WO2017065000A1 - Biomarqueur destiné à prévoir un exemple aux effets remarquables d'inhibiteur de voie d'apoptose – 1 (pd-1) - Google Patents

Biomarqueur destiné à prévoir un exemple aux effets remarquables d'inhibiteur de voie d'apoptose – 1 (pd-1) Download PDF

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WO2017065000A1
WO2017065000A1 PCT/JP2016/078353 JP2016078353W WO2017065000A1 WO 2017065000 A1 WO2017065000 A1 WO 2017065000A1 JP 2016078353 W JP2016078353 W JP 2016078353W WO 2017065000 A1 WO2017065000 A1 WO 2017065000A1
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gene
antibody
registered
ovarian cancer
eef1a2
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潤三 ▲濱▼西
隆介 村上
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国立大学法人京都大学
小野薬品工業株式会社
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    • 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
    • C12N15/09—Recombinant DNA-technology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • 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
    • 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

Definitions

  • the present invention relates to a method for determining drug sensitivity to a PD-1 pathway inhibitor, a biomarker for determining drug sensitivity to a PD-1 pathway inhibitor, and a kit for determining drug sensitivity to a PD-1 pathway inhibitor.
  • PD-1 Programmed Cell Death -1
  • PD-L1 and PD-L2 are known as ligands .
  • new cancer treatments using anti-PD-1 antibodies and anti-PD-L1 antibodies that inhibit this PD-1 pathway have attracted attention, and the search for biomarkers related to their therapeutic effects has been conducted around the world. It has been broken.
  • Patent Document 1 reports that a human monoclonal antibody that specifically binds to PD-1 has been isolated.
  • PD-1 pathway inhibitors nivolumab and pembrolizumab are known as anti-PD-1 antibodies. It is considered that the immune response against cancer cells can be enhanced by inhibiting the PD-1 pathway by using such an anti-PD-1 antibody or an anti-PD-L1 antibody that binds to a ligand.
  • non-patent documents 1 to 3 report biomarkers related to PD-1 pathway inhibitors.
  • Non-Patent Document 1 it has been reported that the expression of PD-L1 by tumors is correlated to some extent with the therapeutic effect of PD-1 pathway inhibitors in many clinical trials. There are still many problems such as inconsistency of timing, sampling method, analysis method and evaluation method.
  • Non-Patent Document 2 describes that a new antigen (neoantigen) generated by mutation in a tumor becomes a target of anti-tumor T cells, and that the neoantigen may cause a strong immune response in vivo. . And it is described that the immunity against the tumor was recovered when the anti-PD-1 antibody treatment was performed on the tumor that became resistant to the immunity against the neoantigen. Thus, what is described in Non-Patent Document 2 is the relationship between neoantigen and PD-1 inhibition.
  • Non-Patent Document 3 reports that in patients with effective anti-PD-1 treatment, the number of cells expressing PD-1 and PD-L1 in the infiltrated tumor is large, and the repertoire of T cell antigen receptors is large. Yes.
  • the present invention finds a gene whose expression is increased in ovarian cancer that is sensitive to a PD-1 pathway inhibitor and provides a method for determining the sensitivity of ovarian cancer to a PD-1 pathway inhibitor using the gene With the goal.
  • Another object of the present invention is to provide a biomarker for determining drug sensitivity of ovarian cancer, and a kit for determining drug sensitivity of ovarian cancer, including the gene.
  • the present inventor conducted a phase II-initiated clinical trial using anti-PD-1 antibody drugs for 20 patients with recurrent ovarian cancer in the Department of Obstetrics and Gynecology, Kyoto University Hospital, and 15% of patients recognized tumor shrinkage, 45% of patients had a therapeutic effect (including no change). Therefore, surgical specimens (tumor tissues) were obtained from these patients, and gene expression analysis was conducted after extracting RNA from tumors. As a result, it was expressed in patients who were confirmed to be completely successful with anti-PD-1 antibody drugs. Statistically extracted genes and gene groups that increased (or decreased). From these genes, candidate genes that could function effectively as biomarkers for determining sensitivity to PD-1 pathway inhibitors were identified.
  • the present invention has been completed on the basis of these findings and has been completed.
  • (I-2) The expression level of at least one gene selected from the group consisting of DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, MMP24, SLCO4A1, UNC5A, and VNN1 is used as an index.
