US20090203538A1 - Method of classifying antibody, method of identifying antigen, method of obtaining antibody or antibody set, method of constructing antibody panel and antibody or antibody set and use of the same - Google Patents

Method of classifying antibody, method of identifying antigen, method of obtaining antibody or antibody set, method of constructing antibody panel and antibody or antibody set and use of the same Download PDF

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US20090203538A1
US20090203538A1 US12/318,829 US31882909A US2009203538A1 US 20090203538 A1 US20090203538 A1 US 20090203538A1 US 31882909 A US31882909 A US 31882909A US 2009203538 A1 US2009203538 A1 US 2009203538A1
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Prior art keywords
antibody
seq
antibodies
reactivity
cdr3
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Inventor
Atsushi Sugioka
Mototaka Sugiura
Yasushi Akahori
Nobuhiro Hayashi
Akihiko Takasaki
Miwa Morita
Gene Kurosawa
Mariko Sumitomo
Susumu Tsutsumi
Keiko Ogawa
Kazuki Matsuda
Chiho Muramatsu
Noriko Satou
Masachika Azuma
Yoshinori Ukai
Kazuhiro Suzuki
Yoshikazu Kurosawa
Miho Tanaka
Mamoru Shiraishi
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INSTITUTE OF ANTIBODIES Co Ltd
Fujita Health University
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Institute for Antibodies Co Ltd
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Assigned to INSTITUTE FOR ANTIBODIES CO., LTD. reassignment INSTITUTE FOR ANTIBODIES CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KUROSAWA, GENE, SUGIOKA, ATSUSHI, MATSUDA, KAZUKI, MORITA, MIWA, UKAI, YOSHINORI, TSUTSUMI, SUSUMU, AKAHORI, YASUSHI, AZUMA, MASACHIKA, KUROSAWA, YOSHIKAZU, MURAMATSU, CHIHO, OGAWA, KEIKO, SATOU, NORIKO, SHIRAISHI, MAMORU, SUGIURA, MOTOTAKA, SUMITOMO, MARIKO, SUZUKI, KAZUHIRO, TANAKA, MIHO, HAYASHI, NOBUHIRO, TAKASAKI, AKIHIKO
Publication of US20090203538A1 publication Critical patent/US20090203538A1/en
Assigned to INSTITUTE OF ANTIBODIES CO., LTD. reassignment INSTITUTE OF ANTIBODIES CO., LTD. CHANGE OF ASSIGNEE'S ADDRESS Assignors: INSTITUTE OF ANTIBODIES CO., LTD.
Assigned to FUJITA HEALTH UNIVERSITY reassignment FUJITA HEALTH UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INSTITUTE FOR ANTIBODIES CO., LTD
Priority to US14/265,416 priority Critical patent/US9388249B2/en
Abandoned legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/005—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies constructed by phage libraries
    • 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
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C07K16/303—Liver or Pancreas
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • 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
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present invention relates to a method of classifying a plurality of antibodies, a method of identifying antigen, a panel displaying characteristics of an antibody, and the like, as well as an antibody related to a disease and a use thereof.
  • Non-patent document 1 Success of Herceptin to breast cancer (see, non-patent document 1) and Rituxan (non-patent document 2) to malignant lymphoma B shows that an antibody is effective as a therapeutic agent to a cancer.
  • Certain antibodies exhibit an ADCC effect (non-patent document 3) and/or a CDC effect (non-patent document 4) by forming a complex with an antigen molecule existing on the cell membrane and the effects kill a target cell (cell expressing an antigen).
  • the ADCC effect or the CDC effect may cause apoptosis.
  • Such an effect of an antibody is specific to an antigen. That is to say, an antibody acts on cells expressing an antigen which the antibody recognizes regardless of whether the cells are cancer cells or normal cells.
  • Patent document 1 WO01/062907
  • Patent document 2 WO2001/096401
  • Patent document 3 Japanese Patent Unexamined Publication No. 2005-185281
  • Mass R et al.: The Concordance Between the Clinical Trials Assay (CTA) and Fluorescence in Situ Hybridization (FISH) in the Herceptin Pivotal Trials.: Proc Am Soci Clin Oncol 19, 75a, 2000
  • Non-patent document 2 Berinstein N L, Grillo-Lopez A J, White C A, Bence-Bruckler I, Maloney D, Czuczman M, et al.
  • the comprehensively obtained antibodies may include unnecessary antibodies from the viewpoint that they do not have sufficient affinity and reactivity, or they have substantially the same as the other antibodies. Therefore, method for efficiently screening useful antibodies has been demanded.
  • the comprehensively obtained antibodies may include antibodies such as candidates of diagnostic agents and therapeutic agents, which are extremely important from the medical viewpoint.
  • the present invention aims at the effective use of comprehensively obtained antibodies to cell surface antigens in medical fields and research fields, and has an object to provide a useful method therefor. That is to say, the present invention has an object to provide a method of classifying a plurality of antibodies to cell surface antigens rapidly. Also, the present invention has another object to provide a method of rapidly identifying an antigen for the antibody. Furthermore, the present invention has a further object to provide a method of promoting to use useful information obtained by such methods. The present invention has a yet further object to provide an antibody effective for treatment and diagnosis of cancers.
  • the present inventors carry out an analysis of an antibody by the following approach: preparing cell lines that are expected to express cell surface antigens for the obtained antibodies; allowing each antibody to react with the cell lines; and carrying out the flow cytometry analysis.
  • the present inventors focus on the histogram of the results of the flow cytometry analysis and classify the antibodies based on the similarity so as to obtain a plurality of antibodies groups. Then, it is confirmed that antigens to antibodies belonging to the same antibody group are common. This fact means that it is possible to determine antigens for all antibodies by selecting the respective antibody in each antibody group and identifying the antigen of the representative antibody. Thus, the present inventors have succeeded in finding a method for identifying antigens comprehensively and rapidly. On the other hand, the present inventors carry out classification of antibodies and identification of an antigen according to the above-mentioned technique and consider the reactivity between each antibody group and clinical samples so as to search for clinically applicable antibodies. As a result, the present inventors have succeeded in finding a novel antibody specific to certain kinds of cancers. Furthermore, they have reached the findings that information obtained by using a clinical sample (relationship between the antibody and disease) is extremely useful for establishing methods for diagnosis and treatment.
  • the present invention provides, for example, a method of classifying antibody, and the like, mentioned below based on the above-mentioned results and findings.
  • a method of classifying antibody including the following steps:
  • step (3) analyzing each cell after step (2) by flow cytometry so as to obtain data showing reactivity between the antibody and the cell surface;
  • [2] The method of classifying antibody according to [1], wherein the cell surface antigen is an intact cell surface antigen.
  • the classifying method according to [1], wherein the plurality of antibodies recognize cell surface antigen are composed of an assembly of antibodies derived from antibody clones selected as being capable of recognizing a cell surface antigen, from an antibody library.
  • the antibody library is a phage antibody library.
  • the classifying method according to [1] wherein the antibody is an antibody to which a label material is bound or fused.
  • step (v) selecting an antibody corresponding to the combination specified in the step (iv) in terms of all parameters among the antibodies subjected to step (i);
  • step (v-1) newly associating the classified antibodies selected in step (v) with a combination of n pieces of parameters in a same manner as in the step (i);
  • step (3) analyzing each cell after step (2) by flow cytometry so as to obtain data showing the reactivity between the antibody and the cell surface;
  • a method of obtaining an antibody having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a method of obtaining an antibody set having a relationship with respect to a certain disease comprising the following steps:
  • a production method of a panel displaying a relationship between an antibody and a disease comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a production method of a panel displaying a relationship between an antibody and a disease comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a production method of a panel displaying a relationship between an antibody and a pathologic condition comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a production method of a panel displaying a relationship between an antibody and a disease comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a production method of a panel displaying a relationship between an antibody and a disease comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a production method of a panel displaying a relationship between an antibody and a pathologic condition comprising the following steps:
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a method of testing a disease in which a cell surface antigen is an indicator comprising the following steps:
  • a method of selecting an optimum treatment method for a certain disease comprising the following steps:
  • the effective antibody is an antibody showing a specific reactivity in the step (2) or an antibody equivalent thereto.
  • the certain disease is a disease in which a cell surface antigen selected from the group consisting of HER1, HER2, CD46, ITGA3, ICAM1, ALCAM, CD147, IgSF4, BCAM, C1qR, CD44, CD73, LAR, EpCAM and HGFR is an indicator.
  • An isolated antibody having affinity to HER1, comprising:
  • a heavy chain variable region CDR3 and a light chain variable region CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3 and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (1) to (3);
  • heavy chain variable regions CDR2 and CDR3 and light chain variable regions CDR2 and CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (4) to (6);
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (7) to (9) and (13) to (18); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (10) to (12) and (19) to (24);
  • SEQ ID NO: 492 VH CDR1
  • SEQ ID NO: 493 VH CDR2
  • SEQ ID NO: 494 VH CDR3
  • SEQ ID NO: 496 VL CDR1
  • SEQ ID NO: 497 VL CDR2
  • SEQ ID NO: 498 VL CDR3
  • SEQ ID NO: 500 (VH CDR1), SEQ ID NO: 501 (VH CDR2), SEQ ID NO: 502 (VH CDR3), SEQ ID NO: 504 (VL CDR1), SEQ ID NO: 505 (VL CDR2), and SEQ ID NO: 506 (VL CDR3)
  • SEQ ID NO: 508 (VH CDR1), SEQ ID NO: 509 (VH CDR2), SEQ ID NO: 510 (VH CDR3), SEQ ID NO: 512 (VL CDR1), SEQ ID NO: 513 (VL CDR2), and SEQ ID NO: 514 (VL CDR3)
  • SEQ ID NO: 516 (VH CDR1), SEQ ID NO: 517 (VH CDR2), SEQ ID NO: 518 (VH CDR3), SEQ ID NO: 520 (VL CDR1), SEQ ID NO: 521 (VL CDR2), and SEQ ID NO: 522 (VL CDR3)
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (3) and (5) to (19); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (4) and (20) to (34);
  • SEQ ID NO: 556 (VH CDR1), SEQ ID NO: 557 (VH CDR2), SEQ ID NO: 558 (VH CDR3), SEQ ID NO: 560 (VL CDR1), SEQ ID NO: 561 (VL CDR2), and SEQ ID NO: 562 (VL CDR3)
  • SEQ ID NO: 604 (VH CDR1), SEQ ID NO: 605 (VH CDR2), SEQ ID NO: 606 (VH CDR3), SEQ ID NO:608 (VL CDR1), SEQ ID NO:609 (VL CDR2), and SEQ ID NO: 610 (VL CDR3)
  • SEQ ID NO: 612 VH CDR1
  • SEQ ID NO: 613 VH CDR2
  • SEQ ID NO: 614 VH CDR3
  • SEQ ID NO: 616 VL CDR1
  • SEQ ID NO: 617 VL CDR2
  • SEQ ID NO: 618 VL CDR3
  • SEQ ID NO: 620 (VH CDR1), SEQ ID NO: 621 (VH CDR2), SEQ ID NO: 622 (VH CDR3), SEQ ID NO: 624 (VL CDR1), SEQ ID NO: 625 (VL CDR2), and SEQ ID NO: 626 (VL CDR3)
  • SEQ ID NO: 628 (VH CDR1), SEQ ID NO: 629 (VH CDR2), SEQ ID NO: 630 (VH CDR3), SEQ ID NO: 632 (VL CDR1), SEQ ID NO: 633 (VL CDR2), and SEQ ID NO: 634 (VL CDR3)
  • SEQ ID NO: 636 (VH CDR1), SEQ ID NO: 637 (VH CDR2), SEQ ID NO: 638 (VH CDR3), SEQ ID NO: 640 (VL CDR1), SEQ ID NO: 641 (VL CDR2), and SEQ ID NO: 642 (VL CDR3)
  • SEQ ID NO: 644 VH CDR1
  • SEQ ID NO: 645 VH CDR2
  • SEQ ID NO: 646 VH CDR3
  • SEQ ID NO: 648 VL CDR1
  • SEQ ID NO: 649 VL CDR2
  • SEQ ID NO: 650 VL CDR3
  • An isolated antibody having affinity to CD46 antigen comprising:
  • a heavy chain variable region CDR3 and a light chain variable region CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3 and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (1) to (7);
  • heavy chain variable regions CDR2 and CDR3 and light chain variable regions CDR2 and CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (8) to (14);
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (15) to (22); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (23) to (30);
  • SEQ ID NO: 59 SEQ ID NO: 60, SEQ ID NO: 63, and SEQ ID NO: 64
  • SEQ ID NO: 34 SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40
  • SEQ ID NO: 42 SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 47, and SEQ ID NO: 48
  • SEQ ID NO: 50 SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56
  • SEQ ID NO: 58 SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 63, and SEQ ID NO: 64
  • SEQ ID NO: 756 (VH CDR1), SEQ ID NO: 757 (VH CDR2), SEQ ID NO: 758 (VH CDR3), SEQ ID NO: 760 (VL CDR1), SEQ ID NO: 761 (VL CDR2), and SEQ ID NO: 762 (VL CDR3)
  • An isolated antibody having affinity to ITAG3, comprising:
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (3) and (5) to (16); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (4) and (17) to (28);
  • SEQ ID NO: 700 (VH CDR1), SEQ ID NO: 701 (VH CDR2), SEQ ID NO: 702 (VH CDR3), SEQ ID NO: 704 (VL CDR1), SEQ ID NO: 705 (VL CDR2), and SEQ ID NO: 706 (VL CDR3)
  • SEQ ID NO: 708 VH CDR1
  • SEQ ID NO: 709 VH CDR2
  • SEQ ID NO: 710 VH CDR3
  • SEQ ID NO: 712 VL CDR1
  • SEQ ID NO: 713 VL CDR2
  • SEQ ID NO: 714 VL CDR3
  • SEQ ID NO: 732 (VH CDR1), SEQ ID NO: 733 (VH CDR2), SEQ ID NO: 734 (VH CDR3), SEQ ID NO: 736 (VL CDR1), SEQ ID NO: 737 (VL CDR2), and SEQ ID NO: 738 (VL CDR3)
  • SEQ ID NO: 740 VH CDR1
  • SEQ ID NO: 741 VH CDR2
  • SEQ ID NO: 742 VH CDR3
  • SEQ ID NO: 744 VL CDR1
  • SEQ ID NO: 745 VL CDR2
  • SEQ ID NO: 746 VL CDR3
  • SEQ ID NO: 764 (VH CDR1), SEQ ID NO: 765 (VH CDR2), SEQ ID NO: 766 (VH CDR3), SEQ ID NO: 768 (VL CDR1), SEQ ID NO: 769 (VL CDR2), and SEQ ID NO: 770 (VL CDR3)
  • SEQ ID NO: 772 (VH CDR1), SEQ ID NO: 773 (VH CDR2), SEQ ID NO: 774 (VH CDR3), SEQ ID NO: 776 (VL CDR1), SEQ ID NO: 777 (VL CDR2), and SEQ ID NO: 778 (VL CDR3)
  • An isolated antibody having affinity to ICAM1, comprising:
  • a heavy chain variable region CDR3 and a light chain variable region CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3 and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (1) to (5);
  • heavy chain variable regions CDR2 and CDR3 and light chain variable regions CDR2 and CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (6) to (10);
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (11) to (15); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (16) to (20);
  • SEQ ID NO: 106 SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 111, and SEQ ID NO: 112
  • SEQ ID NO: 130 SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 135, and SEQ ID NO: 136
  • An isolated antibody having affinity to ALCAM comprising:
  • a heavy chain variable region CDR3 and a light chain variable region CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3 and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (1) to (5);
  • heavy chain variable regions CDR2 and CDR3 and light chain variable regions CDR2 and CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (6) to (10);
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (11) to (15) and (21) to (28); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (16) to (20) and (29) to (36);
  • SEQ ID NO: 138 SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 143, and SEQ ID NO: 144
  • SEQ ID NO: 162 SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 166, SEQ ID NO: 167, and SEQ ID NO: 168
  • SEQ ID NO: 170 SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 175, and SEQ ID NO: 176
  • SEQ ID NO: 804 VH CDR1
  • SEQ ID NO: 805 VH CDR2
  • SEQ ID NO: 806 VH CDR3
  • SEQ ID NO: 808 VL CDR1
  • SEQ ID NO: 809 VL CDR2
  • SEQ ID NO: 810 VL CDR3
  • SEQ ID NO: 828 VH CDR1
  • SEQ ID NO: 829 VH CDR2
  • SEQ ID NO: 830 VH CDR3
  • SEQ ID NO: 832 VL CDR1
  • SEQ ID NO: 833 VL CDR2
  • SEQ ID NO: 834 VL CDR3
  • SEQ ID NO: 836 (VH CDR1), SEQ ID NO: 837 (VH CDR2), SEQ ID NO: 838 (VH CDR3), SEQ ID NO: 840 (VL CDR1), SEQ ID NO: 841 (VL CDR2), and SEQ ID NO: 842 (VL CDR3)
  • An isolated antibody having affinity to CD147 antigen comprising:
  • CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) shown in the following (3); or
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) shown in the following (1); or
  • VH CDR1 SEQ ID NO: 453 (VH CDR2), SEQ ID NO: 454 (VH CDR3), SEQ ID NO: (VL CDR1) 456, SEQ ID NO: 457 (VL CDR2), and SEQ ID NO: 458 (VL CDR3), and
  • An isolated antibody having affinity to CD44 comprising:
  • SEQ ID NO: 460 VH CDR1
  • SEQ ID NO: 461 VH CDR2
  • SEQ ID NO: 462 VH CDR3
  • SEQ ID NO: 464 VL CDR1
  • SEQ ID NO: 465 VL CDR2
  • SEQ ID NO: 466 VL CDR3
  • An isolated antibody having affinity to CD73 comprising:
  • SEQ ID NO: 468 VH CDR1
  • SEQ ID NO: 469 VH CDR2
  • SEQ ID NO: 470 VH CDR3
  • SEQ ID NO: 472 VL CDR1
  • SEQ ID NO: 473 VL CDR2
  • SEQ ID NO: 474 VL CDR3
  • An isolated antibody having affinity to EpCAM comprising:
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) shown in the following (1); or
  • SEQ ID NO: 476 VH CDR1
  • SEQ ID NO: 477 VH CDR2
  • SEQ ID NO: 478 VH CDR3
  • SEQ ID NO: 480 VL CDR1
  • SEQ ID NO: 481 VL CDR2
  • SEQ ID NO: 482 VL CDR3
  • heavy chain variable regions CDR1 to CDR3 and light chain variable regions CDR1 to CDR3 specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR2, SEQ ID NO showing an amino acid sequence of a heavy chain variable region CDR3, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR1, SEQ ID NO showing an amino acid sequence of a light chain variable region CDR2, and SEQ ID NO showing an amino acid sequence of a light chain variable region CDR3) selected from the group consisting of the following (1) to (3); or
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (4) to (6);
  • SEQ ID NO: 652 VH CDR1
  • SEQ ID NO: 653 VH CDR2
  • SEQ ID NO: 654 VH CDR3
  • SEQ ID NO: 656 VL CDR1
  • SEQ ID NO: 657 VL CDR2
  • SEQ ID NO: 658 VL CDR3
  • SEQ ID NO: 660 VH CDR1
  • SEQ ID NO: 661 VH CDR2
  • SEQ ID NO: 662 VH CDR3
  • SEQ ID NO: 664 VL CDR1
  • SEQ ID NO: 665 VL CDR2
  • SEQ ID NO: 666 VL CDR3
  • SEQ ID NO: 668 VH CDR1
  • SEQ ID NO: 669 VH CDR2
  • SEQ ID NO: 670 VH CDR3
  • SEQ ID NO: 672 VL CDR1
  • SEQ ID NO: 673 VL CDR2
  • SEQ ID NO: 674 VL CDR3
  • An isolated antibody having affinity to LAR comprising:
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) selected from the group consisting of the following (1) to (5);
  • An isolated antibody having affinity to BCAM comprising:
  • a heavy chain variable region and a light chain variable region specified by a combination of SEQ ID NOs (SEQ ID NO showing an amino acid sequence of a heavy chain variable region and SEQ ID NO showing an amino acid sequence of a light chain variable region) shown in the group consisting of the following (1);
  • [77] An isolated nucleic acid molecule, which encodes the heavy chain variable region and/or the light chain variable region of the antibody according to any of [63] to [76].
