WO2008041594A1 - procÉdÉ d'analyse de la sensibilitÉ À un mÉdicament À base d'anticorps - Google Patents

procÉdÉ d'analyse de la sensibilitÉ À un mÉdicament À base d'anticorps Download PDF

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Publication number
WO2008041594A1
WO2008041594A1 PCT/JP2007/068723 JP2007068723W WO2008041594A1 WO 2008041594 A1 WO2008041594 A1 WO 2008041594A1 JP 2007068723 W JP2007068723 W JP 2007068723W WO 2008041594 A1 WO2008041594 A1 WO 2008041594A1
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Prior art keywords
cell
cells
antibody drug
test subject
cell culture
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PCT/JP2007/068723
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English (en)
Japanese (ja)
Inventor
Natsuhiko Sugimura
Yuji Mishima
Yasuhito Terui
Kiyohiko Hatake
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Olympus Corporation
Japanese Foundation For Cancer Research
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Priority to JP2008537493A priority Critical patent/JPWO2008041594A1/ja
Publication of WO2008041594A1 publication Critical patent/WO2008041594A1/fr

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    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
    • 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
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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 an antibody drug sensitivity test method.
  • Antibodies have high! /, Binding activity, binding specificity, and stability in blood! /. Therefore, in recent years, attempts have been made to apply these characteristics to diagnosis 'prevention' and treatment of various human diseases. Among them, some chimeric antibodies and humanized antibodies using gene recombination technology have a remarkable therapeutic effect. In recent years, research and development of antibody medicines using these antibodies have attracted attention.
  • trastuzumab (generic name) for breast cancer (Herceptin (trade name: Roche); Her2 humanized monoclonal antibody) and rituximab (CD20 chimera) for B lymphoma.
  • Monoclonal antibodies are known.
  • the action mechanism of an antibody drug includes growth inhibition by signaling, induction of apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and the like.
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cytotoxicity
  • CDC is considered to be effective in a relatively short time after drug administration because complements abundant in blood directly recognize antibodies and attack target cells (non-patent literature). 1).
  • non-patent document 2 for example, in some patients with B lymphoma, it is known that some people are resistant to rituximab! /, (Non-patent document 2).
  • Non-Patent Document 1 Oliver Manches et al., Blood, Vol. 01, No. 3, pp.949-954, 2003
  • Non-Patent Document 2 James M. Foran et al., British J. Hematology, Vol. 114, p. 881, 2001 Year
  • Non-Patent Document 3 Miltue Biotech Co., Ltd., “Isolation of CD 19+ cells by auto MACS”, [online], [Searched on September 21, 2006], Internet URL: http: // www .miltenyibiotec.co.jp / tech_info / prot / pdf_2_human / 130-050-301prot-a.pdr ⁇
  • the present invention has the following configurations 1. to 13.
  • step (3) When it is determined in the step (2) that there are sufficient number of living cells for the test regarding the cells derived from the test subject and, if appropriate, the cells serving as a positive control, the test subject is administered to the test subject. Adding a labeled antibody drug to the cell culture vessel and culturing; and
  • a method for testing antibody drug sensitivity comprising a step of detecting the label bound to the cell surface.
  • step (1) before or after step (5), after step (a), before or after step (d),
  • the method comprises screening cells derived from a test subject for CD19, wherein only positive cells are obtained in the step (1) or The method for testing antibody drug susceptibility in the method of the invention described in 12. above, which is applied to step (a).
  • FIG. 1 This figure is an evaluation of CDC sensitivity of a plurality of B lymphomas by the test method of the present invention.
  • DLBCL diffuse large B-cell lymphoma
  • FL is follicular lymphoma
  • MCL mantle cell lymphoma
  • MALT is maltolymphoma
  • lymphopla smacytic lymphoma is lymphoid $ 10 cells.
  • Small lymphocytic lymphoma represents small lymphocytic lymphoma
  • Burkit represents Burkitt lymphoma
  • Hodgkin represents Hodgkin lymphoma.
  • an antibody drug sensitivity test method comprises:
  • step (3) When it is determined in the step (2) that there are sufficient number of living cells for the test regarding the cells derived from the test subject and, if appropriate, the cells serving as a positive control, the test subject is administered to the test subject. Adding a labeled antibody drug to the cell culture vessel and culturing; and
  • a cell derived from a test subject and, optionally, a positive target cell Get first.