  • the method according to (I-1). (I-3) The method according to (I-1) or (I-2), wherein the expression level of at least one gene selected from the group consisting of EEF1A2, HNF1B, and VNN1 is used as an index.
  • (I-4) detecting the expression level of the gene, The method according to any one of (I-1) to (I-3), which is carried out by detecting mRNA of the gene or a protein encoded by the gene.
  • (I-5) The method according to any one of (I-1) to (I-4), wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody.
  • (I-6) In any one of (I-1) to (I-5), when the expression level is increased, it is determined that ovarian cancer has sensitivity to a PD-1 pathway inhibitor. The method described.
  • (I-7) For a test subject whose ovarian cancer has been determined to be sensitive to a PD-1 pathway inhibitor by the method according to any one of (I-1) to (I-6), PD A method for treating ovarian cancer comprising administering an effective amount of a -1 pathway inhibitor.
  • Biomarkers for determining the sensitivity of ovarian cancer to PD-1 pathway inhibitors (II-1) ATP7B, BAIAP2L2, DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, GRAMD3, LOC100422737, MMP24, NHSL1, PTHLH, RHOD, RNF182, SAA2, VLC1 Comprising at least one gene selected from the group consisting of: A biomarker for determining the sensitivity of ovarian cancer to PD-1 pathway inhibitors.
  • (II-2) comprises at least one gene selected from the group consisting of DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, MMP24, SLCO4A1, UNC5A, and VNN1, (II-1 ).
  • (II-3) The biomarker according to (II-1) or (II-2), comprising at least one gene selected from the group consisting of EEF1A2, HNF1B, and VNN1.
  • (II-4) The biomarker according to any one of (II-1) to (II-3), wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody.
  • Kit for determining sensitivity of ovarian cancer to PD-1 pathway inhibitors (III-1) ATP7B, BAIAP2L2, DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, GRAMD3, LOC100422737, MMP24, NHSL1, PTHLH, RHOD, RNF182, SAA2, VLC1, AVA2, SLC4A A nucleic acid that binds to at least one gene selected from the group, or an antibody or antibody fragment that binds to a protein encoded by the gene, A kit for determining the sensitivity of ovarian cancer to PD-1 pathway inhibitors.
  • (III-2) a nucleic acid that binds to at least one gene selected from the group consisting of DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, MMP24, SLCO4A1, UNC5A, and VNN1, or The kit according to (III-1), comprising an antibody or antibody fragment that binds to a protein encoded by a gene.
  • (III-3) a nucleic acid that binds to at least one gene selected from the group consisting of EEF1A2, HNF1B, and VNN1, or an antibody or antibody fragment that binds to a protein encoded by the gene (III-1) ) Or (III-2).
  • III-4) The kit according to any one of (III-1) to (III-3), wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody.
  • a gene serving as a biomarker relating to the sensitivity of ovarian cancer to a PD-1 pathway inhibitor can be found, and by using the expression level of the gene as an index, an ovary exhibiting sensitivity to a PD-1 pathway inhibitor Whether or not it is cancer can be determined.
  • the present invention makes it possible to efficiently select patients effective for the medicine.
  • a test example it is a figure which shows the result of having performed hierarchical cluster analysis by making CR into a complete successful example and making PR, SD, and PD into other cases.
  • it is a graph which shows the expression level of the EEF1A2 gene of each sample.
  • the vertical axis represents the gene expression intensity, log2 expression signal intensity (the relative amount of gene expression normalized and log2 converted in 17 samples).
  • it is a graph which shows the expression level of VNN1 gene of each sample.
  • the vertical axis represents the gene expression intensity log2 expression signal intensity.
  • it is a graph which shows the expression level of the HNF1B gene of each sample.
  • the vertical axis represents the gene expression intensity log2 expression signal intensity.
  • gene includes double-stranded DNA, single-stranded DNA (sense strand or antisense strand), and fragments thereof unless otherwise specified.
  • gene refers to a regulatory region, a coding region, an exon, and an intron without distinction unless otherwise specified.
  • nucleic acid “nucleotide” and “polynucleotide” are synonymous and include both DNA and RNA, and may be double-stranded or single-stranded.
  • RefSeq ID and UniGene ID shown below are registered on the NCBI web site.
  • some proteins represented by the following RefSeq ID include a signal sequence. In that case, the meaning of a mature protein is also included.