  • a cancer therapeutic agent comprising the antibody according to any of [63] to [76] as an effective ingredient.
  • a reagent for examining or studying cancer comprising the antibody according to any of [63] to [76].
  • a method for examining gallbladder and liver cancer or pancreas cancer comprising the following steps:
  • a method for examining gallbladder and liver cancer or pancreas cancer comprising the following steps:
  • a method for examining kidney cancer, hepatic cell carcinoma or gallbladder and liver cancer comprising the following steps:
  • a method for examining kidney cancer comprising the following steps:
  • FIG. 1 shows one example of a method of obtaining an antibody or an antibody set related to a certain disease.
  • FIG. 2 shows another example of a method of obtaining an antibody set related to a certain disease.
  • FIG. 3 shows a further example of a method of obtaining an antibody set related to a certain disease.
  • FIG. 4 shows a yet further example of a method of obtaining an antibody set related to a certain disease.
  • FIG. 5 is a schematic view showing a vector used for producing an scFv antibody gene library.
  • FIG. 6 is a schematic view showing a structure of pscFvCA9-E8VHdVLd.
  • FIG. 7-1 shows a base sequence (SEQ ID NO: 401) of an insert part of pscFvCA9-E8VHdVLd and an amino acid sequence (SEQ ID NO: 402) encoded by the base sequence.
  • FIG. 7-2 shows a part continuing to FIG. 7-1 .
  • FIG. 8-1 shows a base sequence (SEQ ID NO: 405) of an insert of pscFvCA-E8VHd and a restriction enzyme site and an amino acid sequence (SEQ ID NO: 406).
  • FIG. 8-2 shows a part continuing to FIG. 8-1 .
  • FIG. 9 shows a process of screening of an antibody clone specific to liver cancer cell.
  • FIG. 10 shows an FCM reactivity (representative example) of an antibody clone, showing histogram (right) and cell fluorescence cytology image (left) showing the reactivity between an antibody clones 035-011 and 041-101 and undifferentiated malignant liver cancer cell line HLF.
  • FIG. 11 shows an FCM reactivity (representative example) of an antibody clone, showing histogram (right) and cell fluorescence cytology image (left) showing the reactivity between an antibody clones 041-129, 045-134 and 052-042 and undifferentiated malignant liver cancer cell line HLF.
  • FIG. 12 shows histograms obtained by FCM of seven kinds of antibodies, which are overwritten onto each other. This shows that each histogram has a unique shape.
  • FIG. 13 shows histograms obtained by FCM of seven kinds of antibodies, which are overwritten onto each other. This shows that all the histograms have high similarity to each other.
  • FIG. 14 shows histograms obtained by FCM of four kinds of antibodies, which are overwritten onto each other. This shows that all the histograms have high similarity to each other.
  • FIG. 15 shows histograms obtained by FCM of two kinds of antibodies, which are overwritten onto each other. This shows that two histograms have high similarity to each other.
  • FIG. 16 shows histograms obtained by FCM of three kinds of antibodies in various cells, which are overwritten onto each other. This shows that even when any cells are used, these antibodies provide histograms having a high similarity to each other.
  • FIG. 17 shows a method for classifying the antibody group into groups based on the results of the FCM analysis.
  • FIG. 18 is a table showing a classification of a plurality of antibody clones based on the results of the FCM analysis.
  • Each reference mark in Table is shown by a shift amount from the histogram (reference histogram) provided by the negative control antibody.
  • Double circle mark represents that the shift amount is 20 times or more (the peak value of the is 20 times or more of the reference histogram); “o” (circle mark) represents that the shift amount is 10 times or more; “ ⁇ ” (triangle mark) represents that the shift amount is 3 times or more; and “x” represents that the shift amount is less than 3, respectively (an oblique line means no data is obtained).
  • FIG. 19 shows the results of RNAi in which CD147 is a subject antigen.
  • Gray color (a); cells that have not subjected to RNAi are stained with an anti-influenza antibody YA14 cp3 as a primary antibody; Green color (b); cells that have not subjected to RNAi are stained with 059-053 cp3 as a primary antibody; Red color (c); cells that have subjected to RNAi are stained with 059-053 cp3 as a primary antibody.
  • FIG. 20 shows the results of RNAi in which CD166 is a subject antigen.
  • Gray color (a) cells that have not subjected to RNAi are stained with an anti-influenza antibody YA14 cp3 as a primary antibody; Green color (b); cells that have not subjected to RNAi are stained with 035-234 cp3 as a primary antibody; Red color (c); cells that have subjected to RNAi are stained with 035-234 cp3 as a primary antibody.
  • FIG. 21 shows the results of RNAi in which HER1 is a subject antigen.
  • Gray color (a) cells that have not subjected to RNAi are stained with an anti-influenza antibody YA14 cp3 as a primary antibody; Green color (b); cells that have not subjected to RNAi are stained with 048-006 cp3 as a primary antibody; Red color (c); cells that have subjected to RNAi are stained with 048-006 cp3 as a primary antibody.
  • FIG. 22 shows the results of RNAi in which HER2 is a subject antigen.
  • Gray color (a) cells that have not subjected to RNAi are stained with an anti-influenza antibody YA14 cp3 as a primary antibody; Green color (b); cells that have not subjected to RNAi are stained with 015-126 cp3 as a primary antibody; Red color (c); cells that have subjected to RNAi are stained with 015-126 cp3 as a primary antibody.
  • FIG. 23 shows the results of RNAi in which IgSF4 is a subject antigen.
  • FIG. 24 shows A: an EGF binding inhibitory activity (using A431 cells) of 048-006 antibody and 059-152 antibody; B: an EGF binding inhibitory activity of 048-006 antibody (using low concentration range, A431 cells), and C: an EGF binding inhibitory activity of 048-006 antibody (using low concentration range, A431 cells).
  • FIG. 25 shows A: HER1 phosphorylation signal inhibitory activity of 048-006 antibody and 059-152 antibody (results of Western blotting).
  • Upper part shows the results of Western blotting by using anti-phosphorylation tyrosine antibody (mouse monoclonal antibody).
  • B HER1 phosphorylation signal inhibitory activity of a 048-006 antibody (low concentration range). Lane 1; not treated, lane 2; antibody is not added, lane 3; HR1-007 is added (1 ⁇ g/ml), lane 4; 048-006 antibody added (0.5 ⁇ g/ml), lane 5; 048-006 antibody added (0.1 ⁇ g/ml), lane 6; and 048-006 antibody added (0.05 ⁇ g/ml). After incubation with an antibody for 30 minutes, Her1 was added.
  • FIG. 26 shows a result of BIACORE experiment.
  • Fixation method CM5 chip of BIAcore is used and NHS is used so as to fix a partial sequence of HER1 to sensor.
  • 048-006 antibody is allowed to flow at the above-mentioned concentration to observe signals.
  • FIG. 27 shows a result of an ADCC activity test.
  • An antibody to be used anti-ITGA3 antibody
  • a target culture cell HLF.
  • FIG. 28 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody, a target culture cell: A-431.
  • FIG. 29 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody, a target culture cell: A549.
  • FIG. 30 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody, a target culture cell: ACHN.
  • FIG. 31 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody
  • a target culture cell CCF-RC-1.
  • FIG. 32 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody
  • a target culture cell NCI-H1373.
  • FIG. 33 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER1 antibody, a target culture cell: SK-OV-3.
  • FIG. 34 shows a result of an ADCC activity test.
  • An antibody to be used anti-HER2 antibody, a target culture cell: BT-474.
  • FIG. 35 shows a result of an ADCC activity test.
  • An antibody to be used anti-ALCAM antibody, 066-174 whose, a target culture cell: NCI-H1373.
  • An antibody to be used anti-ALCAM antibody, 066-174, target culture cell: CW2.
  • An antibody to be used anti-ALCAM antibody, 066-174, target culture cell: NCI-H441.
  • FIG. 36 shows a result of an ADCC activity test.
  • An antibody to be used anti-ALCAM antibody, 035-234, target culture cell: CW2.
  • An antibody to be used anti-ALCAM antibody, 035-234, target culture cell: NCI-H441.
  • FIG. 37 shows a result of an ADCC activity test.
  • An antibody to be used anti-ICAM1 antibody, 053-051, target culture cell: NCI-H441.
  • FIG. 38 shows a result of an ADCC activity test.
  • An antibody to be used anti-ICAM1 antibody, 053-059, target culture cell: NCI-H441.
  • FIG. 39 shows a result of an ADCC activity test.
  • An antibody to be used anti-ICAM1 antibody, 053-085, target culture cell: NCI-H441.
  • FIG. 40 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 048-006 antibody or 059-152 antibody,
  • target culture cell CCF-RC-1.
  • FIG. 41 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 048-006 antibody or 059-152 antibody, target culture cell: NCI-H1373.
  • FIG. 42 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 048-006 antibody or 059-152 antibody,
  • target culture cell A-431.
  • FIG. 43 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 041-118 antibody, target culture cell: NCI-H1373.
  • FIG. 44 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-EpCAM antibody, 067-153 antibody, target culture cell: MKN-45.
  • FIG. 45 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-EpCAM antibody, 067-153 antibody, target culture cell: HT-29.
  • FIG. 46 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-EpCAM antibody, 067-153 antibody, target culture cell: NCI-H1373.
  • FIG. 47 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HGFR antibody, 067-133 antibody, target culture cell: NCI-H1373.
  • FIG. 48 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 055-147 antibody or 059-173 antibody, target culture cell: CCF-RC1.
  • FIG. 49 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody. 048-006 antibody, 059-152 antibody, 055-147 antibody or 059-173 antibody, target culture cell: HT-29.
  • FIG. 50 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 048-006 antibody, 055-147 antibody or 059-173 antibody, target culture cell: A431.
  • FIG. 51 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HER1 antibody, 048-006 antibody or 059-152 antibody, target culture cell: ACHN.
  • FIG. 52 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 035-234 antibody or 066-174 antibody,
  • target culture cell NCI-H1373.
  • FIG. 53 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 035-234 antibody or 066-174 antibody, target culture cell: SKOv3.
  • FIG. 54 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 035-234 antibody or 066-174 antibody, target culture cell: CW-2.
  • FIG. 55 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 041-118 antibody, target culture cell: EBC-1.
  • FIG. 56 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ALCAM antibody, 080-040 antibody, target culture cell: NCI-H1373.
  • FIG. 57 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ICAM1 antibody, 053-042 antibody, target culture cell: NCI-H1373.
  • FIG. 58 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ICAM1 antibody, 053-051 antibody, 053-059 antibody or 053-085 antibody, target culture cell: NCI-H1373.
  • FIG. 59 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-EpCAM antibody, 067-153 antibody, target culture cell: EBC-1.
  • FIG. 60 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HGFR antibody 067-133 antibody
  • target culture cell MKN-45.
  • FIG. 61 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-HGFR antibody 067-133 antibody, target culture cell: EBC-1.
  • FIG. 62 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-ITGA3 antibody, 015-003 antibody, target culture cell: ACHN.
  • FIG. 63 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-CD147 antibody, 059-053 antibody, target culture cell: CCF-RC1.
  • FIG. 64 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-CD147 antibody, 059-053 antibody, target culture cell: ACHN.
  • FIG. 65 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-PTP-LAR antibody, 064-044 antibody or 079-085 antibody, target culture cell: PC-14.
  • FIG. 66 shows antibody dosage dependence of the ADCC activity.
  • An antibody to be used anti-CD44 antibody. 064-003 antibody, target culture cell: PC-14.
  • FIG. 67 shows a result of a cell proliferation inhibition test.
  • An antibody to be used anti-HER1 antibody (048-006), target subjected cultured cell: A-431.
  • FIG. 68 shows a result of a cell proliferation inhibition test.
  • An antibody to be used anti-HER1 antibody (048-006), target subjected cultured cell: ACHN.
  • FIG. 69 shows a result of a cell proliferation inhibition test.
  • An antibody to be used anti-HER1 antibody (048-006), target subjected cultured cell: NCI-H1373.
  • FIG. 70 shows a result of a cell proliferation inhibition test.
  • An antibody to be used anti-HER1 antibody (048-006), target subjected cultured cell: SK-OV-3.
  • FIG. 71 shows a result of a cell proliferation inhibition test.
  • An antibody to be used anti-HER2 antibody (015-126), target subjected cultured cell: BT-474.
  • FIG. 72 shows a result of an antitumor experiment using mouse.
  • An antibody to be used anti-HER1 antibody (048-006)
  • subject transplant cell human lung cancer cell H1373 cell.
  • FIG. 73 shows a result of an antitumor experiment using mouse.
  • An antibody to be used anti-HER1 antibody (048-006)
  • subject transplant cell epidermoid tumor A-431.
  • FIG. 74 shows a result of an antitumor experiment using mouse.
  • An antibody to be used anti-HER1 antibody (048-006)
  • subject transplant cell epidermoid tumor A-431.
  • FIG. 75 shows a result of an antitumor experiment using mouse.
  • An antibody to be used anti-HER1 antibody (059-152), subject transplant cell: epidermoid tumor A-431.
  • FIG. 76 is a table showing culture conditions of cell lines to be used in experiments.
  • FIG. 77 is a conceptual diagram of three-dimensional ELISA, showing how each mixture antibody is prepared.
  • FIG. 78 is a conceptual diagram of three-dimensional ELISA, showing a procedure of specifying an antibody clone.
  • FIG. 79 shows a result of ELISA using a plate mixed antibody (antigen is CD147).
  • FIG. 80 shows a result of ELISA using a row mixed antibody (antigen is CD147).
  • FIG. 81 shows a result of ELISA using a column mixed antibody (antigen is CD147).
  • FIG. 82 shows a result of ELISA using a plate mixed antibody (antigen is HER1).
  • FIG. 83 shows a result of ELISA using a row mixed antibody (antigen is HER1).
  • FIG. 84 shows a result of ELISA using a column mixed antibody (antigen is HER1).
  • FIG. 85 shows a result of ELISA using a selected antibody clone (antigen is HER1).
  • FIG. 86 shows a RNAi effect on SKOv-3 cells.
  • A anit-ITGA3 antibody
  • B anit-ITGB1 antibody
  • C 015-003 cp3 antibody.
  • Broken line no RNAi
  • solid line ITGA3 RNAi
  • light-colored solid line ITGB1 RNAi
  • gray and no primary antibody.
  • FIG. 87 shows a correspondence between a tissue that has been diagnosed to be specific in immunostaining using a clinical cancer specimen and each antibody clone.
  • FIG. 88 shows a reactivity of a clinical cancer specimen and each antibody clone. + represents positive to the immunostaining; ⁇ represents weakly positive to the immunostaining; and ⁇ represents negative to the immunostaining.