  • Obtaining cells derived from the test subject can be performed by collecting tissue cells from the affected area of the test subject by a surgical method or by collecting peripheral blood in the case of leukemia.
  • the positive control cell is a cell expressing an antigen recognized by the antibody drug whose sensitivity is evaluated by the method of the present invention on the cell surface, and has been established as a cell line. Get things as appropriate.
  • the cells to be positive are CD20 positive cells such as Daudi cells and Raji cells when the antibody drug is rituximab, and Her2 positive cells such as MCF7 when trastuzumab is used.
  • the tissue obtained from the subject is a tissue
  • a tissue cut the tissue finely using a scalpel or scissors as appropriate, suspend it in a buffer solution (for example, Hanks-Buffer), and then add the suspension to the strainer. Collect only floating cells that have passed through.
  • the tissue collected from the test subject is rubbed against frosted glass, and the released cells are collected with a buffer solution, and only those that have passed through the strainer are collected. Through these operations, cells in a state suitable for testing are obtained.
  • the following steps (1) to (4) are sequentially performed.
  • a cell culture vessel together with a culture medium suitable for the test (such as unpigmented RPMI1640 (Roswell Park Memorial Institute) medium or PBS (phosphate buffered saline)).
  • a culture medium suitable for the test such as unpigmented RPMI1640 (Roswell Park Memorial Institute) medium or PBS (phosphate buffered saline)
  • a cell culture vessel to be used a normal cell culture vessel can be mentioned.
  • a cell culture vessel having a size and capacity suitable for culturing a small amount of cells of about 1 ⁇ 10 2 to 1 ⁇ 10 4 is preferable.
  • the step of concentrating the cell types can optionally be performed.
  • rituximab anti-CD20 antibody
  • cells expressing CD19 on the cell surface may be concentrated in advance using an anti-CD19 antibody.
  • CD19 antigen which is a surface antigen of B cells, has almost the same expression time as CD20 antigen, and B cells expressing CD19 are considered to express CD20.
  • information on the expression time of the antigen on the cell surface derived from the test subject is clarified. Therefore, it is particularly effective when there is an antibody that can be obtained at a lower price than an antibody drug.
  • the viability of each cell cultured in the cell incubator is determined.
  • various known reagents for cell viability can be used. For example, if a dye for nuclear staining (P Propidium Iodide) is added to the cell culture compartment and the cells are observed with a microscope after incubation for a certain period of time, the nuclei of living cells will not be stained, whereas the cells of dead cells will be stained. Therefore, cell viability can be determined by the presence or absence of staining.
  • a dye for nuclear staining P Propidium Iodide
  • the step of determining whether or not the patient is alive or dead includes a plurality of cells within a single visual field of a microscope, and the viability thereof is at least 50% or more, more preferably 80%. This corresponds to searching for a specific field of view. More preferably, after determining a visual field suitable for evaluation, photographing of the visual field is performed. By assigning an address to each cell in the field of view after imaging, it becomes easier to collate with the observation and measurement results of the subsequent process.
  • the antibody drug to be administered to the subject to be examined is added with a label. Add to the culture vessel and continue culturing.
  • the antigen recognized by the antibody is expressed on the surface of the living cell derived from the test subject, the antibody to which the label is attached binds to the antigen. Since some resistant patients may not express the CD20 antigen on the B cell surface, the labeled antibody does not bind to the cell surface.
  • the presence or absence of antigen expression on the surface of the living cell can be determined by photographing the visual field containing the living cell in a state suitable for detection of the label. Is possible.
  • the number of cells to be analyzed is preferably 20 to 20000, more preferably 100 to 10000, even more preferably 200, and 3000 , Most preferably 500 pcs, 2,000 pcs [0032]
  • the antibody drug is particularly preferably a chimeric antibody, a humanized antibody, or a human antibody from the viewpoint of the ability to use a chimeric antibody, humanized antibody, human antibody, mouse antibody, or the like.
  • the presence or absence of antigen expression is determined in a state suitable for detection of a label added to the antibody drug.
  • the label is a fluorescent dye
  • it is performed by irradiating light suitable for detection of the dye.