  • ATP7B ATPase, Cu 2+ transporting, beta polypeptide
  • NM_000053 SEQ ID NO: 1
  • NM_001005918 NM_0012431821
  • amino acid sequence is also referred to as RefSeq Accession No. NP_000044 (SEQ ID NO: 2)
  • NP_001005918 and NP_001230111 are registered.
  • ATP7B is registered as UniGene ID: Hs.492280.
  • BAIAP2L2 BAI1-associated protein 2-like ⁇ 2 gene
  • the base sequence of the BAIAP2L2 (BAI1-associated protein 2-like ⁇ 2) gene is registered as RefSeq Accession No.NM_025045 (SEQ ID NO: 3), and the amino acid sequence is also registered as RefSeq Accession No.NP_079321 (SEQ ID NO: 4).
  • BAIAP2L2 is registered as UniGene ID: Hs.474822.
  • DNAH5 (Dynein, axonemal, heavy chain 5) gene is registered as RefSeq Accession No.NM_001369 (SEQ ID NO: 5), and the amino acid sequence is also registered as RefSeq Accession No.NP_001360 (SEQ ID NO: 6). Yes.
  • DNAH5 is registered as UniGene ID: Hs.212360.
  • DUX2 Double homeobox 2
  • NM_012147 SEQ ID NO: 7
  • amino acid sequence is also registered as RefSeq Accession No. NP_036279 (SEQ ID NO: 8).
  • DUX2 is registered as UniGene ID: Hs.729867.
  • DUX4 Double homeobox 4
  • the base sequence of the DUX4 (Double homeobox 4) gene is registered as RefSeq Accession No.NM_033178 (SEQ ID NO: 9), and the amino acid sequence is also registered as RefSeq Accession No.NP_149418 (SEQ ID NO: 10). Further, DUX4 is registered as UniGene ID: Hs.553518.
  • DUX4L2 Double homeobox 4 like 2 gene is registered as RefSeq Accession No.NM_001127386 (sequence number 11), and the amino acid sequence is also registered as RefSeq Accession No.NP_001120858 (sequence number 12).
  • DUX4L2 is registered as UniGene ID: Hs.714689.
  • DUX4L4 Double homeobox 4 like 4
  • NM_001177376 SEQ ID NO: 13
  • amino acid sequence is also registered as RefSeq Accession No. NP_001170847 (SEQ ID NO: 14).
  • DUX4L4 is registered as UniGene ID: Hs.725918.
  • EEF1A2 Eukaryotic translation elongation factor 1 alpha 2 gene
  • RefSeq Accession No.NM_001958 SEQ ID NO: 15
  • amino acid sequence is also registered as RefSeq Accession No.NP_001949 (SEQ ID NO: 16) Yes.
  • EEF1A2 is registered as UniGene ID: Hs.433839.
  • EPHA7 EPH receptorceptA7
  • NM_004440 SEQ ID NO: 17
  • amino acid sequence is also registered as RefSeq Accession No. NP_004431 (SEQ ID NO: 18).
  • EPHA7 is registered as UniGene ID: Hs.73962.
  • HNF1B HNF1 homeobox B gene
  • RefSeq Accession No.NM_000458 SEQ ID NO: 19
  • NM_001165923 The base sequence of HNF1B (HNF1 homeobox B) gene
  • amino acid sequence is also registered as RefSeq Accession No.NP_000449 (SEQ ID NO: 20) and NP_001159395 Yes.
  • HNF1B is registered as UniGene ID: sHs.191144.
  • IL12RB2 Interleukin 12 receptor, beta 2
  • RefSeq Accession No. The nucleotide sequence of the IL12RB2 (Interleukin 12 receptor, beta 2) gene is registered as RefSeq Accession No. ), NP_001245143, NP_001245144, and NP_001245145.
  • IL12RB2 is registered as UniGene ID: Hs.479347.
  • GRAMD3 GRAM domain containing 3
  • RefSeq Accession No. The base sequence of the GRAMD3 (GRAM domain containing 3) gene is registered as RefSeq Accession No. ), NP_001139792, NP_001139793, NP_001139794, and NP_0076416.
  • GRAMD3 is registered as UniGene ID: Hs.363558.
  • LOC100422737 The base sequence (long non-coding RNA) of the LOC100422737 gene is registered as RefSeq Accession No.NR_033557 (SEQ ID NO: 25). LOC100422737 is registered as UniGene ID: Hs.634681.