  • disease herein is used interchangeably with the terms meaning that some function failure occurs, for example, illness and sickness. Furthermore, unless otherwise noted, in this specification, this term is used to encompass the words meaning the condition (state) of disease such as condition, pathologic condition, symptom, and state of health. That is to say, the term “disease” is used interchangeably with the terms such as condition and pathologic condition.
  • isolated means a state in which it is taken out from the original environment (for example, a natural environment in the case of a natural material), that is to say, means a state that is a different state from the original existing state by an artificial manipulation.
  • an “isolated antibody” does not include an antibody in a state in which it is natural state and no external manipulation (artificial manipulation) is given. It does not include an antibody produced in the individual body and remaining therein.
  • An isolated antibody is typically present in a state in which other kinds of antibodies are not contaminated, that is, present singly (as an assembly of the same kinds of antibodies).
  • an “isolated” state of the CDR region in addition to the state which is present singly, a state which is present together with the other regions of the antibody is included. That is, the term “isolated CDR” includes not only a CDR that is present singly but also a CDR that is present as a part of an isolated antibody is included.
  • HER1 is also referred to as erbB1, c-erbB-1, EGFR (Epidermal Growth Factor Receptor), or v-erbB.
  • erbB1 a gene corresponding to a cancer gene erbB found in the retrovirus that infects chicken and causes carcinogenesis (erythroleukemia) on the genome is isolated. And this gene is determined to be a receptor of EGF.
  • EGF Epidermal Growth Factor
  • EGF is a peptide composed of 53 amino acids and has a characteristic structure including three disulfide loops formed of six cysteine residues. Thereafter, this structure has been found in a large number of proteins and is referred to as EGF-like domain.
  • the EGF family has one or more EGF-like domains and directly binds to a receptor type tyrosine kinase EGF receptor (EGFR) family (another name: ErbB family) so as to activate this.
  • EGFR tyrosine kinase EGF receptor
  • ErbB-1 ErbB-1
  • ErbB-2 ErbB-3
  • ErbB-4 ErbB-1 and ErbB-2 overexpress in various human tumors and are involved in the deterioration of the prognosis or survival rate.
  • stimuli of these receptors are involved in cell proliferation and in turn involved in several processes related to progress, infiltration, and metastasis of tumor.
  • a phosphorylation inhibiting agent specific to EGFR have been approved as a therapeutic agent for lung cancer. They are found to highly express in many cancers.
  • Cetuximab (ERBITUX, which is mouse/human chimeric antibody) has been developed by ImClone Systems and already marketed. ERBITUX inhibits the initial process of activation of the information transmission passage by the phosphorylation of dimerized-EGFR when it binds to a receptor of EGF as a ligand. Note here that the amino acid sequence of HER1 is shown in SEQ ID NO: 369.
  • HER2 is also referred to as erbB-2, c-erbB-2, or neu.
  • HER2 belongs to a receptor type tyrosine kinase family and its over-expression and gene amplification in the breast cancer, ovarian cancer, stomach cancer, and the like, have been reported.
  • HER2 is a molecule that was found in 1985 when DNA containing a region of gene similar to EGFR was amplified (gene amplification) in the brain tumor and breast cancer derived from glia cells was observed.
  • HER2 has low shedding level and is thought to be very effective as a target molecule in treating cancers.
  • the monoclonal antibody (MoAb) showing effects of promoting or suppressing the tumor proliferation has been produced.
  • MoAb showing a tumor proliferation suppressing effect is used for clinical test as a simple substance of the antibody or in combination with anti-cancer drugs such as cisplatin, and its efficacy has been reported.
  • the EGFR family includes four kinds, but only EGFR (HER1) and HER4 have both the ligand binding sites and tyrosine phosphorylation enzymatic activity sites.
  • HER2 does not have the ligand binding site. Instead using a ligand, HER2 has a structure that is activated from the first in terms of dimer formation ability.
  • HER3 lacks the tyrosine phosphorylation activity. Therefore, HER2-HER3 hetero-dimer is a functional molecule.
  • HER2 Genentech isolated 11 kinds of mouse monoclonal antibodies to HER2 in 1989. Among them, 4D5 was made into a humanized antibody and succeeded in developing Trastuzumab (Herceptin). Note here that the amino acid sequence of HER2 is shown in SEQ ID NO: 370.
  • CD46 antigen is an O-type sugar chain bonded non-disulfide bonded dimer protein having a molecule weight of 56 to 66 kDa, which is also referred to as MCP (Membrane Co-factor Protein), gp45-70, HuLY-m5, measles virus receptor, MIC10, TLX-B antigen, TRA2, trophoblast leucocyte common antigen, and trophoblast-lymphocyte cross-reactive antigen.
  • MCP Membrane Co-factor Protein
  • MCP Membrane Co-factor Protein
  • IGA3 (integrin alpha 3) is also referred to as alpha 3 beta 1 Epiligrin Receptor, alpha 3 beta 1 Integrin, Epiligrin Receptor, CD49c, VLA-3, Gap b3, Galactoprotein b3, or Laminin-5 Receptor in which integrin ⁇ 3 chain having a molecular weight of 150 kDa and integrin ⁇ 1 chain (CD29 molecule) having a molecular weight of 130 kDa are bonded to each other non-covalently to form a VLA-3 complex ( ⁇ 3 ⁇ 1 or CD49c/CD29). It is known as a receptor of laminin, collagen, fibronectin, invasion and epiligrin.
  • Integrin is a hetero dimer molecule composed of ⁇ chain and ⁇ chain. Twenty four types of ⁇ chains and nine types of ⁇ chain form a variety of molecule groups by various combination and selective splicing.
  • the extracellular domain binds to the extracellular matrix (for example, collagen, fibronectin, laminin).
  • the side of cytoplasm is bonded to actin filament via talin, filanin, and ⁇ -actinin. It functions as an adhesive molecule and further functions as an important role as information transmission molecule.
  • ⁇ 3 ⁇ 1 molecule is associated with a tetraspanin molecule C151. Note here that the amino acid sequence of ITGA3 is shown in SEQ ID NO: 372.
  • ICAM1 Intercellular adhesion molecule-1
  • CD54 Antigen Intercellular Adhesion Molecule 1 or CD54 Antigen and is transmembrane glycoprotein having seven binding sites of the N-bonding sugar chain. The molecular weight is 90 kDa.
  • ICAM belongs to Ig-superfamily and is known to be mainly involved with adhesion of leukocyte. It also mediates T lymphocyte adhesion to an antigen presenting cell (APC) and is involved with the interaction between T cell and T cell or between T cell and B cell. It also involved with the adhesion to endothelial cell in which monocyte, lymphocyte, and neutrophil are activated.
  • APC antigen presenting cell
  • ICAM is bonded to integrin of LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Furthermore, it also is a receptor of rhinovirus. It is expressed on various kinds of activated cells in addition to the endothelial cells. For example, it is expressed on the monocyte. On B- and T-lymphocytes, thymus gland cells, dendritic cells, endothelial cells, fibroblast, keratinocyte, chondrocyte and epithelium cells, expression is enhanced. The characteristics required to obtain during the cancerization process of epithelium cells include capability of invading into cells, and furthermore migrating and being fixed in metastasis.
  • adhesion factor contributes to carcinogenesis.
  • the adhesion factor is roughly classified into five groups, i.e., selectin (E-, P-, and L-), molecules (Ig-superfamily) having an immunoglobulin-like domain, integrin, Cadherin, and CD44.
  • selectin E-, P-, and L-
  • molecules Ig-superfamily having an immunoglobulin-like domain
  • integrin integrin
  • Cadherin integrin
  • CD44 CD44
  • the expression of E Cadherin is suppressed.
  • Abnormal expression in some cancer cases has been reported. Note here that the amino acid sequence of ICAM1 is shown in SEQ ID NO: 373.
  • ALCAM Active leukocyte cell adhesion molecule
  • CD166 antigen KG-CAM
  • CD6 Ligand CD6 Ligand
  • Neurolin is an immunoglobulin superfamily molecule including ten N-bonding type sugar chain added sites.
  • ALCAM has a molecular weight of 100 to 105 kDa and is composed of five extracellular Ig-like domains and the intracellular terminus having 32 amino acid, and short transmembrane region.
  • ALCAM is one of the adhesive molecules, is present on the activated leukocyte and is identified as a ligand molecule to CD6 molecule (which functions as a signal receptor in T cells).
  • ALCAM also functions as an adhesion factor in homophylic (ALCAM-ALCAM) or heterophylic (ALCAM-CD6) interaction. It is suggested that ALCAM can form oligomer at intercellular adhesion site via three C2-like domains near the membrane.
  • the distribution of ALCAM is not restricted by cell strains and ALCAM is expressed in various types of cells such as hematopoietic cells, endothelial cells, epithelium cells of the thymic cortex and thymic medulla, mesenchymal cell of the bone marrow, fibroblast, liver cells, and the like. In the peripheral blood, it is weakly expressed in activated T- and B-cells, monocyte, circulated dendritic cells, and granulocyte.
  • ALCAM shows wide dispersion of tissues, the expression of ALCAM is generally limited to cell populations involved in proliferation or migration. In the thymus gland, since ALCAM is expressed in CD6+thymus gland cells, and thymus gland epithelium cells, its interaction with CD6 molecule is thought to play a role in the differentiation of T cells. In addition, it is suggested that ALCAM adhesive molecules are involved in the fetal blood formation, differentiation of angioblastic cells, and capillary angiogenesis.
  • ALCAM in cancerization is variously assumed (e.g., controlling of MMP activation, causing internalization and recycling, functioning as a substrate of ADM17 and ADAM10 (abbreviation of a disintegrin and metalloprotease), protecting from apoptosis and autophasy), however, no decisive roles have not reported.
  • ADM17 and ADAM10 abbreviation of a disintegrin and metalloprotease
  • the interaction of ALCAM-CD6 is thought to be carried out in the both direction.
  • the amino acid sequence of ALCAM is shown in SEQ ID NO: 374.
  • CD147 antigen is membrane glycoprotein belonging to an immunoglobulin superfamily and is also referred to as BSG, TCSF (Tumor cell-derived collagenase stimulatory factor), 5F7 protein, OK blood group protein, basigin protein, collagenase stimulatory factor protein, EMMPRIN (Extracellular matrix metalloproteinase Inducer), M6 activation antigen, human leukocyte activation antigen M6, or the like.
  • D147 antigen has two aspects. One is observed when it functions on the cell surface, it exhibits the activation of MMP-1, 2, 3 (matrix metalloprotease) and the lectin activity recognizing oligomannose as membrane glycoprotein having two Ig domains.
  • MMP The activation of MMP receives much attention in cancers (which is also known as EMMPRIN in Europe and America). That is to say, CD147 antigen expressing in cancer cells activates MMP expressing in the surrounding fibroblast and contributes to the infiltration of cancers. On the other hand, the activation of oligomannose lectin is especially important in the interaction of nerve cells and indicated to have a relationship with respect to neurite outgrowth.
  • the second aspect is a function in cells. CD147 antigen forms a homo dimer. It is reported that this formation needs N-terminal Ig domain and does not need addition of sugar chain.
  • CD147 has the following interesting reports: integrin ⁇ 3 ⁇ 1 and CD147 form a complex, and in this case, TM4SF (tetraspanin) molecule does not join the complex.
  • TM4SF tetraspanin
  • the production of D147 changes anchorage-dependent growth to independent growth, which is promoted by the production of hyaluronic acid (hyaluronam).
  • the receptor of hyaluronic acid includes CD44 and RHAMM.
  • CD147 induces the production of MMP, and a part of CD147 is solubilized due to the effect of the MMP.
  • CD147 acts on integrin so as to change the structure of cells.
  • CD147 affects the angiogenesis. Furthermore, mass expression-cell proliferation of CD147 and Cyclophin A has been found.
  • the amino acid sequence of the CD147 antigen is shown in SEQ ID NO: 375.
  • IgSF4 is an abbreviation of immunogloblin superfamily member 4 and is also referred to as BL2, ST17, NECL2, TSLC1, IGSF4A, SYNCAM, and sTSLC-1.
  • IgSF4 has homology of NCAM (neural cell adhesion molecule) and amino acid sequence. IgSF4 is thought to be expressed from human 11-chromosome, 11q23.2. It has been reported that IgSF4 expressed as a suppression gene in a lung cancer specific manner and that IgSF4 is involved in the nerve adhesion in the brain (Biederer T et al. Science. 2002 Aug. 30; 297 (5586): 1525-31).
  • IgSF4 The sequence information of IgSF4 is recorded in a NCBI-PUBMED database (Accession No. NM — 01433, Definition: Homo sapiens immunoglobulin superfamily, member 4 (IGSF4), mRNA).
  • IGSF4 Homo sapiens immunoglobulin superfamily, member 4
  • TSLC1 tumor suppressor in lung cancer 1
  • IgSF4 shows high expression in 100% adult T cell leukemia (ATL) cells and it is suggested that IgSF4 may work as oncogene.
  • ATL adult T cell leukemia
  • the amino acid sequence of IgSF4 is shown in SEQ ID NO: 376.
  • C1qR is a complement receptor encoding a type I membrane protein. This protein functions as a receptor for complement protein C1q, mannose binding lictin, and lung surfactant protein A. Two or more polypeptides of 70 kDa are bonded by disulfide bonding so as to form C1qR. Removing an immune complex is an important function of the complement and the C1q receptor is a functional receptor that is bonded to a collagen portion of C1q thereby linking the immune complex to phagocyte. It is suggested that C1qR forms complex with CD43. The amino acid sequence of C1 qR is shown in SEQ ID NO: 446.
  • CD44 is a transmembrane protein belonging to a hyaladherin family, which is cell surface glycoprotein related to cellular interaction, cell adhesion and cell migration. It is a hyaluronic acid receptor. It is thought that a wide variety of the structural and functional isoforms of proteins by the selective splicing or post-translation modification of this molecule may be involved in tumor metastasis.
  • the CD44 molecule is expressed in almost all the cells and tissues. However, in general, it is not expressed in the platelet, liver cell, cardiac muscle, uridiferous tubule epithelium, testis, and skin.
  • the amino acid sequence of CD44 is shown in SEQ ID NO: 447.
  • CD73 is also referred to as 5-prime-ribonucleotide phosphohydrolase and transforms purine 5-prime mononucleotides into nucleosides at the neutral pH.
  • the enzyme mediates glycosylphosphatidyl inositol to the surface of the outside of the plasma membrane and is bonded to the surface of the outside of the plasma membrane.
  • CD73 is a homodimer composed of two 70 kDA subunits. CD73 is used as a marker of the lymphocyte differentiation. It has been known that the deletion of this gene is related to various immune defective diseases.
  • the amino acid sequence of CD73 is shown in SEQ ID NO: 448.
  • EpCAM has 22 or more names as to only the number of names used and cited several times in research paper. This antigen exists on genome 2p21. This antigen is a protein having a full length of 314aa, and 34920 Da. In the documents in which this molecule is examined at the mRNA level, it is detected in healthy human individuals, 100% in the peripheral blood (PB) level and 40% in the bone marrow (BM) level. It has been reported that it can be detected in large intestine but cannot detected in the liver, prostate, and lung. In cancer cell line, in the relationship with respect to p53, the methylation of EpCAM is lost due to the mutation or deletion of p53 and the amplification is induced. The amino acid sequence of EpCAM is shown in SEQ ID NO: 449.
  • HGF Hepatocyte growth factor receptor
  • HGFR Hepatocyte growth factor receptor
  • HGFR Hepatocyte growth factor receptor
  • HGFR is a receptor having a ligand binding domain outside the cells and has a tyrosine phosphorylation enzymatic activity site at the cytoplasm side, however, the function is extremely different.
  • the cell proliferation factor or a differentiation induction factor when the cell proliferation factor or a differentiation induction factor is bonded to a receptor so as to cause the phosphorylation of protein, it finally activates the transcription factor and expresses a certain gene set by way of some of the limited information transmission pathway (Ras/MAP kinase pathway, and the like). In this case, the type of the cell response is finally determined by transcription factor.
  • the cancerization may activate some of the proliferation factors-receptor, it is thought that changes other than cancerization are not likely to occur in the cells.
  • EMT epithelial-mesenchymal transition
  • the amino acid sequence of HGFR is shown in SEQ ID NO: 450.
  • LAR Leukocyte common Antigen-Related belongs to a PTP (protein tyrosine phosphatase) family.
  • the PTPs are known to be molecules to modulate the process in the various aspects of the cancerization, division cycle, differentiation, cell growth, and the like.
  • the structure thereof includes an extracellular region, mono-transmembrane region, and two tandem catalyzing domain in the cytoplasm (homolog of protein tyrosine phosphatase).
  • the extracellular region has a structure similar to nerve cell adhesion factor, which includes three Ig-like domains and nine non-Ig like domains (homolog of NCAM). The function of this molecule is involved in the cell adhesion in the formation adherents junctions in the epithelium.
  • anti-LAR antibody has an insulin receptor inhibitory activity of the insulin receptor forced expressing body (Knock-down of LAR protein tyrosine phosphatase induces insulin resistance: Mander A, Hodgkinson C P, Sale G J.: FEBS Lett. 2005 Jun. 6; 579 (14): 3024-8.).
  • LAR is expressed on the membrane of all the leukocytes and is referred to as protein tyrosine phosphatase receptor type F (PTPRF) and protein sequence (SEQ ID NO: 941) thereof is registered as TDHULK in Protein sequence database of the Protein Information Resource (PIR).