  • An optical apparatus used for cell observation, label detection, etc. in these steps can be performed by, for example, Olympus laser scanning confocal microscope FV-1000.
  • (6) a step of detecting the label bound to the cell surface and further determining the viability of the cell after addition of complement.
  • complement is added.
  • the same type of antibody drug as used that is, when the antibody drug is a humanized antibody, it is preferable to use human-derived complement, particularly preferably the subject of the subject. is there. More specifically, serum derived from healthy subjects or test subjects is added to the incubator, for example, so that the ratio to the total culture broth after addition is about 10% (v / v), and cultured for a certain period of time. To do.
  • a complement source serum, plasma, whole blood, purified complement fluid and the like can be used. Complements are fragile and must be handled while fresh. Therefore, serum or plasma is preferable from the viewpoint of easy availability and handling.
  • the step (6) of detecting the presence of the antigen on the cell surface is performed in the same manner as in the above step (4). If the antibody drug is bound to the cell surface after the step (3), the step (5 ) Complementation causes CDC and destroys the cell membrane. Therefore, the cells labeled in the above step (4) are detected by staining the nucleus with the staining reagent added in the above step (2), for example. On the other hand, the cells determined as dead cells in the step (2) are also determined as dead cells in this step, and when the cells derived from the test subject are antibody drug resistant, they are determined as live cells.
  • the step of determining the ratio of cell viability can be further included.
  • a predetermined rate for example, 80% or more
  • the effectiveness of the antibody drug can be quantitatively shown by determining the survival rate of cells derived from the test subject. Therefore, by performing this step (7), it is possible to confirm whether or not the complement has sufficiently acted and the degree of effectiveness of the antibody drug in the treatment.
  • a reagent for determining the viability of cells in the step (b) and an antibody drug to be administered to the test subject are labeled.
  • the operation according to the above aspect including the steps (1) to (4), except that it is added to the cell culture vessel Do the same operation.
  • This test method including the steps (a) to (c) can be applied particularly when the survival rate of the cells derived from the test subject is high.
  • a complement source for complement added in the above step (d) serum, plasma, whole blood, purified complement fluid and the like can be used.
  • Complements are fragile and must be handled while fresh. Therefore, serum or plasma is preferable from the viewpoint of easy availability and handling.
  • CDC occurs when the antibody drug is bound to the cell surface antigen by the step (c). Then, detection of the label on the cell surface after addition of complement, determination of viability of the cell, and ratio of viability of the cell are determined to determine whether the test subject has resistance to the antibody drug and complement. Whether or not the body worked effectively.
  • (X) comparing the viability ratio of cells derived from the subject to be tested and the viability ratio of cells serving as a positive control.
  • the inspection method of the present invention may further include the step of (Y) adding a foil to each compartment in the cell culture container.
  • this addition time is after step (1), or before or after step (5), more preferably immediately after step (1). After or just after step (5).
  • it is after step (a) or before or after step (d), more preferably immediately after step (a) or immediately after step (d).
  • the oil defined here is a liquid that covers the cells to be examined, cell culture fluid, various drugs, etc., and has an action of preventing evaporation. Any liquid that is immiscible with water with a specific gravity lower than water and has a low vapor pressure is acceptable. Particularly preferred are mineral oil and silicone oil.
  • the reason for including the oil addition step is that when the number of cells derived from the test subject is small in the test method of the present invention, the culture is performed in a culture compartment having a small volume (range from 11 1 to 1 ml). This is because the temperature of the culture environment may cause a problem of medium evaporation. By adding oil in an amount sufficient to cover the surface of the medium in each compartment, it is possible to prevent the medium from evaporating.
  • the specific gravity of oil is light relative to the medium and complement sources (serum, plasma, whole blood, purified complement fluid), complement may be added even if oil is added before step (5). Drops on the oil, the complement automatically passes through the oil layer and mixes with the underlying medium. Oil also does not affect optical observations.