  • MMP24 (Matrix metallopeptidase 24 (membrane-inserted)) gene is registered as RefSeq Accession No.NM_006690 (SEQ ID NO: 26), and the amino acid sequence is also registered as RefSeq Accession No.NP_006681 (SEQ ID NO: 27). ing. MMP24 is registered as UniGene ID: Hs.715494.
  • NHSL1 (NHS-like 1) gene
  • NM_020464 SEQ ID NO: 28
  • NM_001144060 amino acid sequence
  • amino acid sequence is also registered as RefSeq Accession No.NP_065197 (SEQ ID NO: 29) and NP_001137532 ing.
  • NHSL1 is registered as UniGene ID: Hs.652741.
  • PTHLH thyroid hormone-like hormone
  • NM_198965 SEQ ID NO: 30
  • NM_002820 NM_198964, NM_198966
  • amino acid sequence is also RefSeq Accession No. NP_945316 (SEQ ID NO: 31)
  • NP_002811 NP_945315
  • NP_945317 NP_945317
  • RHOD Ras homolog family member D
  • NM_014578 SEQ ID NO: 32
  • amino acid sequence is also registered as RefSeq Accession No.NP_055393 (SEQ ID NO: 33).
  • RHOD is registered as UniGene ID: sHs.15114.
  • RNF182 Ring finger protein 182
  • NM_152737 SEQ ID NO: 34
  • NM_001165034 NM_001165033
  • NM_001165032 amino acid sequence
  • NP_689950 SEQ ID NO: 35
  • the RNF 182 is registered as UniGene ID: Hs.111164.
  • SAA2 Sem amyloid A2
  • NM_030754 SEQ ID NO: 36
  • NM_001127380 amino acid sequence is also registered as RefSeq Accession No.NP_110381 (SEQ ID NO: 37) and NP_001120852 Yes.
  • SAA2 is registered as UniGene ID: Hs.731376.
  • SLCO4A1 Solute carrier organic anion transporter family, member 4A1
  • SLCO4A1 Solute carrier organic anion transporter family, member 4A1
  • NM_016354 SEQ ID NO: 38
  • amino acid sequence is also registered as RefSeq Accession No.NP_057438 (SEQ ID NO: 39) Has been.
  • SLCO4A1 is registered as UniGene ID: Hs.235782.
  • UNC5A Unc-5 netrin receptor A gene is registered as RefSeq Accession No.NM_133369 (SEQ ID NO: 40), and the amino acid sequence is also registered as RefSeq Accession No.NP_588610 (SEQ ID NO: 41). ing. UNC5A is registered as UniGene ID: Hs.33191.
  • VNN1 (Vanin 1) gene is registered as RefSeq Accession No. NM_004666 ⁇ ⁇ (SEQ ID NO: 42), and the amino acid sequence is also registered as RefSeq Accession No. NP_004657 (SEQ ID NO: 43). Also, VNN1 is registered as UniGene ID: sHs.12114.
  • the above genes include degenerate products and mutants other than those having the nucleotide sequences registered in the database as described above. What encodes a protein having a biological activity equivalent to that of the protein comprising the above amino acid sequence is desirable. Examples of proteins having equivalent biological activity include proteins derived from other organisms.
  • mutants examples include (a) 1 or 2 or more, for example, 1-50, 1-25, 1-12, 1-9, in the amino acid sequence registered in the database as described above.
  • the identity of the base sequence can be calculated using an analysis tool that is commercially available or available through a telecommunication line (Internet).
  • the base sequence identity (%) can be determined using a program commonly used in the art (for example, BLAST, FASTA, etc.) by default. *
  • a method for determining the sensitivity of PD-1 pathway inhibitor to ovarian cancer in a test subject of the present invention is ATP7B in a biological sample collected from the subject.
  • the gene is preferably at least one gene selected from the group consisting of DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, MMP24, SLCO4A1, UNC5A, and VNN1, and more preferably Is at least one gene selected from the group consisting of EEF1A2, HNF1B, and VNN1.
  • the method of the present invention does not exclude the use of the expression level of genes other than the above in addition to the above genes, and determines the sensitivity of the expression levels of genes other than the above to PD-1 pathway inhibitors. Can be used.