  • PPRF protein tyrosine phosphatase receptor type F
  • SEQ ID NO: 941 protein sequence (SEQ ID NO: 941) thereof is registered as TDHULK in Protein sequence database of the Protein Information Resource (PIR).
  • BCAM basic cell adhesion molecule
  • CD239 antigen and its protein sequence is registered as Q86VC7 (UniProtKB/Swiss-Prot) and 13800 (PIR) (SEQ ID NO: 942). It produces a selective splicing product from a single gene in the chromosome 19q13.2-q13.3. It is a glycoprotein having an immunoglobulin-like domain. It is a mono-transmembrane type and expressed widely. Its expression in the pancreas is high and its expression in the brain is low.
  • the BCAM antigen is modulated excessively in certain cells, thus inducing the malignant alteration of cancers. Also, it is shown that it is overexpressed in the living body with ovarian cancers.
  • liver cancer is intended to be widely interpreted and it includes liver carcinoma and liver sarcoma.
  • cancer in the present invention is interchangeably with “tumor.”
  • tumor in the stages before the pathological diagnosis is not established, that is, before whether the tumor is benign or malignant has not been determined, the term may include benign tumor, benign-malignant borderline lesion, and malignant tumor collectively.
  • Cancers are called under the name of the organs in which the cancers are developed or the name of development body tissue.
  • Main examples include tongue cancer, gingival cancer, pharynx cancer, maxillary cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, stomach cancer, small intestinal cancer, large bowel cancer, rectum cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreas cancer, lung cancer, breast cancer, thyroid gland cancer, adrenal gland cancer, hypophyseal tumor, pinealoma, uterine cancer, ovarian cancer, vaginal cancer, urinary bladder cancer, kidney cancer, prostate cancer, urethral cancer, retinoblastoma, conjunctival cancer, gliocystoma, glioblastoma, skin cancer, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyoblastoma, leiomyosarcoma, blood vessel sarcom
  • cancers are subclassified into, for example, upper, middle, and lower pharynx cancers, upper, middle, and lower esophageal cancers, gastric cardia cancer, gastropyloric cancer, cervical cancer, cancer of uterine body, and the like. These cancers are included in the “cancers” of the present invention but the cancers are not limited to these alone.
  • the first aspect of the present invention relates to a method of classifying antibody.
  • the classifying method of the present invention includes the following steps.
  • step (3) analyzing each cell after step (2) by flow cytometry so as to obtain data showing reactivity between the antibody and the cell surface;
  • the classifying method of the present invention firstly, a plurality of antibodies recognizing cell surface antigen are prepared.
  • the antibody classified by the classifying method of the present invention is also referred to as a “sample antibody.”
  • the “cell surface antigen” is a molecule in which at least a part thereof exists outside the cell and which forms an antigenic determinant on the surface of the cell.
  • protein such as transmembrane type protein having a cell membrane transmembrane domain and an extracellular domain and GPI anchor type protein, which are linked to cell membrane via glycolipid and the like and existing on the surface of the extracellular surface, can form such an antigenic determinant.
  • the cell surface antigen can be formed by a simple protein (basically, constituent includes only amino acids), a conjugated protein (constituent other than amino acid are contained.
  • glycoprotein and lipoprotein or a modified protein (a protein modified by, for example, phosphorylation, acetylation, and methylation), and the like.
  • a modified protein a protein modified by, for example, phosphorylation, acetylation, and methylation
  • two or more same types or different types of molecules may cooperatively form an antigen determinant.
  • the “cell surface antigen” of the present invention is not particularly limited to animal cells and may include cell surface antigens of plant cells, microorganism cells, and the like.
  • “cell surface antigen” of the present invention is the cell surface antigen of animal cells. It is known that the animal cells have various cell surface antigens.
  • the “animal cells” herein include mammalian cells and non-mammalian cells, but preferably mammalian cells. Above all, human cells are preferable.
  • a plurality of antibodies recognizing the intact cell surface antigen are prepared.
  • the “intact state” means that the original state is maintained. It has the same meaning that “not denatured state.”
  • the “antibody recognizing cell surface antigen” represents an antibody recognizing and binding the cell surface antigen with highly specific recognition mechanism between the antigen and the antibody.
  • the origins, types, classes, forms and the like, of antibodies are not particularly limited. Therefore, the “antibody” in the present invention includes an antibody of non-human animals such as mouse and rat, a chimeric antibody in which a part of the region is substituted with that of other animal (including human), a humanized antibody, and human antibody.
  • human antibody or human type antibody humanized antibody
  • Antibody fragments such as Fab, Fab′, F(ab′)2, scFv, and dsFv antibody may be used.
  • An antibody for treatment application includes an antibody in which VH and VL (Fv region) are converted into IgG type is included.
  • An antibody recognizing a cell surface antigen can be prepared by, for example, bringing an antibody library into contact with the cell surface antigens and recovering the antibodies bound to the cell surface antigens.
  • One of such preparation methods is a method reported by the present inventors before (Japanese Patent Unexamined Publication No. 2005-185281). This method makes it possible to select an antibody clone recognizing intact cell surface antigen from the phage antibody library.
  • the present invention can preferably use the antibody assembly derived from each antibody clone.
  • the “assembly derived from each antibody clone” herein includes the selected antibody clone itself, or the product prepared by using the gene.
  • the latter example includes an antibody in which genes of the selected antibody clone is transformed by an appropriate host (for example, E. coli ) and the host is expressed, or an antibody to which further genetic engineering modification is added in the host or by the use of the host and then the modified antibody is expressed.
  • an appropriate host for example, E. coli
  • the above-mentioned publication discloses as the antibody having a human Fv region, scFv-CL-cp3 antibody (an antibody in which a phage protein cpIII is fused to scFV via the light chain constant region), scFv-CL-pp antibody (an: antibody in which two proteins A are fused to scFV via the light chain constant region), scFv-CL-pp-Avi antibody (an antibody in which avidin is fused to scFv-CL-pp antibody), scFv-CL-Avi antibody (an antibody in which avidin is fused to scFV via the light chain constant region), scFv-CL-pp-Avi or antibody obtained by biotining scFv-CL-Avi antibody (an antibody in which biotin is bonded to an avidin part), and the like.
  • the present invention can preferably use any of these types of antibodies.
  • These antibodies having a human Fv region are very useful in providing an antibody
  • a combination of separately prepared antibodies may be used as the “plurality of antibodies recognizing cell surface antigen” in the present invention.
  • the preparation method of each antibody may be the same as or different from each other.
  • label sample antibody An antibody in which a label material has been bound or fused in advance (which is collectively referred to as “labeled sample antibody”) may be used.
  • the former example can include an antibody labeled with fluorescence pigment.
  • the latter example can include an antibody in which fluorescence proteins (fluorescence protein fused antibody) such as GFP (Green Fluorescent Protein) and RFP (Red Fluorescent Protein) have been fused.
  • fluorescence protein fused antibody fluorescence protein fused antibody
  • GFP Green Fluorescent Protein
  • RFP Red Fluorescent Protein
  • the sample antibodies are brought into contact with cells of the same kinds, respectively. That is to say, cells to be used are determined, and then the cells are brought into contact with the sample antibody for each sample antibody.
  • the sample antibody recognizing the surface antigen of the cells to be used binds to the cell surface.
  • the binding amount of the sample antibody is dependent upon the expression amount of the cell surface antigen recognized by the antibody.
  • Cells that are brought into contact with the sample antibody are not particularly limited and may be arbitrarily selected from animal cells, plant cells, microorganism cells, and the like.
  • cells derived from a patent having a certain disease are used.
  • the “certain disease” includes various kinds of cancers, for example.
  • the tissues or organs from which the cells are derived are not particularly limited.
  • An example of the certain disease include kidney cancer, hepatic cell carcinoma, gallbladder and liver cancer, alveolar cell carcinoma, lung squamous cell cancer, pulmonary adenocarcinoma, pancreas cancer, adenocarcinoma, ovarian cancer, and the like.
  • Cells forming a highly uniform cell population are preferably used. It is preferable because such cells can provide easier or simpler data, facilitates the comparison of data and provides more reliable comparison results in the below-mentioned flow cytometry analysis.
  • the typical example of such cells is established cell line (cell line).
  • Preferable examples include established cancer cell line such as liver cancer cell line HepG2, undifferentiated liver cancer cell line HLF, liver cancer cell line OCTH, intrahepatic bile duct cancer cell line RBE, pancreatic cancer cell line PANC-1, pancreas cancer cell line MIA-Paca2, kidney cancer cell line CCFRC1, kidney cancer cell line Caki-1, kidney cancer cell line ACHN, kidney cancer cell line 293T, ovarian cancer cell line KF28, ovarian cancer cell line SKOv3, ovarian cancer cell line KF-28, ovarian cancer cell line RMG-1, ovarian cancer cell line RMG-2, breast cancer cell line BT474, vulvar mucosa epithelium cell line A431, stomach cancer cell line SNU-5, stomach cancer cell line MKN45, stomach cancer cell line NCI-N87, cancer cell line RERF-LC-AI, pulmonary adenocarcinoma cell line PCI4, lung cancer cell line NCI-H441, lung squamous cell can
  • Each sample antibody is brought into contact with cells in an appropriate solution.
  • the conditions are set so that the properties of the sample antibody are not affected and cells are not damaged.
  • cells and the sample antibodies are co-existed in the culture solution suitable for the existence and proliferation of the cells, in the phosphoric acid buffer and citric acid buffer, in physiologic saline, or in a solution in which BSA for suppressing non-specific adsorption is added, at room temperature to low temperatures (for example, 0° C. to 25° C., preferably 4° C. to 15° C.), for 20 minutes to 3 hours. During this time, the solution may be stirred.
  • labeling is carried out if necessary (other than the case when a labeled sample antibody is used).
  • labeling herein denotes labeling the sample antibody bound to the surface of the cells.
  • labeling can be carried out by reacting (contacting) an antibody having a specific binding ability to the sample antibody to which a label material has been bound (antibody to be detected) with cells after the contacting operation. Instead of directly binding an antibody to be detected to the sample antibody, other antibodies and the like may be interposed therebetween.
  • various labeling techniques can be employed and a person skilled in the art can select an appropriate technique.
  • fluorescent dye is used as a label material. Fluorescent dye such as Alexa488, AMCA, Cascade Blue (registered trademark), FITC, PerCPTM, CyTM3, Texas Red (registered trademark), CyTM5, APC, TRITC, and the like, can be used.
  • cells after subjecting to the step (2) are analyzed by flow cytometry so as to obtain data showing the reactivity between the antibody and the cell surface. That is to say, cells after subjecting the contacting operation to the sample antibody are subjected to the flow cytometry analysis, and the binding property to the sample antibody is examined.
  • the data showing the “reactivity” herein histogram showing the relationship between the antibody binding amount and the number of cells is used. That is to say, one-parameter histogram in which the antibody binding amount is used as a parameter is used.
  • the one-parameter histogram is one display method in the flow cytometry.
  • the one-parameter histogram is generally shown in a graph in which X-axis represents one indicator (parameter) and Y-axis represents the number of cells.
  • X-axis represents one indicator (parameter)
  • Y-axis represents the number of cells.
  • devices from BECKMAN COULTER, Japan Becton, Dickinson and Company, and the like can be used in the present invention. The operation may be carried out according to the basic operation and analysis conditions attached to the device.
  • many research paper and documents about the flow cytometry analysis are published. See, for example, Cao T M, et al. Cancer. 2001 Jun. 15; 91 (12): 2205-13., Storek K J, et al. Blood 97: 3380-3389, WEIR'S HANDBOOK OF EXPERIMENTAL IMMUNOLOGY Vol. II ⁇ Blackwell Science>, Little MT and R. Storb Nature Reviews Cancer 2002 2: 231-238.
  • Typical procedure of the flow cytometry analysis is described below.
  • the sample antibody and cells are reacted with each other, then reacted with antibody to be detected labeled with fluorescent dye, so that cells are labeled with fluorescence.
  • the amount of sample antibody to be bound varies depending upon the amount of antigen existing on the surface of the cells. As a result, the amount of fluorescent label of the cells becomes different. Therefore, by measuring the fluorescence intensity, the affinity between the antigen existing on the surface of the cell and the ample antibody and the amount of antigen can be estimated.
  • FSC forward scatter light
  • SSC side scatter light
  • the forward scatter light and the side scatter light are shown in X-axis and Y-axis, respectively.
  • the cell population (when established cell lines or cultured cells are used, the cell population becomes extremely uniform) that are assumed to be living cells from the data obtained by dot plot expansion are gated, and the fluorescence intensity within the gate is measured.
  • the measurement result is shown in a form of, for example, histogram. Note here that the terms related to the histogram obtained in the flow cytometry analysis are mentioned below.
  • the “number of samples” denotes number of data and generally represented by n.
  • the “total” denotes a total of data and generally represented by T.
  • “Mean value” denotes an average of data and is calculated by dividing the total by the number of samples.
  • the mean value is susceptible to abnormal data.
  • the “median value” is a value located in the middle when the data are aligned in ascending numeric order. When the number of data is odd number, the average of two middle values is defined as a median value. The median value is less susceptible to abnormal data as compared with the mean value and shows the characteristics of the population more accurately.
  • the “mode” denotes a value whose frequency is maximum in the data. In the case of the flow cytometry analysis, the mode is the same as a peak value. The mode is less susceptible to abnormal data as compared with the mean value.
  • the “maximum value” is a maximum value of data and generally represented by Max.
  • the “range value” is difference between the maximum value and the minimum value and generally called range and referred to as R.
  • the “dispersion” is a value showing the degree of variation of data. The larger the dispersion is, the larger the variation is. In general, it is referred to as V.
  • the dispersion is obtained by dividing the sum of squares deviation by the number of samples (in the case of sample survey, divided by (number of samples ⁇ 1)).
  • the “standard deviation” denotes square root of the dispersion and is generally referred to as u.
  • the “coefficient of variation” is a value obtained by dividing the standard deviation by an average value and is generally referred to as CV.
  • the “kurtosis” is one of the indicators representing the distribution in the population and generally is referred to as H.
  • the distribution in which the kurtosis is 0 is defined as normal distribution.
  • the kurtosis is larger than 0, the distribution has sharper apex than the normal distribution.
  • the kurtosis is smaller than 0, the distribution becomes more flatness than the normal distribution.
  • the “skewness” denotes a value showing the left-right symmetry of the population and generally is referred to as G. When the skewness is 0, distribution becomes left-right symmetric. When the skewness is larger than 0, the distribution distorts in the right direction. When the skewness is smaller than 0, the distribution distorts in the left direction.
  • a plurality of antibodies having the identical or highly similar data are classified into one antibody group.
  • plurality of antibodies having extremely similar histogram is defined as one group when the shape of the histogram showing the distribution of cells is determined by the kurtosis, skewness and the like.
  • each antibody is classified by one or two or more criteria selected from the above-mentioned classification criteria (a) to (c).
  • the similarity of data can be determined based on the parameter specifying the data. However, the specific determination method is dependent upon the types of data. In the case where data are represented by numeric values, it is possible to determine the similarity based on the degree of similarity of numeric values (for example, when 1, 2, and 5 are given as data, it is determined that the similarity between 1 and 2 has high similarity).
  • the similarity of data can be determined by comparison by visual observation or by comparison of one or two or more of parameters specifying the histogram.
  • the parameters herein can employ one or more values selected from the group consisting of median value, mode, maximum value, range, standard deviation, kurtosis, and skewness of the histogram.
  • determination is carried out in terms of two or more values, furthermore preferably three or more values, and yet furthermore preferably four or more values.
  • the median value, mode, or kurtosis that are parameters deeply related to the shapes of the histogram are employed for carrying out the determination at high accuracy.
  • a combination of two or more of these parameters is used.
  • the similarity of the histogram may be determined based on the median value, mode, and kurtosis.
  • the similarity between the two data is determined to be high.
  • the difference between two values 100 ⁇ (A ⁇ B)/A (%) when the two values are A, B (A ⁇ B)
  • the two values are determined to be similar.
  • sample antibodies having a low reactivity to the cell surface antigen are removed.
  • an antibody group including highly useful sample antibodies can be formed.
  • the degree of the reactivity of the antibody can be determined by using the results of the flow cytometry analysis. Specifically, the mode (peak value) of the histogram obtained with respect to the sample antibody to be determined and the mode (that is to say, the maximum mode in the group) of the histogram obtained with respect to the sample antibody having the maximum reactivity in the antibody group to which the sample antibody belongs.
  • the former is 1 ⁇ 2 or less of the latter, preferably 1 ⁇ 5 or less, furthermore preferably 1/10, it is determined that the sample antibody to be determined has low reactivity.
  • the reactivity of each sample antibody is examined in two or more kinds of cells and the sample antibodies are classified by using the results. That is to say, two or more kinds of cells are prepared and by using the prepared cells, steps (2) to (4) are carried out.
  • the expression amount, distribution, and the like of the cell surface antigens are dependent upon the kinds of cells. Therefore, two antibodies having high similarity in data obtained by using certain cells, that is, two antibodies having the common antigens should provide data having high similarity when the other cells are used. Thus, when the two antibodies to be compared provide data with high similarity with respect to more than two kinds of cells, the probability that the antibodies have the common antigens is extremely high. Furthermore, when such results are obtained, it can be easily determined that the two antibodies have the common antigens. Thus, the use of two kinds or more cells can make it accurate and easy to determine the identity of antigens.
  • sample antibodies having identical or highly similar data with respect to at least two kinds of cells are classified into one antibody group.