  • the oil can be added at any stage of the process of the present invention. However, from the viewpoint of preventing the medium from evaporating, it is preferable to add it in an amount sufficient to cover the medium surface before adding the complement. In addition, when oil is added after complement is added, it is desirable to carry out immediately after complement addition from the same viewpoint.
  • the cell culture vessel may have compartments, each compartment having a diameter of 1 to 4 mm, a depth of 2 to 5 mm, and a volume of! .
  • each compartment having a diameter of 1 to 4 mm, a depth of 2 to 5 mm, and a volume of! .
  • the label can be detected optically, and the label can be detected with a microscope. More specifically, the label is a fluorescent label such as Alexa488, Cy3, y5, TRITC (tetramethylrhodamine isothiocyanate), or riTC (fluorescein isothiocyanate).
  • the examination method of the present invention can be carried out on, for example, a patient with B-cell lymphoma. In this case, it is possible to use a cell derived from a lymphoma tissue collected from the patient as a cell derived from the test subject and an anti-CD20 antibody (rituximab) as an antibody drug.
  • B-cell lymphoma is a disease that accounts for about 70% of non-Hodgkin lymphoma, and CD20 antigen is usually expressed in B cells. Therefore, it is possible to generate CDC by a combination of anti-CD20 antibody and complement, and it can be a test object of the test method of the present invention.
  • B cell lymphoma to which the test method of the present invention can be applied include precursor B lymphoblastic leukemia / lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, B cell prolymphocyte Leukemia, lymphoid plasma cell lymphoma, splenic marginal zone B cell lymphoma, hairy cell leukemia, plasma cell tumor, extranodal follicular marginal B cell lymphoma, nodal follicular marginal zone B cell lymphoma, follicular lymphoma Mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal large cell B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma.
  • Other antibody drugs include ibritumomab for B-cell lymphoma, trastuzumab for breast cancer (anti-Her2 antibody drug), and the like.
  • Lymphoma tissues collected from various lymphoma patients were chopped with scissors or a scalpel and suspended in hanks-buffer, and this suspension was further passed through a strainer to collect floating cells. Daudi cells were prepared as a positive control for cells derived from lymphoma tissue. For lymphoma-derived cells, only CD19-positive cells were isolated using magnetic beads (Non-patent Document 3).
  • Rituximab was labeled with Alexa488 according to the method of Alexa488 Monoclonal antibody labeling kit (A20 181) manufactured by Invitrogen. Labeled rituximab was used at a concentration of 10 ng / ml. PI was used as a nuclear staining dye at a concentration of S ⁇ g / ml.
  • rituximab and PI were added to the medium, and after culturing for 5 minutes, the cells were transferred to a glass bottom container or a 384 well plate for cell observation. Observe the cells in the container with an inverted microscope, and 1000 to 10,000 cells per culture compartment I did it. The container was then placed on a microscope stage held at 37 ° C. From the bottom of the container, cells were observed, photographed, fluorescent labels were detected, and the presence or absence of nuclear staining was detected. In this first observation, a fluorescent dye labeled with rituximab is detected to confirm the expression state of the CD20 antigen and the state of nuclear staining. Cells that express CD20 antigen live without staining their nuclei but only their cell membranes. Dead cells are stained with the nuclear dye PI. Therefore, a region where the cell density of living cells expressing CD20 antigen is appropriate is selected as the observation region.
  • human serum (complement source) was added at an arbitrary rate of 1-20% of the total culture compartment volume and incubated at 37 ° C for 5-30 minutes. Again, cells were observed and photographed from the bottom of the container, fluorescent labels were detected, and the presence or absence of nuclear staining was detected.
  • the viability of the cells was compared from the expression state of the CD20 antigen before and after complement addition. From the number of living cells and the number of dead cells, the ratio of CDC reaction (CDC sensitivity) was determined. The results are shown in Fig. 1. It is a figure which shows the ratio (CDC sensitivity) which the disease name and CDC reaction which were determined by the pathological examination etc. produced. Thus, it was found that there is a big difference in the sensitivity of CDC even with the same clinical name. Therefore, it became clear that the present invention is very effective for the selection of antibody drugs.
  • the antibody drug sensitivity test method of the present invention makes it possible to easily test the sensitivity of an antibody drug using a small amount of cells.

