de la vessie WO2016143805A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
JP2019528674A (ja) * 2016-09-30 2019-10-17 セレックス ライフ サイエンシズ，インコーポレーテッド タンパク質をロードしたエキソソームを含む組成物、並びにその調製及び送達のための方法
WO2022030626A1 (fr) * 2020-08-06 2022-02-10 株式会社Ｌｓｉメディエンス Méthode de diagnostic du cancer de la vessie

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JP2009528817A (ja) * 2006-02-10 2009-08-13 パシフィック エッジ バイオテクノロジー リミティド 癌の検出のための尿遺伝子発現比
WO2012178087A1 (fr) * 2011-06-22 2012-12-27 Oncocyte Corporation Méthodes et compositions pour traitement et diagnostique d'un cancer de la vessie

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JP2009528817A (ja) * 2006-02-10 2009-08-13 パシフィック エッジ バイオテクノロジー リミティド 癌の検出のための尿遺伝子発現比
WO2012178087A1 (fr) * 2011-06-22 2012-12-27 Oncocyte Corporation Méthodes et compositions pour traitement et diagnostique d'un cancer de la vessie

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Title
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019528674A (ja) * 2016-09-30 2019-10-17 セレックス ライフ サイエンシズ，インコーポレーテッド タンパク質をロードしたエキソソームを含む組成物、並びにその調製及び送達のための方法
WO2022030626A1 (fr) * 2020-08-06 2022-02-10 株式会社Ｌｓｉメディエンス Méthode de diagnostic du cancer de la vessie

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