  • a classification result is displayed as a panel.
  • the “panel” in this specification is a product in which a plurality of elements (for example, antigen, antibody, antibody group, cell, name of disease, name of pathologic condition), are displayed in the form of tables or drawings, in which the elements are associated with each other, on media such as a display and paper.
  • Each element is represented by general name, abbreviation, alias, or symbol or code representing thereof, and the like.
  • the panel of the present invention shows the relationship with respect to two kinds or more of elements.
  • sociating to in the present invention means that two or more elements are linked. Therefore, in the tabular format panel showing the association between an antigen and an antibody group, for example, both elements are displayed in adjacent to each other, or both elements are displayed in the same cells, or both elements are linked by a line or something, so that it can be understood that the both elements form a pair.
  • antibody groups are displayed in a way in which they are associated with each other for each antigen (or for each antigen having high association) expressed by the cells that have been subjected to the flow cytometry analysis. Therefore, this panel makes it possible to access antibodies useful for studying surface antigens of the cells. Thus, the panel itself of the present invention has a great value.
  • a panel formed by using two kinds or more of cells makes it possible to understand the presence, expression amount, and the like, of antigens expressing between cells. Such a panel has further higher values.
  • antibodies may be arranged regularly in accordance with the reactivity to antigens.
  • the difference in the reactivity between antibodies can be made obvious.
  • a plurality of antibodies recognizing the same antigen (or antigens having high association) are associated with each other.
  • antibody assembly antibody group
  • antibody groups are useful for studying cell surface antigen and have high usability.
  • a large number of antibodies can be classified rapidly for each antigen (or for each antigen having high association). That is to say, the classifying method of the present invention is useful for classification of a large number of antibodies and allows comprehensive classification of antibodies.
  • highly associated or “having high association” used for antigen means that two or more antigens have a close association in a living body, for example, the antigens are not the same molecules but exhibit one function cooperatively (for example, two antigens are bound so as to form one complex functionally).
  • plurality of antibodies are associated with each other for each antigen (or for each antigen having high association). Therefore, in studying certain antigens, a plurality of antibodies can be used or suitable antibodies can be selectively used if necessary, which leads to better results or significant findings and means that studying can be proceeded advantageously.
  • the classifying method of the present invention provides useful information on the properties of the certain cells and is useful for studying the cells (in particular, the surface antigens).
  • antibodies are classified based on the reactivity between the antigens and certain cell surfaces and the antibody groups are formed. Therefore, antibodies belonging to the same antibody group have the same (or highly similar) reactivity to the surface of cells used for classification. However, it is not necessarily ensured that all the antibodies belonging to the same antibody group can recognize the same antigens. Even if the recognizing antigen is the same, the reactivity to cells expressing antigens on the cell surface may be different. Furthermore, the opposite case may occur (even if the recognizing antigen is different, the reactivity to cells expressing antigens on the cell surface may be the same, for example, one of the complex may be recognized).
  • one embodiment of the present invention carries out the following steps (i) to (vi) after the step (4).
  • step (v) selecting an antibody corresponding to the combination specified in the step (iv) in terms of all parameters among the antibodies subjected to step (i);
  • an antibody group can be formed for each antigen to be recognized. That is to say, antibody groups having various individualities recognizing the same antigen can be obtained. Furthermore, the combination of the plurality of parameters is associated with each antigen and then an antibody mixture is prepared according to a predetermined regulation. Then, based on the results of ELISA (Enzyme-Linked immunosorbent assay) using the antibody mixture, an antibody recognizing a target antigen is determined.
  • ELISA Enzyme-Linked immunosorbent assay
  • the classifying method of this embodiment is a method of rapidly and efficiently obtaining an antibody whose antigen has been identified, which dramatically promote the increase in the number of antibodies whose antigens have been identified.
  • the classification results show the presence form or expression from on the cell surface used in flow cytometry analysis, which provides extremely useful information for study and development of the application of antibody (for example, treatment of cancer).
  • the classifying method of this embodiment efficiently functions as determining a novel antigen or novel molecule complex.
  • the classifying method of this embodiment is also referred to as “n dimensional ELISA method.”
  • each antibody has n-dimensional address (a parameter value of the first parameter, a parameter value of the second parameter, . . . , and a parameter value of the n-th parameter).
  • association is carried out with respect to all the antibodies that have been classified in the preceding steps, although the association is not limited to this. That is to say, the association may be carried out only a part of the antibodies that has been classified in the preceding steps. In this case, a part of antibodies are excluded from the antibodies to be classified.
  • n is an integer of two or more. That is to say, to each antibody, two or more combinations of parameters are associated.
  • the number of “n” does not have an upper limit. When the number of “n” is too large, operations in the subsequent steps (for example, preparation of an antibody mixture, specification of an antibody mixture showing the reactivity) may be excessively complicated. Therefore, “n” is preferably three to five.
  • each parameter is made to have two or more parameter values and the same parameter values of each parameter are made to be provided to two or more kinds of antibodies.
  • parameter values of the first parameter may be 1, 2, 3 and 4, and each parameter value is provided to five kinds of antibodies, respectively.
  • the number of the parameter values is set for each parameter. Furthermore, similar to the number of parameters, the number of the parameter values does not have an upper limit.
  • each parameter value may be set so that the kinds of antibodies contained in each antibody mixture is preferably 200 or less, and furthermore preferably, 100 or less. Specifically, for example, the number of the parameter values can be set to between 2 and 100. Note here that the kind of antibodies contained in each antibody mixture is dependent upon the setting of the parameter, and may not be equal between antibody mixtures.
  • an antibody mixture in which antibodies having the same parameter value are mixed, is prepared.
  • the antibody mixture is prepared for each parameter.
  • an antibody mixture mixing antibodies to which 1 is given as the first parameter an antibody mixture mixing antibodies to which 2 is given as the first parameter, an antibody mixture mixing antibodies to which 3 is given as the first parameter, and an antibody mixture mixing antibodies to which 4 is given as the first parameter are prepared.
  • antibody mixtures are prepared.
  • antibody mixtures in the same number as the total number of the number of the first parameter, the number of the second parameter, and the number of the n-th parameter are prepared.
  • an antibody mixture in which all antibodies having the same parameter values are mixed, are prepared although the antibody mixture is not limited to this.
  • An antibody mixture may be prepared by selecting a part of all antibodies having the same parameter values and mixing thereof. Thus, the selection of antibodies may be carried out in this stage.
  • an antibody mixture is prepared so that all antibodies are contained in equal amount and the amount of each antibody (that is, concentration for each antibody) is equal between antibody mixtures. Adjusting the amount of antibodies in this way facilitates the specification of the antibody mixture based on the reactivity in the following ELISA.
  • the reactivity between each of the antibody mixtures and the target antigen is examined by ELISA so as to specify the antibody mixture showing the reactivity.
  • a plurality of antibody mixtures shows the reactivity.
  • any of the antibody mixtures will not show reactivity. In this case, the operation is terminated without continuing the following operations.
  • the target antigen herein nay include HER1, HER2, CD46, ITGA3, ICAM1, ALCAM, CD147, IgSF4, BCAM, CIqR, CD44, CD73, LAR, EpCAM, HGFR, and the like.
  • the target antigen can be arbitrarily selected.
  • the antigen determined by the below-mentioned identification methods (step (5) and (6)) may be used as the target antigen herein.
  • a combination of a parameter name and a parameter value that are common to the antibody group contained in the specified antibody mixture is specified.
  • the combination specified herein is referred to as “positive combination.”
  • the positive combination is specified like (first parameter, parameter value a1), (second parameter, parameter value a2), . . . , (the n-th parameter, parameter value an).
  • specification may be carried out for each level of the reactivity.
  • the middle level of positive combination may be specified like (first parameter, parameter value a1), (second parameter, parameter value a2), . . .
  • the n-th parameter, parameter value an (the n-th parameter, parameter value an); and the high level of positive combination may be specified like (first parameter, parameter value b1), (second parameter, parameter value b2), . . . , (the n-th parameter, parameter value bn).
  • antibodies corresponding to the combination specified in step (iv) as to all parameters are selected from the antibody subjected to step (i). That is to say, antibodies in which all parameters are positive combination are selected.
  • antibodies having (parameter value a1, parameter value a2, . . . , parameter value an) is selected.
  • the selected antibodies are classified into one antibody group.
  • an antibody group showing the reactivity to the target antigen can be made into one group.
  • an antibody group whose antigen is determined can be obtained. Note here that when only one antibody is selected in the step (v), this only one antibody makes one an antibody group.
  • the steps (i) to (v) are tried a plurality of times under the conditions in which the combination of parameters is changed every trial.
  • the first trial analysis is carried out in which four parameter combinations composed of numeric values (for example, antibody 1 (001, 001, 001, 001), antibody 2 (002, 002, 002, 002), . . . ) are associated with each antibody.
  • the second trial analysis is carried out in which three parameter combinations composed of alphabets (for example, antibody 1 ( ⁇ , ⁇ , ⁇ ), antibody 2 ( ⁇ , ⁇ , ⁇ , ⁇ ), . . . ) are associated with each antibody.
  • each trial is carried out so that the antibody group formed in each trial is not completely identical.
  • the “antibody group is completely identical” means that the numbers of groups are the same and the kinds of antibodies contained in each group are the same over the all groups.
  • the step (vi) is carried out by using the selected antibody (a plurality of antibodies).
  • the number of times of trial in the steps (i) to (v) is not particularly limited. It may be arbitrarily set by considering the number of antibodies to be treated, the number of “positive combinations” that is anticipated at one trial. For example, the number of times of trial can be twice to five times.
  • step (v) the following steps are carried out between the step (v) and the step (vi).
  • step (v-1) newly associating the classified antibodies selected in step (v) with a combination of n pieces of parameters in a same manner as in the step (i);
  • steps (v-1) to (v-4) are repeated twice or more, if necessary.
  • a combination of parameters is newly associated with antibodies selected in one trial. Then, the selection of antibody is carried out again. By repeating trials, the intended antibody is narrowed. Thus, classification accuracy is improved.
  • FIGS. 77 and 78 are conceptual diagrams in a case where n is 3 (three dimensional ELISA method).
  • n 3 (three dimensional ELISA method).
  • a general-purposed 96-well microwell plate is used. Firstly, plates in the number necessary to the number of antibody clones are prepared. In this example, the number of antibody clones is made to be 4,800 and 50 plates (4,800 well in total) are prepared.
  • each antibody clone is placed in the well sequentially and the antibody clones are arranged in the plate.
  • each antibody clone is associated with an address consisting of a plate number (first parameter), a plate row name (second parameter), and a plate column number (third parameter).
  • first parameter a plate number
  • second parameter a plate row name
  • third parameter a plate column number
  • the address of the antibody clone in the first plate, row A and first column in a well becomes (1, A, 1).
  • a mixture of antibody clones having the same plate number (referred to as a plate mixed antibody), a mixture of antibody clones having the same plate row name (referred to as a row mixed antibody), and a mixture of antibody clones having the same plate column number (referred to as a column mixed antibody) are prepared, respectively ( FIG. 77 ).
  • the number of the respective mixed antibodies are 50 (first plate mixed antibody to fifth plate mixed antibody), 8 (row A mixed antibody to row H mixed antibody), and 12 (first column mixed antibody to twelfth column mixed antibody), sequentially.
  • the mixed antibodies prepared as mentioned above are placed in wells in a newly prepared 96-well microwell plate sequentially, and the mixed antibodies are aligned in the plate.
  • the first to seventh columns are assigned to the plate mixed antibody
  • the eighth column is assigned to the row mixed antibody
  • the ninth to tenth columns are assigned to the column mixed antibody (upper part of FIG. 78 ).
  • the thus obtained plates are used and ELISA method is carried out. Then, by examining the well showing the reactivity, the address of the intended antibody clone (antibody clone showing the reactivity to the target antigen) is specified.
  • the second aspect of the present invention provides an identifying method of an antigen to each antibody classified in the classifying method of the present invention.
  • the identification method of the present invention following the above-mentioned steps (1) to (4) in the classifying method of the present invention, the below-mentioned steps are carried out.
  • antibodies to be identified are selected.
  • the criteria of selection are not particularly limited, and antibodies that are judged to have high reactivity with respect to antigen from the results of the flow cytometry analysis may be selected. This is because when such an antibody is used, the identification operation using the antigen antibody reaction can be carried out advantageously.
  • the number of antibody to be selected is typically one, but the number is not necessarily limited to one. If necessary, several antibodies (for example, two or three antibodies) are selected. When a plurality of antibodies are selected from one antibody group, the identification results of antibodies can be compared with each other, and thereby the reliability of the identification results can be improved. On the other hand, when the identification operation is carried out by selecting a more than necessary number of antibodies, excessive workload is applied. As a result, the effect that is originally intended by the present invention is decreased. Then, it is preferable that the number of antibodies to be selected is small. Specifically, the number is preferably five or less, further preferably three or less, and the most preferably two or less. In order to maximize the effect of the present invention, the number of antibody to be selected from each antibody group is one.
  • Identification of an antigen to an selected antibody can be carried out by using a method such as mass spectrometry, immunoprecipitation test, Western blotting, affinity chromatography, RNAi, proteomics techniques (analysis by electrophoresis, mass spectrometry, genome data base retrieve, and bioinformatics), and analysis of expression of corresponding gene.
  • a method by the proteomics technique based on the mass spectrometry is suitable for identification of unknown antigen and preferable for the identification method employed in the present invention. Note here that these methods are not exclusive to each other and two or more of them can be used if necessary.
  • the mass spectrometry is a method of determining the mass of samples by separating ions generated from samples such as protein and peptide according to mass/electric charge (m/z), and measuring the intensity thereof. Since soft ionization methods such as an ESI method (Electro Spray Ionization) and an MALDI method (Matrix Assisted Laser Deporption Ionization) are developed, the mass spectrometry is widely used for analyzing living body sample such as protein and peptide.
  • a mass spectrometer is generally composed of ion source, mass spectrometer, and detector. According to sample types and analysis purposes, various mass spectrometers are commercially available. For identification of protein or peptide, MS/MS (Mass spectrometry/mass spectrometry) by a tandem mass spectrometry such as ESI Q-TOF MS, MALDI-TOF MS, and the like are used.
  • MS/MS Mass spectrometry/mass spectrometry
  • ESI Q-TOF MS ESI Q-TOF MS
  • MALDI-TOF MS MALDI-TOF MS
  • a measurement method combining liquid chromatography and mass spectrometer LC-MAS (liquid chromatography/Electro Spray Ionization mass spectrometer), LC-MS/MS, etc.), and the like, can be also used.
  • tandem mass spectrometer two mass spectrometers are linked in series in which ions generated in the ion source are separated in the first mass spectrometer (MS 1) and allowed to pass through only a single ion peak. Then, inactive gas particles are allowed to collide with the ions so as to be degraded into product ions. This product ion is analyzed by the second mass spectrometer (MS 2). According to the combination of the first mass spectrometer (MS 1) and the second mass spectrometer (MS 2), tandem mass spectrometers such as Q-TOF, TOF-TOF, Q-Q, and Q-IT (Iontrap) are present.
  • tandem mass spectrometers such as Q-TOF, TOF-TOF, Q-Q, and Q-IT (Iontrap) are present.
  • hybrid type tandem mass spectrometer composed of two different kinds of mass spectrometers is excellent in MS/MS measurement ability and suitable for identifying the amino acid sequence of protein and peptide.
  • a PMF method peptide mass fingerprinting method of carrying out genome data search by using experiment results, MS/MS ion search method and the like, are used. Furthermore, de novo sequencing method of determining the amino acid sequence by mathematical operation from the MS/MS spectrum without carrying out genome data search may be used.
  • an immunoprecipitation test Western blotting technique, affinity chromatography, RNAi, and the like, are effective method when a selected antibody is anticipated to recognize the known antigen. These methods can examine the reactivity between the selected antibody and well-known antigen. That is to say, in the immunoprecipitation test, it is examined whether or not the selected antibody and certain known antigen form an immunoprecipitate. When an immunoprecipitate is formed, the known antigen is determined to be the antigen of the selected antibody. On the other hand, in the Western blotting technique, it is examined whether or not the selected antibody can recognize an antigen protein transferred to a PVDF membrane etc.
  • RNAi of the known antigen is allowed to act on forcedly expressed cells or cells to which an antibody is reacted. It is determined that the subject antibody recognizes the subject antigen when the staining property FCM or the degree of cell immunostaining is reduced.
  • the identification method of the present invention following the step (5), it is assumed that antigens to each antigen belonging to the same antibody group are identical or have high association. According to the assumption, the antigens identified in the step (5) are associated with an antibody group. Thus, all antibodies belonging to the same antibody group are associated with one antigen.
  • the above assumption (estimation as to the association of antigen) is verified. That is to say, in this embodiment, the reactivity between the antigen identified in the step (5) and the antibody belonging to the antibody group with which the antigen is associated in the step (6) is examined so as to confirm that the above assumption is correct. Specifically, firstly, antibodies are selected from the antibody group that needs verification. Preferably, all the antibodies are selected, and the reactivity thereof is verified. Next, the reactivity of each antibody to the identified antigen (hereinafter, referred to as “identified antigen”) is examined by using the immunoprecipitation test or ELISA (including cell ELISA), and RNAi.
  • ELISA including cell ELISA
  • the immunoprecipitation test by reacting the antibody to an solution or an extracted solution of cells that express the identified antigen, then, proteins recovered as the immunoprecipitates are detected by, for example, electrophoresis. Thereby, the reactivity of each antibody to the identified antigen can be confirmed.