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Abstract

La présente invention concerne un procédé d'analyse simple de la sensibilité à (de la présence ou de l'absence de résistance contre) un médicament à base d'anticorps, comprenant les étapes consistant à : déterminer si une cellule provenant d'un sujet d'analyse, et éventuellement une cellule témoin positive, est vivante ou pas, à faire réagir la cellule avec un médicament à base d'anticorps marqué devant être administré au sujet et à détecter le marqueur lié à la surface de la cellule. Dans ce procédé, après la détection du marqueur, un complément peut être ajouté à la cellule.
PCT/JP2007/068723 2006-09-26 2007-09-26 procÉdÉ d'analyse de la sensibilitÉ À un mÉdicament À base d'anticorps WO2008041594A1 (fr)

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JP2008537493A JPWO2008041594A1 (ja) 2006-09-26 2007-09-26 抗体医薬感受性検査方法

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JP2006261207 2006-09-26
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Cited By (6)

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WO2010082497A1 (fr) * 2009-01-15 2010-07-22 株式会社アルバック Procédé pour mesurer la concentration systémique d'un médicament protéiné
WO2012133047A1 (fr) * 2011-03-25 2012-10-04 コニカミノルタエムジー株式会社 Procédé de coloration immunohistologique pour déterminer l'efficacité d'une préparation d'anticorps l'utilisant
JP2013525805A (ja) * 2010-05-07 2013-06-20 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト エクスビボでの細胞の検出のための診断的方法
JP2015510125A (ja) * 2012-02-10 2015-04-02 シアトル ジェネティクス，インコーポレーテッド Ｃｄ３０＋癌の検出と治療
WO2016175275A1 (fr) * 2015-04-30 2016-11-03 国立大学法人京都大学 Procédé pour prévoir l'effet thérapeutique d'un inhibiteur de pd-1/pd-l1 en utilisant une anomalie dans pd-l1(cd274) comme indice
JPWO2015004917A1 (ja) * 2013-07-10 2017-03-02 株式会社ニコン 観察方法、細胞シート製造方法、細胞シート製造装置、および細胞シート観察装置

Non-Patent Citations (3)

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MEERTEN T. ET AL.: "Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity", CLIN. CANCER RES., vol. 12, no. 13, 1 July 2006 (2006-07-01), pages 4027 - 4035 *
TERUI Y. ET AL.: "Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab", CANCER SCIENCE, vol. 97, no. 1, January 2006 (2006-01-01), pages 72 - 79, XP055032086, DOI: doi:10.1111/j.1349-7006.2006.00139.x *

Cited By (15)

* Cited by examiner, † Cited by third party
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JPWO2010082497A1 (ja) * 2009-01-15 2012-07-05 株式会社アルバック タンパク質系薬剤の体内濃度の測定方法
WO2010082497A1 (fr) * 2009-01-15 2010-07-22 株式会社アルバック Procédé pour mesurer la concentration systémique d'un médicament protéiné
JP2013525805A (ja) * 2010-05-07 2013-06-20 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト エクスビボでの細胞の検出のための診断的方法
JP5900489B2 (ja) * 2011-03-25 2016-04-06 コニカミノルタ株式会社 免疫組織染色法、およびこれを用いた抗体医薬の有効性を判定する方法
JPWO2012133047A1 (ja) * 2011-03-25 2014-07-28 コニカミノルタ株式会社 免疫組織染色法、およびこれを用いた抗体医薬の有効性を判定する方法
WO2012133047A1 (fr) * 2011-03-25 2012-10-04 コニカミノルタエムジー株式会社 Procédé de coloration immunohistologique pour déterminer l'efficacité d'une préparation d'anticorps l'utilisant
JP2015510125A (ja) * 2012-02-10 2015-04-02 シアトル ジェネティクス，インコーポレーテッド Ｃｄ３０＋癌の検出と治療
JP2018109645A (ja) * 2012-02-10 2018-07-12 シアトル ジェネティクス，インコーポレーテッド Ｃｄ３０＋癌の検出と治療
US10444241B2 (en) 2012-02-10 2019-10-15 Seattle Genetics, Inc. Detection and treatment of CD30+ cancers
JP2020122793A (ja) * 2012-02-10 2020-08-13 シアトル ジェネティクス インコーポレーテッド Ｃｄ３０＋癌の検出と治療
JP7026158B2 (ja) 2012-02-10 2022-02-25 シージェン インコーポレイテッド Ｃｄ３０＋癌の検出と治療
JP2022070958A (ja) * 2012-02-10 2022-05-13 シージェン インコーポレイテッド Ｃｄ３０＋癌の検出と治療
US11366118B2 (en) 2012-02-10 2022-06-21 Seagen Inc. Detection and treatment of CD30+ cancers
JPWO2015004917A1 (ja) * 2013-07-10 2017-03-02 株式会社ニコン 観察方法、細胞シート製造方法、細胞シート製造装置、および細胞シート観察装置
WO2016175275A1 (fr) * 2015-04-30 2016-11-03 国立大学法人京都大学 Procédé pour prévoir l'effet thérapeutique d'un inhibiteur de pd-1/pd-l1 en utilisant une anomalie dans pd-l1(cd274) comme indice

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