  • the test subject in the present invention is a mammal (human, mouse, rat, monkey, dog, cat, rabbit, pig, horse, cow, etc.) suffering from ovarian cancer, preferably a human, particularly a human female.
  • Biological samples include cells, tissues (biopsy samples, specimens removed by surgery, tissue specimens, etc.), body fluids (blood, plasma, serum, lymph, saliva, urine, spinal fluid, etc.), feces, etc.
  • tumor cells or tissues particularly ovarian cancer cells or tissues.
  • the type of ovarian cancer is not particularly limited, and can be applied to any tissue type such as mucinous adenocarcinoma, clear cell adenocarcinoma, endometrioid adenocarcinoma, serous adenocarcinoma and the like.
  • any drug that can inhibit the PD-1 pathway can be used without particular limitation.
  • the PD-1 pathway inhibitor in the present invention those used particularly for humans are desirable.
  • PD-1 pathway inhibitors can inhibit immune suppression against cancer cells by inhibiting the PD-1 pathway, and are thought to be able to enhance immune responses against cancer cells.
  • Examples of PD-1 pathway inhibitors include drugs that inhibit the binding of PD-L1 and / or PD-L2 to PD-1.
  • examples of such agents include compounds (eg, antibodies) that bind to PD-L1, PD-L2, or PD-1.
  • the PD-1 pathway inhibitor in the present invention is preferably an anti-PD-1 antibody.
  • Nivolumab and pembrolizumab are known as such anti-PD-1 antibodies.
  • the antibody may be a monoclonal antibody or a polyclonal antibody, or may be a humanized chimeric antibody.
  • Antibody isotypes include IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, etc., but any may be used without limitation.
  • the antibody may also be an antibody fragment, and examples of such an antibody fragment include Fab, Fab ′, F (ab ′) 2 , Fv, scFv and the like.
  • a method for detecting the expression level of a gene it may be performed by detecting mRNA of the gene or a protein encoded by the gene. Extraction of mRNA or protein from a biological sample can be performed according to a conventional method.
  • the method for detecting mRNA is not particularly limited as long as it is a method capable of quantifying mRNA.
  • the detection method include a DNA chip (or microarray) method, a realtime PCR method, a northern blot method, and the like.
  • the method for detecting mRNA here also includes detecting cDNA corresponding to mRNA.
  • the method for detecting the protein is not particularly limited as long as it can quantitate the protein.
  • Examples of the detection method include immunohistochemical staining, immune cell staining, flow cytometry, protein chip, ELISA method, Western blotting analysis method, and the like.
  • the ovarian cancer to be tested has sensitivity to a PD-1 pathway inhibitor using the expression level of the gene as an index.
  • the expression level of the gene is higher than a preset cutoff value
  • the cut-off value can be appropriately set by those skilled in the art. For example, the average or median expression level of the gene in ovarian cancer cells or tissues that are not sensitive to PD-1 pathway inhibitors. The value can be significantly higher than that. Further, the cut-off value can be a standardized value from data obtained in the past.
  • the expression level of the gene is preferably 10% or more, more preferably 50%, compared to the expression level of a biological sample in a test subject in which ovarian cancer is not sensitive to a PD-1 pathway inhibitor. %, More preferably 100% or more, particularly preferably 200% or more, it can be determined that the subject ovarian cancer is sensitive to PD-1 pathway inhibitors.
  • the expression level as described above is increased in two or more genes.
  • the ovarian cancer to be tested is also a PD- when the expression profile of a plurality of sets of genes includes characteristics when the ovarian cancer has sensitivity to a PD-1 pathway inhibitor. It can be determined to have sensitivity to a single pathway inhibitor.
  • the expression level of the gene set is scored, and when the score is higher than a preset cutoff value, it is determined that the ovarian cancer to be tested has sensitivity to the PD-1 pathway inhibitor.
  • a technique for scoring the expression level of a gene set is well known.
  • the ssGSEA single-sample-gene-set-enrichment-analysis
  • the above cut-off value can be appropriately set by those skilled in the art. For example, the average value or the center of the score obtained from the expression level of ovarian cancer cells or tissues that are not sensitive to PD-1 pathway inhibitors. The value can be significantly higher than the value. Further, the cut-off value can be a standardized value from data obtained in the past.
  • the method for determining sensitivity according to the present invention includes the meaning of a method for predicting a therapeutic effect.