  • ELISA for example, by a series of operations including preparation of well in which an identified antigen is fixed, addition of antibody, addition of labeled antibody, and measurement amount of labeled antibodies, the reactivity of each antibody with respect to the identified antigen can be confirmed. Furthermore, also by examining the binding property to cells forcedly expressing the identified antigen, the reactivity of each antigen to the identified antigen can be confirmed.
  • RNAi In the verification by RNAi, by allowing the known RNAi to act on cells forcedly expression the identified antigen or subjected cells showing the antibody reaction. When, the staining property of the subjected antibody in FCM and cell immunostaining is reduced, it is recognized that the subjected antigen is recognized.
  • disease-related molecules disease causative gene products, etc.
  • the intermolecular interaction between such molecules and the antibodies can be examined in vitro (classical methods using fluorescence spectroscopy, gel filtration, and ultracentrifugation; a method using surface plasmon resonance phenomenon; a method using quartz-crystal resonator microbalance, and the like) or in vivo (monomolecular tracing method, fluorescence resonance energy metastasis (fluorescence resonance energy transfer: FRET) observation method, and the like).
  • identification results are displayed on a panel.
  • the panel is any of the following (a) to (c).
  • a panel displaying as one antibody group a plurality of antibodies providing histogramidentical to or similar to each other in the flow cytometry analysis in the step (3) in which each antibody group, its antigen and a cell expressing a cell surface antigen recognized by the antibody are associated with each other.
  • the above-mentioned panels are useful for studying identified antigens, and for studying or classifying certain cells displayed on the panel.
  • the panel (a) displays the relationship between each antigen to the antibody group. Therefore, it is useful in searching an antibody to a certain antigen.
  • the panel (a) can be formed by displaying by the use of diagrams or tabular formats the association between each antibody group and the antigen by using identification results by steps (5) and (6) of the present invention in which a plurality of antibodies providing identical or highly similar data in the flow cytometry analysis in the step (3) of the present invention are defined as one group.
  • the panel (b) shows the association between the antibody group and cells. Therefore, it is useful in searching an antibody to a certain cell surface antigen. Furthermore, when the panel displays the association between the antibody group and a plurality of cells, useful information on the distribution of cell surface antigen can be provided.
  • the panel (b) can be formed by displaying by the use of diagrams or tabular formats the association between each antibody group and cells expression the cell surface antigen recognized thereby by using identification results by steps (5) and (6) of the present invention in which a plurality of antibodies providing identical or highly similar data in the flow cytometry analysis in the step (3) of the present invention are defined as one group.
  • the panel (c) combines the panel (a) and the panel (b). This panel shows that the kinds or distribution state of a cell surface antigen expressed by certain cells and allows easy and rapid search of antibodies to the antigens of interest.
  • the panel (c) can be formed by displaying by the use of diagrams or tabular formats the association between each antibody group and cells expression the cell surface antigen recognized by the antigen and each antibody group by using identification results by steps (5) and (6) of the present invention in which a plurality of antibodies providing identical or highly similar histogram in the flow cytometry analysis in the step (3) of the present invention are defined as one group.
  • identification of antigen with respect to only a part of the antibodies in the antibody group, and as to the other antibodies, antigens are determined by estimation. Therefore, as compared with the case where identification operation is carried out for each antibody, necessary labor and time can be radically reduced. In other words, according to the identification method of the present invention, antigen of each antibody can be determined rapidly and easily. Note here that as shown in the below-mentioned Examples, as far as the present inventors have investigated, error in estimation has not been confirmed. The reliability of this method has been confirmed.
  • the identification method of the present invention it is possible to understand the kinds of surface antigens expressed by certain cells. Furthermore, information on the expression amount can be obtained. When the classification of antibodies is carried out by using two kinds or more cells, information on the distribution state of the cell surface antigens can be obtained. Thus, the identification method of the present invention brings useful information as to the cell surface antigen.
  • the identification method of the present invention it is possible to obtain an assembly of antibodies capable of recognizing antigens for each identified antigen (or for each of the plurality of antigens having high association).
  • These antibody groups are useful for study of the cell surface antigens, classification and diagnosis of diseases, and the like. These antibody groups are expected to be applied to the field of treatment.
  • the present invention further provides an application of information obtained by the classifying method or the identification method of the present invention.
  • the third aspect of the present invention relates to a method of obtaining an antibody or an antibody set having a association with respect to a certain disease.
  • the method of obtaining the antibody of the present invention includes the following steps.
  • a method of obtaining an antibody set of the present invention includes the step (3′) instead of the step (3):
  • FIG. 1 it is assumed that the antibody groups 1 to 5 are obtained by the classifying method of the present invention and three antibodies belong to each antibody group. Furthermore, in this example, it is assumed that antigens to each antibody group have been already identified.
  • step (1) focused antibody group (antibody groups 1, 3, and 5) are selected ( FIG. 1 , ( 1 )).
  • two or more antibody groups may be selected.
  • the reactivity between an antibody to each of the selected antibody groups and a certain disease is examined. Specifically, a sample (cells or tissues) derived from a patient having a certain disease is prepared, and then, the reactivity of each antibody to the sample is examined ( FIG. 1 , ( 2 )). Two or more antibodies from each of the selected antibody groups are selected, and thereby the reactivity of them may be examined.
  • the “certain disease” herein is not particularly limited but it may include various kinds of cancers, for example, kidney cancer, hepatic cell carcinoma, gallbladder and liver cancer, alveolar cell carcinoma, lung squamous cell cancer, pulmonary adenocarcinoma, pancreas cancer, adenocarcinoma, or ovarian cancer.
  • the reactivity with respect to two kinds or more of diseases are examined simultaneously.
  • the examination is not limited to this alone.
  • the reactivity to one disease may be examined.
  • the reactivity with respect to a certain pathologic condition in the certain disease may be examined.
  • the reactivity with respect to the samples derived from a patient can be detected and evaluated by using an immunohistochemical staining technique, an immunoprecipitation method, flow cytometry analysis, cell ELISA and the like. These methods are not exclusive to each other and therefore two or more of these methods can be used if necessary. Among them, it is preferable to employ the immunohistochemical staining technique.
  • the immunohistochemical staining technique permits rapid and sensitive detection. Furthermore, its operation is relatively simple.
  • the method of the present invention can be carried out according to the following immunohistochemical staining technique.
  • the immunohistochemical staining of living tissue is generally carried out by the following procedures (a) to 0).
  • the immunohistochemical staining of living tissue can be referred to as various documents and publications (for example, “Enzyme-labeled Antibody Method” 3rd revised edition, K. Watanabe and K. Nakane (ed), Gakusai Kikaku).
  • treatment is carried out with xylene, alcohol, and purified water sequentially in this order.
  • antigen activation for example, enzyme treatment, heat treatment and/or pressurization treatment are carried out.
  • Non-specific reaction is inhibited by treating a section with bovine serum albumin solution (for example, 1% solution) for several minutes to several tens of minutes. Note here that this process may be omitted when the following primary antibody reaction is carried out by using an antibody solution impregnated with bovine serum albumin.
  • bovine serum albumin solution for example, 1% solution
  • peroxidase As the label material, peroxidase is frequently used. Secondary antibody bonded to peroxidase is dropped on the section and then allowed to react for ten minutes to several hours. After reaction, the reacted product is washed with an appropriate buffer solution such as phosphate buffer.
  • DAB (3,3′-diaminobenzidine) is dissolved in Tris buffer. Then, hydrogen peroxide solution is added. The thus prepared coloring solution is impregnated into a section for several minutes (for example, five minutes) so as to color the section. After coloring, the section is sufficiently washed with tapped water so as to remove DAB.
  • the section is subjected to nuclear staining by reacting it with Mayer hematoxylin for several seconds to several tens seconds. It was washed with flowing water for saddening (in general, for several minutes).
  • the section is dehydrated with alcohol, clearing treated with xylene, and finally encapsulated with synthesized resin, glycerine, rubber syrup, and the like.
  • an antibody that is recognized to have specific reactivity to any of diseases can detect a cell surface antigen characterizing the disease with high sensitivity. Such an antibody is expected to be used as a diagnosis or treatment antibody of the disease.
  • an antibody of the antibody group including such an antibody is selected ( FIG. 1 ( 3 )).
  • disease A an antibody (antibody 1-1, 1-2 or 1-3) of the antibody group 1 and an antibody of the antibody group 3 (antibody 3-1, 3-2 or 3-3) are selected.
  • disease B an antibody (antibody 5-1, 5-2 or 5-3) of the antibody group 5 is selected. In this way, a specific antibody for a certain diseases can be obtained.
  • a disease in which two or more antibodies show the specific reactivity is selected, and then, each antibody is selected from the antibody group to which the antibody showing the specific reactivity to the disease belongs, is selected, and the selective antibodies are combined ( FIG. 1 , ( 3 ′)). That is to say, in this example, the disease A is selected and the antibodies of antibody groups 1 and 3, which are antibody groups to which the antibody showing the specific reactivity to the disease A belongs, are combined. Thus, the antibody set showing specific to a certain disease is obtained.
  • an antibody having the most excellent property may be selected (in this example, antibody 1-2, antibody 3-3, and antibody 5-3 are selected. See, FIG. 1 , ( 4 )). By adding this step, more useful antibody or antibody set can be obtained.
  • an antibody set may be structured by combining an arbitrary antibody that does not have reactivity to the diseases with the antibodies selected as the antibodies showing the reactivity to a certain disease (in this example, for example, the antibody 4-1 is combined to an antibody of the antibody group 1 and antibody of antibody group 3).
  • the antibody 4-1 is combined to an antibody of the antibody group 1 and antibody of antibody group 3.
  • an antibody (or antibody set) to a disease-specific antigen can be obtained.
  • the antibody (or antibody set), which are as it is or to which necessary modification is added, is useful for study, classifying, diagnosing and treating the disease or the pathologic condition.
  • this method provides an extremely useful tool in the field of medicine.
  • the third embodiment of this aspect provides the obtaining method of antibody set including the following steps.
  • the antibody groups 1 to 6 are obtained by the classifying method of the present invention and three antibodies belong to each antibody group.
  • the antigens (antigen A) in the antibody groups 1 to 3 are common.
  • the antigens (antigen B) in the antibody groups 4 and 5 are also common.
  • step (1) of this embodiment two or more antibody groups recognizing different antigens (antibody groups 1, 4, and 6) are selected (see, FIG. 2 (1)).
  • step (2) the reactivity between the antibodies (antibodies 1-1, 4-1, and 6-1) in each of the selected antibody groups and certain diseases (diseases A to D) are examined ( FIG. 2 , ( 2 )).
  • step (3) antibodies in the antibody groups to which the antibody belong showing specific reactivity to any of diseases are combined. That is to say, in this example, an antibody of antibody group 1 to which an antibody 1-1 showing specific reactivity to disease A and an antibody of antibody group 4 to which an antibody 4-1 showing specific reactivity to disease B are combined to form an antibody set ( FIG. 2 , ( 3 )).
  • an antibody set (the antibody 1-1 and the antibody 4-1) including an antibody specific to disease A and an antibody specific to disease B is obtained.
  • This antibody set is useful for detecting, for example, disease A or disease B and this antibody is a reagent effective to the discrimination of the diseases A and B.
  • an antibody having the most excellent property may be selected (In this example, the antibody 1-2 and the antibody 4-3 are selected. FIG. 2 , ( 4 )). By adding this step, it is possible to obtain a more useful antibody set.
  • the fourth embodiment of this aspect provides a obtaining method of an antibody set including the following steps.
  • the antibody groups 1 to 6 are obtained by the classifying method of the present invention and three antibodies belong to each antibody group.
  • the antigens (antigen A) in the antibody groups 1 to 3 are common.
  • the antigens (antigen B) in the antibody groups 4 and 5 are also common.
  • step (1) of this embodiment two or more antibody groups recognizing different antigens (antibody groups 1, 4, and 6) are selected (see, FIG. 3 ( 1 )).
  • step (2) the reactivity between the antibodies (antibodies 1-1, 4-1, and 6-1) in each of the selected antibody groups- and certain diseases (diseases A to D) are examined ( FIG. 3 , ( 2 )).
  • step (3) an antibody of the antibody group to which an antibody showing the specific reactivity to any of diseases and an antibody belonging to other antibody group whose antigen is common to the group are selected, respectively.
  • the selected antibodies are combined so as to form an antibody set ( FIG. 3 , ( 3 )).
  • an antibody in antibody group 1 to which antibody 1-1 belongs showing specific reactivity to disease A and an antibody of the antibody groups 2 and 3 whose antigens are common are combined.
  • an antibody set specific to the disease A is obtained.
  • an antibody set specific to the disease B is obtained.
  • “another antibody group” herein is not particularly one but a plurality antibody groups may be present.
  • the pathologic condition (grade of malignancy) may be largely different.
  • the difference in such pathologic conditions is thought to be involved to the expression forms of the specific antigens.
  • the antibody sets obtained in this embodiment are not different in the level recognized by an antigen but include antibodies that are different in the level of epitope. That is to say, this is an antibody set including a plurality of antibodies that are different in the epitope to be recognized.
  • Such an antibody set permits multilateral detection or evaluation of expression forms of antigen.
  • such an antibody set is useful for detection of certain pathologic conditions in, for example, cancers, or a determination of the grade of malignancy.
  • the fifth embodiment of this aspect provides a obtaining method of an antibody set including the following steps.
  • the antibody groups 1 to 6 are obtained by the classifying method of the present invention and three antibodies belong to each antibody group.
  • the antigens (antigen A) in the antibody groups 1 to 3 are common.
  • the antigens (antigen B) in the antibody groups 4 and 5 are also common.
  • step (1) of this embodiment two or more antibody groups recognizing common antigen (antibody groups 1 to 3) are selected (see, FIG. 4 ( 1 )).
  • step (2) the reactivity between the antibodies (antibodies 1-1, 2-1, and 3-1) in each of the selected antibody groups and certain various diseases are examined ( FIG. 4 , ( 2 )).
  • samples cells or tissue
  • the obtained reactivity is associated with each other ( FIG. 4 , ( 2 ), right column), and then antibodies of each of the selected antibody groups (antibody groups 1 to 3) are combined so as to form an antibody set ( FIG.
  • antibody sets specific to the certain pathologic condition of certain disease is obtained (in this example, an antibody set specific to pathologic condition of disease A including antibodies of the antibody groups 1 to 3 is obtained).
  • the antibody set obtained in this embodiment is typically not different in the level of an antigen but include antibodies that are different in the level of epitope. Therefore, similar to the antibody set according to the above-mentioned embodiment, for example, the antibody set is useful detecting the certain pathologic condition in, for example, cancer, or a determination of the grade of malignancy. Note here that it is preferable that an antibody set is constructed by excluding antibodies showing no specific reactivity with respect to any pathologic conditions.
  • an antibody having the most excellent property may be finally selected (in this example, antibodies 1-2, 2-1 and 3-3 are selected, FIG. 4 , ( 4 )). By adding this step, it is possible to obtain a more useful antibody set.
  • a further aspect of the present invention provides a production method of a panel displaying a association between an antibody and a disease (or pathologic condition).
  • the following steps are carried out.
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a panel displaying the association with respect to a certain disease can be obtained.
  • difference or points of difference one caused by the cross reactivity and the like
  • the step (2) it is preferable to examine the reactivity of the antibody as to two or more diseases.
  • a panel displaying the association (linkage) between each antibody and two or more diseases can be obtained.
  • the panel displays more pieces of information and further displays the association between diseases. Suggestion that is useful and important for study, classification and diagnosis of the diseases can be obtained.
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a panel displaying the association between a plurality of antibodies whose antigen is different and a certain disease can be obtained.
  • This panel gives information on an antibody group useful for study, classification and diagnosis for a disease and the panel itself has a great value.
  • the association (linkage) between a plurality of antigens and disease can be read out. That is to say, the panel gives important suggestions as to the association between each antigen and disease as well as the association between antigens.
  • the step (2) it is preferable to examine the reactivity of the antibody as to two or more diseases.
  • a panel displaying the association between each antibody and two or more diseases can be obtained.
  • the panel displays more pieces of information and further displays the association between diseases. Suggestion that is useful and important for study, classification and diagnosis of the diseases can be obtained.
  • step (3) associating the results of the step (2) with each antibody and displaying by using a drawing or a tabular format.
  • a panel displaying the association with respect to a pathologic condition of a certain disease can be obtained.
  • This panel gives information on antibody group that is useful for study of each pathologic condition, study of difference between pathologic conditions, classification of pathologic conditions, or diagnosis on the level of the pathologic condition.
  • the panel itself has a great value.
  • the step (2) it is preferable to examine the reactivity of the antibody as to two or more pathologic conditions.
  • a panel displaying the association between each antibody and two or more pathologic conditions can be obtained.
  • This panel displays not only more pieces of information but also the association between the pathologic conditions. Suggestion that is useful and important to study, classification and diagnosis of each pathologic condition can be obtained.
  • the first embodiment of this aspect corresponds to the first and second embodiments of the third aspect.
  • the third aspect of the second embodiment corresponds to the third and fourth embodiments of the third aspect, respectively. Therefore, as to the matters that are not specifically noted in this aspect, the explanation of the corresponding third aspect is employed.
  • the term “association between antibody and disease (or pathologic condition)” is displayed by characters showing subject diseases (or pathologic conditions) are positive or negative to the antibody (for example, “to positive,” “to negative,” “positive,” and “negative”) or marks (for example, “o,” “x,” “P,” and “N”) etc.
  • the display is not limited to two-stage display and, display may be carried out in four stages, for example, strongly positive, moderate positive, weak positive, and negative.
  • the number of antibodies displayed in one panel is not particularly limited.
  • the number is 1 to 1000, preferably 2 to 100, and further preferably 5 to 59.
  • an antigen to each antibody may be shown.
  • the combination of the panel of this aspect and the antibody (or antibody set) obtained in the above-mentioned obtaining method of the present invention becomes an effective tool for study, classification and diagnosis of diseases, pathologic conditions, or the like. That is to say, according to the combination, both information, i.e., an antibody (or an antibody set) specific to a disease or a pathologic condition and the association between the antibody (or the antibody set) and the disease or the pathologic condition can be obtained simultaneously.
  • the present invention further relates to a method of testing a disease in which a cell surface antigen is an indicator, the method comprising the following steps.
  • the testing method of the present invention as to a disease or a pathologic condition to be tested (hereinafter, referred to as “diseased to be tested”), information about the presence of contraction of a subject, contraction risk, pathologic conditions, and the like, can be obtained. That is to say, the testing method of the present invention is effective means for diagnosing the subjected disease. Furthermore, when the testing method of the present invention is carried out along with the treatment, the therapeutic effect can be evaluated based on the testing results. Thus, the testing method of the present invention may be used for monitoring the therapeutic effect.
  • step (1) cells or tissue separated from a subject (that is, a living body) (hereinafter, referred to as “subject cell, and the like”) are prepared.
  • the term “separated from a subject” means a state in which a part of cells or tissue of a subject is extracted and completely isolated form a subject as a living body.
  • a person who needs information about a disease to be tested is a subject.
  • a subject may be a patient of a disease to be tested or may be an apparent healthy person.
  • the “apparent healthy person” means a person who has not recognized to be a patient of a disease to be tested prior to the application of the testing method of the present invention.
  • the reactivity between the subject cells and the like and each antibody displayed on the panel of the present invention is examined. That is to say, by using an immunologic procedure (for example, immunohistochemical staining technique), whether or not the tested cells express an antigen recognized by each antibody is examined.
  • an immunologic procedure for example, immunohistochemical staining technique
  • information on the expression amount of antigens can be obtained. Therefore, in addition to the presence of expression antigen, the expression amount may be also examined.
  • An example of the immunologic procedure includes ELISA method, radioimmunoassay, flow cytometry analysis, immunoprecipitation method, immune-blotting, and the like.
  • step (3) the results of the step (2) (reactivity of each antibody) is collated with the panel of the present invention.
  • the panel of the present invention displays the association between each antibody and a disease or a pathologic condition. Therefore, this step clarifies the association between the tested cells etc. and the disease via the reactivity with respect to each antibody.
  • a further application of the above-mentioned panel also includes the following method of the present invention, that is, the optimum method of treating certain diseases, which includes the following steps.
  • an effective antibody is selected (the step (4)).
  • an effective antibody typically, an antibody showing a specific reactivity in the step (2) is selected.
  • An antibody equivalent to the antibody showing a specific reactivity in the step (2) may be also selected.
  • the “equivalent antibody” means an antibody having equivalent properties (reactivity or activity) to the reference antibody.
  • An example of the equivalent antibody may be an antibody in which the sequence of the heavy chain variable region and the sequence of the light chain variable region are not substantially different from that of the reference antibody (completely identical, or slightly different so that the reactivity or activity is not affected).
  • Another example of the equivalent antibody may be an antibody in which no difference is observed in all of the sequence of each CDR constituting heavy chain variable region and the sequence of each CDR constituting light chain variable region when it is compared with the reference antibody.
  • Diseases to which the selection method of the present invention is applied is a disease in which cell surface antigen selected from the group consisting of HER1, HER2, CD46, ITGA3, ICAM1, ALCAM, CD147, IgSF4, BCAM, C1qR, CD44, CD73, LAR, EpCAM and HGFR is an indicator. That is to say, for selecting optimum treatment methods suitable for various diseases characterized by the expression of the cell surface antigen, the present invention can be used. According to the present invention, optimum treatment method suitable for each patient can be selected. Thus, tailor-made medicine can be realized.
  • the panel used in the selection method of the present invention displays two or more antibodies selected from the group consisting of 048-006 antibody, 057-091 antibody, 059-152 antibody, 048-040 antibody, 054-101 antibody, 055-147 antibody, 059-173 antibody, 067-149 antibody, 067-176 antibody, 015-126 antibody, 015-044 antibody, 015-102 antibody, 015-136 antibody, 015-143 antibody, 015-209 antibody, 039-016 antibody, 053-216 antibody, 075-024 antibody, 075-110 antibody, 086-032 antibody, 086-035 antibody, 086-036 antibody, 086-061 antibody, 086-138 antibody, 086-182 antibody, 035-224 antibody, 045-011 antibody, 051-144 antibody, 052-053 antibody, 052-073 antibody, 053-049 antibody, 3172-120 antibody, 066-069 antibody, 015-003 antibody, 064-002 antibody, 064-006 antibody, 064-012a antibody, 064-012b antibody, 064-014 antibody
  • step (1) of this embodiment a panel displaying the reactivity between an antibody successfully obtained by the present inventor and clinical cancer tissue of a certain disease is prepared.
  • cells or tissue separated from a subject are prepared.
  • step (2) or later are carried out similar to the above-mentioned embodiments.
  • a specific example of the panel to be used in this embodiment is a panel shown in FIG. 69 .
  • an antibody showing the specific reactivity in the step (2) or the equivalent antibody thereto is selected as an effective antibody.
  • the selection method of this embodiment is preferred for selecting the suitable treatment method of squamous carcinoma, adenosquamous carcinoma, alveolar adenocarcinoma, adenocarcinoma, or large cell carcinoma.
  • a certain disease can be newly classified based on the expression state of an antigen and further such a disease can be examined.
  • a further aspect of the present invention provides an antibody successfully obtained by the present inventors and the application thereof.
  • the present inventors succeeded in obtaining nine kinds of antibodies to HER1 (048-006 antibody, 057-091 antibody, 059-152 antibody, 048-040 antibody, 054-101 antibody, 055-147 antibody, 059-173 antibody, 067-149 antibody, and 067-176 antibody), 16 kinds of antibodies to HER2 (015-126 antibody, 015-044 antibody, 015-102 antibody, 015-136 antibody, 015-143 antibody, 015-209 antibody, 039-016 antibody, 053-216 antibody, 075-024 antibody, 075-110 antibody, 086-032 antibody, 086-035 antibody, 086-036 antibody, 086-061 antibody, 086-138 antibody, and 086-182 antibody), eight kinds of antibodies to CD46 (035-224 antibody, 045-011 antibody, 051-144 antibody, 052-053 antibody, 052-073 antibody, 053-049 antibody, 3172
  • these antibodies are recognize an extracellular domain of antigen in a state in which it is expressed on the surface of the cell membrane, they are useful for staining cells and tissues, and the like.
  • sequence information is obtained. Note here that, following to the antibody name, the amino acid sequence of the heavy chain variable region; the amino acid sequence of the heavy chain CDR1; the amino acid sequence of the heavy chain CDR2; the amino acid sequence of the heavy chain CDR3; the amino acid sequence of the light chain variable region; the amino acid sequence of the light chain CDR1; the amino acid sequence of the light chain CDR2; and the amino acid sequence of the light chain CDR3 are described sequentially in this order.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned nine kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 1 VH
  • SEQ ID NO: 2 VH CDR1
  • SEQ ID NO: 3 VH CDR2
  • SEQ ID NO: 4 VH CDR3
  • SEQ ID NO: 5 VL
  • SEQ ID NO: 6 VL CDR1
  • SEQ ID NO: 7 VL CDR2
  • SEQ ID NO: 8 VL CDR3
  • SEQ ID NO: 9 VH
  • SEQ ID NO: 10 VH CDR1
  • SEQ ID NO: 11 VH CDR2
  • SEQ ID NO: 12 VH CDR3
  • SEQ ID NO: 13 VL
  • SEQ ID NO: 14 VL CDR1
  • SEQ ID NO: 15 VL CDR2
  • SEQ ID NO: 16 VL CDR3
  • 059-152 antibody SEQ ID NO: 17 (VH); SEQ ID NO: 18 (VH CDR1); SEQ ID NO: 19 (VH CDR2); SEQ ID NO: 20 (VH CDR3); SEQ ID NO: 21 (VL); SEQ ID NO: 22 (VL CDR1); SEQ ID NO: 23 (VL CDR2); SEQ ID NO: 24 (VL CDR3)
  • SEQ ID NO: 483 VH
  • SEQ ID NO: 484 VH CDR1
  • SEQ ID NO: 485 VH CDR2
  • SEQ ID NO: 486 VH CDR3
  • SEQ ID NO: 487 VL
  • SEQ ID NO: 488 VL CDR1
  • SEQ ID NO: 489 VL CDR2
  • SEQ ID NO: 490 VL CDR3
  • SEQ ID NO: 491 VH
  • SEQ ID NO: 492 VH CDR1
  • SEQ ID NO: 493 VH CDR2
  • SEQ ID NO: 494 VH CDR3
  • SEQ ID NO: 495 VL
  • SEQ ID NO: 496 VL CDR1
  • SEQ ID NO: 497 VL CDR2
  • SEQ ID NO: 498 VL CDR3
  • SEQ ID NO: 499 VH
  • SEQ ID NO: 500 VH CDR1
  • SEQ ID NO: 501 VH CDR2
  • SEQ ID NO: 502 VH CDR3
  • SEQ ID NO: 503 VL
  • SEQ ID NO: 504 VL CDR1
  • SEQ ID NO: 505 VL CDR2
  • SEQ ID NO: 506 VL CDR3
  • SEQ ID NO: 507 VH
  • SEQ ID NO: 508 VH CDR1
  • SEQ ID NO: 509 VH CDR2
  • SEQ ID NO: 510 VH CDR3
  • SEQ ID NO: 511 VL
  • SEQ ID NO: 512 VL CDR1
  • SEQ ID NO: 513 VL CDR2
  • SEQ ID NO: 514 VL CDR3
  • SEQ ID NO: 515 VH
  • SEQ ID NO: 516 VH CDR1
  • SEQ ID NO: 517 VH CDR2
  • SEQ ID NO: 518 VH CDR3
  • SEQ ID NO: 519 VL
  • SEQ ID NO: 520 VL CDR1
  • SEQ ID NO: 521 VL CDR2
  • SEQ ID NO: 522 VL CDR3
  • SEQ ID NO: 523 VH
  • SEQ ID NO: 524 VH CDR1
  • SEQ ID NO: 525 VH CDR2
  • SEQ ID NO: 526 VH CDR3
  • SEQ ID NO: 527 VL
  • SEQ ID NO: 528 VL CDR1
  • SEQ ID NO: 529 VL CDR2
  • SEQ ID NO: 530 VL CDR3
  • pancreatic cancer cell line PANC-1 kidney cancer cell line CCFRC1, kidney cancer cell line Caki-1, ovarian cancer cell line KF28, stomach cancer cell line SNU-5, lung squamous cell carcinoma line RERF-LC-AI, ovarian cancer cell line RMG-1, undifferentiated hepatic cell carcinoma cancer cell line HLF, ovarian cancer cell line SKOv3, pulmonary adenocarcinoma cell line PC14, kidney cancer cell line ACHN, lung squamous cell carcinoma line EBC1, vulva mucosal epithelial cell line A431, pulmonary adenocarcinoma cell line H1373, hepatic cell carcinoma cell line HepG2, and kidney cancer clinical specimen established cell line (as to the above mention, based on the results of the cell line staining), as well as the relationships between these antibodies and kidney cancer, hepatic cell carcinoma, gallbladder and liver cancer, lung squamous cell
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned 16 kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 25 (VH); SEQ ID NO: 26 (VH CDR1); SEQ ID NO: 27 (VH CDR2); SEQ ID NO: 28 (VH CDR3); SEQ ID NO: 29 (VL); SEQ ID NO: 30 (VL CDR1); SEQ ID NO: 31 (VL CDR2); SEQ ID NO: 32 (VL CDR3)
  • SEQ ID NO: 531 VH
  • SEQ ID NO: 532 VH CDR1
  • SEQ ID NO: 533 VH CDR2
  • SEQ ID NO: 534 VH CDR3
  • SEQ ID NO: 535 VL
  • SEQ ID NO: 536 VL CDR1
  • SEQ ID NO: 537 VL CDR2
  • SEQ ID NO: 538 VL CDR3
  • SEQ ID NO: 539 (VH); SEQ ID NO: 540 (VH CDR1); SEQ ID NO: 541 (VH CDR2); SEQ ID NO: 542 (VH CDR3); SEQ ID NO: 543 (VL); SEQ ID NO: 544 (VL CDR1); SEQ ID NO: 545 (VL CDR2); SEQ ID NO: 546 (VL CDR3)
  • SEQ ID NO: 555 VH
  • SEQ ID NO: 556 VH CDR1
  • SEQ ID NO: 557 VH CDR2
  • SEQ ID NO: 558 VH CDR3
  • SEQ ID NO: 559 VL
  • SEQ ID NO: 560 VL CDR1
  • SEQ ID NO: 561 VL CDR2
  • SEQ ID NO: 562 VL CDR3
  • SEQ ID NO: 603 VH
  • SEQ ID NO: 604 VH CDR1
  • SEQ ID NO: 605 VH CDR2
  • SEQ ID NO: 606 VH CDR3
  • SEQ ID NO: 607 VL
  • SEQ ID NO: 608 VL CDR1
  • SEQ ID NO: 609 VL CDR2
  • SEQ ID NO: 610 VL CDR3
  • SEQ ID NO: 611 VH
  • SEQ ID NO: 612 VH CDR1
  • SEQ ID NO: 613 VH CDR2
  • SEQ ID NO: 614 VH CDR3
  • SEQ ID NO: 615 VL
  • SEQ ID NO: 616 VL CDR1
  • SEQ ID NO: 617 VL CDR2
  • SEQ ID NO: 618 VL CDR3
  • SEQ ID NO: 635 VH
  • SEQ ID NO: 636 VH CDR1
  • SEQ ID NO: 637 VH CDR2
  • SEQ ID NO: 638 VH CDR3
  • SEQ ID NO: 639 VL
  • SEQ ID NO: 640 VL CDR1
  • SEQ ID NO: 641 VL CDR2
  • SEQ ID NO: 642 VL CDR3
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. Finally 87 kinds of antibody clones are identified. As to the below-mentioned eight kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 33 VH
  • SEQ ID NO: 34 VH CDR1
  • SEQ ID NO: 35 VH CDR2
  • SEQ ID NO: 36 VH CDR3
  • SEQ ID NO: 37 VL
  • SEQ ID NO: 38 VL CDR1
  • SEQ ID NO: 39 VL CDR2
  • SEQ ID NO: 40 VL CDR3
  • SEQ ID NO: 41 VH
  • SEQ ID NO: 42 VH CDR1
  • SEQ ID NO: 43 VH CDR2
  • SEQ ID NO: 44 VH CDR3
  • SEQ ID NO: 45 VL
  • SEQ ID NO: 46 VL CDR1
  • SEQ ID NO: 47 VL CDR2
  • SEQ ID NO: 48 VL CDR3