  • the therapeutic effect expected when it is determined that sensitivity is high may be any of complete response (CR), partial response (PR) and unchanged (SD), but preferably complete response (CR) ).
  • a therapeutic effect on ovarian cancer is considered to be high, and thus a PD-1 pathway inhibitor is administered to a test subject. Therefore, it is desirable to treat ovarian cancer.
  • the administration method of the PD-1 pathway inhibitor is not particularly limited, and can be performed by, for example, intraarterial administration, intravenous administration, buccal administration, rectal administration, enteral administration, transdermal administration, oral administration, and the like.
  • PD-1 pathway inhibitors can be used as active ingredients as they are or in combination with non-toxic carriers, diluents or excipients that are acceptable in pharmaceuticals, tablets (plain tablets, dragees, effervescent tablets, film-coated tablets, chewable tablets). Tablets, troches, etc.), capsules, pills, powders (powder), fine granules, granules, solutions, suspensions, emulsions, syrups, pastes, injections (when used, distilled water Or, it is prepared and used in a form such as amino acid infusion, electrolyte infusion and the like, which is prepared as a liquid preparation.
  • non-toxic carriers diluents or excipients that are acceptable in pharmaceuticals, tablets (plain tablets, dragees, effervescent tablets, film-coated tablets, chewable tablets). Tablets, troches, etc.), capsules, pills, powders (powder), fine granules, granules, solutions, suspension
  • the content of the active ingredient in the PD-1 pathway inhibitor administered to the test subject is appropriately within the range of 0.0001 to 100% by weight, preferably 0.001 to 99.9% by weight, more preferably 0.01 to 99% by weight, based on the total amount of the pharmaceutical preparation. It is possible to select.
  • the dose of the PD-1 pathway inhibitor can be appropriately determined according to various conditions such as the patient's weight, age, sex, and symptoms. *
  • Biomarkers for determining the sensitivity of ovarian cancer to PD-1 pathway inhibitors of the present invention include ATP7B, BAIAP2L2, DNAH5, DUX2, DUX4, DUX4L2, Characterized in that it comprises at least one gene selected from the group consisting of DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, GRAMD3, LOC100422737, MMP24, NHSL1, PTHLH, RHOD, RNF182, SAA2, SLCO4A1, UNC5A, and VNN1 To do.
  • the expression level of the gene as an indicator, it can be determined whether or not the ovarian cancer is sensitive to a PD-1 pathway inhibitor. It can be a biomarker for sensitivity determination.
  • Ovarian cancer Ovarian cancer, PD-1 pathway inhibitors, sensitivity determination methods, etc. are the same as those described above.
  • Kit for determining sensitivity to PD-1 pathway inhibitor of ovarian cancer of the present invention is ATP7B, BAIAP2L2, DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, Nucleic acid that binds to at least one gene selected from the group consisting of EPHA7, HNF1B, IL12RB2, GRAMD3, LOC100422737, MMP24, NHSL1, PTHLH, RHOD, RNF182, SAA2, SLCO4A1, UNC5A, and VNN1, or codes to the gene It comprises an antibody or antibody fragment that binds to the protein to be produced.
  • the nucleic acid that binds to the gene is a polynucleotide that can hybridize to the gene, for example, by detecting mRNA by using it in a DNA chip (or microarray) method, realtime PCR method, Northern blot method, The expression level of the gene can be detected.
  • the antibody or antibody fragment that binds to the protein is mainly intended to be an antibody that specifically binds to the protein.
  • the antibody or antibody fragment can be obtained according to a known method.
  • the antibody may be either a monoclonal antibody or a polyclonal antibody, or may be a humanized chimeric antibody.
  • Antibody isotypes include IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, etc., but any can be used without limitation.
  • Examples of antibody fragments include Fab, Fab ′, F (ab ′) 2 , Fv, scFv, and the like, and the antibody or antibody fragment may be modified with a fluorescent dye or the like.
  • the antibody or antibody fragment is used for immunohistochemical staining, immune cell staining, flow cytometry, protein chip, ELISA, Western blotting analysis, etc. to detect the protein and detect the expression level of the gene be able to.
  • the expression level of the gene in the biological sample of the test control is detected in the same manner as described above, and the ovarian cancer is expressed in PD- It can be determined whether or not there is sensitivity to a single pathway inhibitor.
  • kit of the present invention may contain other than the above if necessary.
  • examples of such a product include a positive control, a negative control, and an instruction describing a method for detecting the gene using the kit of the present invention.
  • Ovarian cancer Ovarian cancer, PD-1 pathway inhibitors, sensitivity determination methods, etc. are the same as those described above.
  • the expression level of a gene serving as a biomarker for susceptibility to PD-1 pathway inhibitors (especially anti-PD-1 antibodies) of ovarian cancer is used as an index to show sensitivity to PD-1 pathway inhibitors. It becomes possible to determine whether or not the cancer is ovarian cancer. This makes it possible to efficiently select patients effective for PD-1 pathway inhibitors (particularly, anti-PD-1 antibodies) (patients that exhibit significant effects).
  • Test example ⁇ subject> Approved by the Ethics Committee out of 20 patients who underwent an anti-PD-1 antibody (nivolumab) test for platinum-resistant recurrent / advanced ovarian cancer at the Department of Obstetrics and Gynecology, Kyoto University Hospital After obtaining consent from patients or their families, 17 subjects who were able to evaluate the following comprehensive gene expression analysis (microarray analysis) were included.
  • an anti-PD-1 antibody nivolumab
  • expression analysis using GeneChip (registered trademark) Human Transcriptome Array 2.0 was performed using the labeled DNA, and GeneChip (registered trademark) Scanner 3000 system (Affymetrix, Part No. 00-0218), the microarray was scanned to obtain microarray data.
  • microarray data was subjected to Signal ⁇ ⁇ ⁇ Space Transformation-Robust multi-array Average (SST-RMA) normalization by Expression Conver 1.4.1 (Affymetrix) and analyzed at the gene level.
  • SST-RMA Signal ⁇ ⁇ ⁇ Space Transformation-Robust multi-array Average
  • genes involved in gene mutation and cell proliferation and particularly contributed to sensitivity were three genes, EEF1A2, VNN1 and HNF1B (FIGS. 2 to 4).

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Abstract

L'invention concerne un procédé qui indique un niveau d'expression d'au moins une sorte de gène choisi dans un groupe constitué de ATP7B, BAIAP2L2, DNAH5, DUX2, DUX4, DUX4L2, DUX4L4, EEF1A2, EPHA7, HNF1B, IL12RB2, GRAMD3, LOC100422737, MMP24, NHSL1, PTHLH, RHOD, RNF182, SAA2, SLCO4A1, UNC5A et VNN1, dans un échantillon biologique prélevé sur un sujet, et qui est destiné à juger la sensibilité vis-à-vis d'un inhibiteur de voie d'apoptose – 1 de cancer de l'ovaire chez le sujet. L'invention concerne également un biomarqueur ainsi qu'un kit pour juger la sensibilité vis-à-vis d'un inhibiteur de voie d'apoptose – 1 de cancer de l'ovaire.
PCT/JP2016/078353 2015-10-15 2016-09-27 Biomarqueur destiné à prévoir un exemple aux effets remarquables d'inhibiteur de voie d'apoptose – 1 (pd-1) WO2017065000A1 (fr)

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WO2021053152A1 (fr) * 2019-09-18 2021-03-25 Universiteit Hasselt Méthode et moyen de diagnostic de la spondylarthrite
WO2024096042A1 (fr) * 2022-11-04 2024-05-10 学校法人大阪医科薬科大学 PROCÉDÉ DE MESURE DE LA QUANTITÉ DE PROTÉINE Vanin-1 DANS UN ÉCHANTILLON AU MOYEN D'UNE IMMUNOCHROMATOGRAPHIE ET D'UN TESTEUR

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018097166A1 (fr) * 2016-11-24 2018-05-31 第一三共株式会社 Procédé permettant de prédire la sensibilité d'un cancer à un traitement avec un inhibiteur de point de contrôle immunitaire pd-1
WO2021053152A1 (fr) * 2019-09-18 2021-03-25 Universiteit Hasselt Méthode et moyen de diagnostic de la spondylarthrite
WO2024096042A1 (fr) * 2022-11-04 2024-05-10 学校法人大阪医科薬科大学 PROCÉDÉ DE MESURE DE LA QUANTITÉ DE PROTÉINE Vanin-1 DANS UN ÉCHANTILLON AU MOYEN D'UNE IMMUNOCHROMATOGRAPHIE ET D'UN TESTEUR

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