  • SEQ ID NO: 49 VH
  • SEQ ID NO: 50 VH CDR1
  • SEQ ID NO: 51 VH CDR2
  • SEQ ID NO: 52 VH CDR3
  • SEQ ID NO: 53 VL
  • SEQ ID NO: 54 VL CDR1
  • SEQ ID NO: 55 VL CDR2
  • SEQ ID NO: 56 VL CDR3
  • SEQ ID NO: 57 VH
  • SEQ ID NO: 58 VH CDR1
  • SEQ ID NO: 59 VH CDR2
  • SEQ ID NO: 60 VH CDR3
  • SEQ ID NO: 61 VL
  • SEQ ID NO: 62 VL CDR1
  • SEQ ID NO: 63 VL CDR2
  • SEQ ID NO: 64 VL CDR3
  • SEQ ID NO: 65 VH
  • SEQ ID NO: 66 VH CDR1
  • SEQ ID NO: 67 VH CDR2
  • SEQ ID NO: 68 VH CDR3
  • SEQ ID NO: 69 VL
  • SEQ ID NO: 70 VL CDR1
  • SEQ ID NO: 71 VL CDR2
  • SEQ ID NO: 72 VL CDR3
  • SEQ ID NO: 755 VH
  • SEQ ID NO: 756 VH CDR1
  • SEQ ID NO: 757 VH CDR2
  • SEQ ID NO: 758 VH CDR3
  • SEQ ID NO: 759 VL
  • SEQ ID NO: 760 VL CDR1
  • SEQ ID NO: 761 VL CDR2
  • SEQ ID NO: 762 VL CDR3
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned 13 kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 675 VH
  • SEQ ID NO: 676 VH CDR1
  • SEQ ID NO: 677 VH CDR2
  • SEQ ID NO: 678 VH CDR3
  • SEQ ID NO: 679 VL
  • SEQ ID NO: 680 VL CDR1
  • SEQ ID NO: 681 VL CDR2
  • SEQ ID NO: 682 VL CDR3
  • SEQ ID NO: 683 VH
  • SEQ ID NO: 684 VH CDR1
  • SEQ ID NO: 685 VH CDR2
  • SEQ ID NO: 686 VH CDR3
  • SEQ ID NO: 687 VL
  • SEQ ID NO: 688 VL CDR1
  • SEQ ID NO: 689 VL CDR2
  • SEQ ID NO: 690 VL CDR3
  • SEQ ID NO: 691 VH
  • SEQ ID NO: 692 VH CDR1
  • SEQ ID NO: 693 VH CDR2
  • SEQ ID NO: 694 VH CDR3
  • SEQ ID NO: 695 VL
  • SEQ ID NO: 696 VL CDR1
  • SEQ ID NO: 697 VL CDR2
  • SEQ ID NO: 698 VL CDR3
  • SEQ ID NO: 699 VH
  • SEQ ID NO: 700 VH CDR1
  • SEQ ID NO: 701 VH CDR2
  • SEQ ID NO: 702 VH CDR3
  • SEQ ID NO: 703 VL
  • SEQ ID NO: 704 VL CDR1
  • SEQ ID NO: 705 VL CDR2
  • SEQ ID NO: 706 VL CDR3
  • SEQ ID NO: 715 VH
  • SEQ ID NO: 716 VH CDR1
  • SEQ ID NO: 717 VH CDR2
  • SEQ ID NO: 718 VH CDR3
  • SEQ ID NO: 719 VL
  • SEQ ID NO: 720 VL CDR1
  • SEQ ID NO: 721 VL CDR2
  • SEQ ID NO: 722 VL CDR3
  • SEQ ID NO: 723 VH
  • SEQ ID NO: 724 VH CDR1
  • SEQ ID NO: 725 VH CDR2
  • SEQ ID NO: 726 VH CDR3
  • SEQ ID NO: 727 VL
  • SEQ ID NO: 728 VL CDR1
  • SEQ ID NO: 729 VL CDR2
  • SEQ ID NO: 730 VL CDR3
  • SEQ ID NO: 731 VH
  • SEQ ID NO: 732 VH CDR1
  • SEQ ID NO: 733 VH CDR2
  • SEQ ID NO: 734 VH CDR3
  • SEQ ID NO: 735 VL
  • SEQ ID NO: 736 VL CDR1
  • SEQ ID NO: 737 VL CDR2
  • SEQ ID NO: 738 VL CDR3
  • SEQ ID NO: 739 VH
  • SEQ ID NO: 740 VH CDR1
  • SEQ ID NO: 741 VH CDR2
  • SEQ ID NO: 742 VH CDR3
  • SEQ ID NO: 743 VL
  • SEQ ID NO: 744 VL CDR1
  • SEQ ID NO: 745 VL CDR2
  • SEQ ID NO: 746 VL CDR3
  • hepatic cell carcinoma cell line HLF ovarian cancer cell line SKOv3, kidney cancer cell line ACHN, kidney cancer cell line Caki-1, pulmonary adenocarcinoma cell line H1373, lung squamous cell cancer EBC1, vulva mucosal epithelial cell line A431, breast cancer cell line BT474, pulmonary adenocarcinoma cell line PC14, kidney cancer cell line CCFRC1, hepatic cell carcinoma cell line OCTH, intrahepatic bile duct cell cancer RBE, pancreas cancer cell line PANC-1, pancreas cancer cell line MIA-Paca2, pulmonary adenocarcinoma cell line A549, pulmonary adenocarcinoma cell line NCI-N441, lung squamous cell carcinoma line Calu-3, lung squamous cell carcinoma line RERF-LC-AI, stomach cancer cell line SNU5, stomach cancer
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. Finally, 22 kinds of antibody clones are identified. As to the below-mentioned five kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 97 VH
  • SEQ ID NO: 98 VH CDR1
  • SEQ ID NO: 99 VH CDR2
  • SEQ ID NO: 100 VH CDR3
  • SEQ ID NO: 101 VL
  • SEQ ID NO: 102 VL CDR1
  • SEQ ID NO: 103 VL CDR2
  • SEQ ID NO: 104 VL CDR3
  • SEQ ID NO: 105 VH
  • SEQ ID NO: 106 VH CDR1
  • SEQ ID NO: 107 VH CDR2
  • SEQ ID NO: 108 VH CDR3
  • SEQ ID NO: 109 VL
  • SEQ ID NO: 110 VL CDR1
  • SEQ ID NO: 111 VL CDR2
  • SEQ ID NO: 112 VL CDR3
  • liver cancer cell line HepG2 liver cancer cell line HepG2
  • pulmonary adenocarcinoma cell line PC14 cell line established from kidney clinical specimen
  • the relationships between these antibodies and hepatic cell carcinoma are experimentally confirmed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned 13 kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 137 VH
  • SEQ ID NO: 138 VH CDR1
  • SEQ ID NO: 139 VH CDR2
  • SEQ ID NO: 140 VH CDR3
  • SEQ ID NO: 141 VL
  • SEQ ID NO: 142 VL CDR1
  • SEQ ID NO: 143 VL CDR2
  • SEQ ID NO: 144 VL CDR3
  • SEQ ID NO: 145 VH
  • SEQ ID NO: 146 VH CDR1
  • SEQ ID NO: 147 VH CDR2
  • SEQ ID NO: 148 VH CDR3
  • SEQ ID NO: 149 VL
  • SEQ ID NO: 150 VL CDR1
  • SEQ ID NO: 151 VL CDR2
  • SEQ ID NO: 152 VL CDR3
  • SEQ ID NO: 153 VH
  • SEQ ID NO: 154 VH CDR1
  • SEQ ID NO: 155 VH CDR2
  • SEQ ID NO: 156 VH CDR3
  • SEQ ID NO: 157 VL
  • SEQ ID NO: 158 VL CDR1
  • SEQ ID NO: 159 VL CDR2
  • SEQ ID NO: 160 VL CDR3
  • SEQ ID NO: 161 VH
  • SEQ ID NO: 162 VH CDR1
  • SEQ ID NO: 163 VH CDR2
  • SEQ ID NO: 164 VH CDR3
  • SEQ ID NO: 165 VL
  • SEQ ID NO: 166 VL CDR1
  • SEQ ID NO: 167 VL CDR2
  • SEQ ID NO: 168 VL CDR3
  • SEQ ID NO: 779 VH
  • SEQ ID NO: 780 VH CDR1
  • SEQ ID NO: 781 VH CDR2
  • SEQ ID NO 782 VH CDR3
  • SEQ ID NO: 783 VL
  • SEQ ID NO: 784 VL CDR1
  • SEQ ID NO: 785 VL CDR2
  • SEQ ID NO: 786 VL CDR3
  • SEQ ID NO: 787 VH
  • SEQ ID NO: 788 VH CDR1
  • SEQ ID NO: 789 VH CDR2
  • SEQ ID NO: 790 VH CDR3
  • SEQ ID NO: 791 VL
  • SEQ ID NO: 792 VL CDR1
  • SEQ ID NO: 793 VL CDR2
  • SEQ ID NO: 794 VL CDR3
  • SEQ ID NO: 795 VH
  • SEQ ID NO: 796 VH CDR1
  • SEQ ID NO: 797 VH CDR2
  • SEQ ID NO: 798 VH CDR3
  • SEQ ID NO: 799 VL
  • SEQ ID NO: 800 VL CDR1
  • SEQ ID NO: 801 VL CDR2
  • SEQ ID NO: 802 VL CDR3
  • SEQ ID NO: 803 VH
  • SEQ ID NO: 804 VH CDR1
  • SEQ ID NO: 805 VH CDR2
  • SEQ ID NO: 806 VH CDR3
  • SEQ ID NO: 807 VL
  • SEQ ID NO: 808 VL CDR1
  • SEQ ID NO: 809 VL CDR2
  • SEQ ID NO: 810 VL CDR3
  • SEQ ID NO: 811 VH
  • SEQ ID NO: 812 VH CDR1
  • SEQ ID NO: 813 VH CDR2
  • SEQ ID NO: 814 VH CDR3
  • SEQ ID NO: 815 VL
  • SEQ ID NO: 816 VL CDR1
  • SEQ ID NO: 817 VL CDR2
  • SEQ ID NO: 818 VL CDR3
  • SEQ ID NO: 819 VH
  • SEQ ID NO: 820 VH CDR1
  • SEQ ID NO: 821 VH CDR2
  • SEQ ID NO: 822 VH CDR3
  • SEQ ID NO: 823 VL
  • SEQ ID NO: 824 VL CDR1
  • SEQ ID NO: 825 VL CDR2
  • SEQ ID NO: 826 VL CDR3
  • SEQ ID NO: 827 VH
  • SEQ ID NO: 828 VH CDR1
  • SEQ ID NO: 829 VH CDR2
  • SEQ ID NO: 830 VH CDR3
  • SEQ ID NO: 831 VL
  • SEQ ID NO: 832 VL CDR1
  • SEQ ID NO: 833 VL CDR2
  • SEQ ID NO: 834 VL CDR3
  • SEQ ID NO: 835 VH
  • SEQ ID NO: 836 VH CDR1
  • SEQ ID NO: 837 VH CDR2
  • SEQ ID NO: 838 VH CDR3
  • SEQ ID NO: 839 VL
  • SEQ ID NO: 840 VL CDR1
  • SEQ ID NO: 841 VL CDR2
  • SEQ ID NO: 842 VL CDR3
  • liver cancer cell line HepG2, OCTH, Hep3B, and HLF
  • kidney cancer cell line Caki-1, CCFRC1, ACHN, 293T, and cell line established from the clinical specimen
  • lung cancer cell line PC14, NCI-H441, EB.
  • ovarian cancer cell line SKOv3, KF-28, RMG1, and RMG2
  • stomach cancer cell line NCI-N87
  • large bowel cancer cell line CW2
  • breast cancer cell line BT474
  • acute myelocytic leukemia AML clinical specimen and hamster ovarian cancer cell line CHO (as to the above mention, based on the results of the cell line staining), as well as the relationships between these antibodies and kidney cancer, hepatic cell carcinoma, gallbladder and liver cancer, lung squamous cell cancer, alveolar cell carcinoma, and adenocarcinoma (as to the above mention, based on the results of the tissue staining) are experimentally confirmed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • SEQ ID NO: 177 VH
  • SEQ ID NO: 178 VH CDR1
  • SEQ ID NO: 179 VH CDR2
  • SEQ ID NO: 180 VH CDR3
  • SEQ ID NO: 181 VL
  • SEQ ID NO: 182 VL CDR1
  • SEQ ID NO: 183 VL CDR2
  • SEQ ID NO: 184 VL CDR3
  • kidney cancer cell line HepG2 kidney cancer cell line CCFRC1, kidney cancer cell line ACHN, kidney cancer cell line Caki-1, pulmonary adenocarcinoma PC14, and cell line established from kidney cancer clinical specimen (as to the above mention, based on the results of the cell line staining), as well as the relationships between these antibodies and kidney cancer (as to the above mention, based on the results of the tissue staining) are experimentally confirmed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • SEQ ID NO: 459 VH
  • SEQ ID NO: 460 VH CDR1
  • SEQ ID NO: 461 VH CDR2
  • SEQ ID NO: 462 VH CDR3
  • SEQ ID NO: 463 VL
  • SEQ ID NO: 464 VL CDR1
  • SEQ ID NO: 465 VL CDR2
  • SEQ ID NO: 466 VL CDR3
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • SEQ ID NO: 475 VH
  • SEQ ID NO: 476 VH CDR1
  • SEQ ID NO: 477 VH CDR2
  • SEQ ID NO: 478 VH CDR3
  • SEQ ID NO: 479 VL
  • SEQ ID NO: 480 VL CDR1
  • SEQ ID NO: 481 VL CDR2
  • SEQ ID NO: 482 VL CDR3
  • an extremely excellent cancer-specific stained image is obtained in each clinical specimen of large bowel cancer, pulmonary adenocarcinoma, lung squamous cell cancer, stomach cancer.
  • a stained image having a weak cancer specific positive property is obtained in a part of hepatic cell carcinoma clinical specimens.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. Finally 87 kinds of antibody clones are identified. As to the below-mentioned three kinds of antibody clones, the sequences are analyzed.
  • SEQ ID NO: 651 VH
  • SEQ ID NO: 652 VH CDR1
  • SEQ ID NO: 653 VH CDR2
  • SEQ ID NO: 654 VH CDR3
  • SEQ ID NO: 655 VL
  • SEQ ID NO: 656 VL CDR1
  • SEQ ID NO: 657 VL CDR2
  • SEQ ID NO: 658 VL CDR3
  • SEQ ID NO: 659 VH
  • SEQ ID NO: 660 VH CDR1
  • SEQ ID NO: 661 VH CDR2
  • SEQ ID NO: 662 VH CDR3
  • SEQ ID NO: 663 VL
  • SEQ ID NO: 664 VL CDR1
  • SEQ ID NO: 665 VL CDR2
  • SEQ ID NO: 666 VL CDR3
  • SEQ ID NO: 667 VH
  • SEQ ID NO: 668 VH CDR1
  • SEQ ID NO: 669 VH CDR2
  • SEQ ID NO: 670 VH CDR3
  • SEQ ID NO: 671 VL
  • SEQ ID NO: 672 VL CDR1
  • SEQ ID NO: 673 VL CDR2
  • SEQ ID NO: 674 VL CDR3
  • a weak positive property to cancer portion in a part of lung squamous cell cancer clinical specimen is obtained.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned five kinds of antibody clones, the sequence is analyzed.
  • a plurality of antibodies clones are obtained. Among them, antibodies having the same amino acid sequence are included. As to the below-mentioned one kind of antibody clone, the sequence is analyzed.
  • the first embodiment of this aspect provides an isolated antibody having a specific binding property to HER1.
  • the antibody of this form includes the heavy chain variable region CDR3 and the light chain variable region CDR3 specified by the combination of SEQ ID NOs (SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR3, and SEQ ID NO showing the amino acid sequence of the light chain variable region CDR3) selected from the group consisting of the following (1) to (3).
  • the heavy chain variable regions CDR2 and CDR3 and the light chain variable regions CDR2 and CDR3 specified by the combination of SEQ ID NOs (SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR2, SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR3, SEQ ID NO showing the amino acid sequence of the light chain variable region CDR2, and SEQ ID NO showing the amino acid sequence of the light chain variable region CDR3) selected from the group consisting of the following (4) to (6).
  • CDR3 selected from the group consisting of the following (7) to (9) and (13) to (18).
  • SEQ ID NO: 4 SEQ ID NO: 8
  • SEQ ID NO: 500 VH CDR1
  • SEQ ID NO: 501 VH CDR2
  • SEQ ID NO: 502 VH CDR3
  • SEQ ID NO: 504 VL CDR1
  • SEQ ID NO: 505 VL CDR2
  • SEQ ID NO: 506 VL CDR3
  • SEQ ID NO: 508 (VH CDR1), SEQ ID NO: 509 (VH CDR2), SEQ ID NO: 510 (VH CDR3), SEQ ID NO: 512 (VL CDR1), SEQ ID NO: 513 (VL CDR2), SEQ ID NO: 514 (VL CDR3)
  • SEQ ID NO: 516 (VH CDR1), SEQ ID NO: 517 (VH CDR2), SEQ ID NO: 518 (VH CDR3), SEQ ID NO: 520 (VL CDR1), SEQ ID NO: 521 (VL CDR2), SEQ ID NO: 522 (VL CDR3)
  • (1), (4), (7), and (10) correspond to 048-006 antibody; (2), (5), (8), and (11) correspond to 057-091 antibody; (3), (6), (9), and (12) correspond to 059-152 antibody; (13) and (19) correspond to 048-040 antibody; (14) and (20) correspond to 054-101 antibody; (15) and (21) correspond to 055-147 antibody; (16) and (22) correspond to 059-173 antibody; (17) and (23) correspond to 067-149 antibody; as well as (18) and (24) correspond to 067-176 antibody. Therefore, the antibody of the present invention is expected to have high specificity to HER1.
  • the second embodiment of this aspect provides an isolated antibody having a specific binding property to HER2.
  • the antibody of this form includes the heavy chain variable region CDR3 and the light chain variable region CDR3 specified by the combination of SEQ ID NOs (SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR3, and SEQ ID NO showing the amino acid sequence of the light chain variable region CDR3) shown in the following (1).
  • SEQ ID NO: 28 SEQ ID NO: 32
  • SEQ ID NO: 612 VH CDR1
  • SEQ ID NO: 613 VH CDR2
  • SEQ ID NO: 614 VH CDR3
  • SEQ ID NO: 616 VL CDR1
  • SEQ ID NO: 617 VL CDR2
  • SEQ ID NO: 618 VL CDR3
  • SEQ ID NO: 620 (VH CDR1), SEQ ID NO: 621 (VH CDR2), SEQ ID NO: 622 (VH CDR3), SEQ ID NO: 624 (VL CDR1), SEQ ID NO: 625 (VL CDR2), SEQ ID NO: 626 (VL CDR3)
  • SEQ ID NO: 628 (VH CDR1), SEQ ID NO: 629 (VH CDR2), SEQ ID NO: 630 (VH CDR3), SEQ ID NO: 632 (VL CDR1), SEQ ID NO: 633 (VL CDR2), SEQ ID NO: 634 (VL CDR3)
  • SEQ ID NO: 636 (VH CDR1), SEQ ID NO: 637 (VH CDR2), SEQ ID NO: 638 (VH CDR3), SEQ ID NO: 640 (VL CDR1), SEQ ID NO: 641 (VL CDR2), SEQ ID NO: 642 (VL CDR3)
  • SEQ ID NO: 644 (VH CDR1), SEQ ID NO: 645 (VH CDR2), SEQ ID NO: 646 (VH CDR3), SEQ ID NO: 648 (VL CDR1), SEQ ID NO: 649 (VL CDR2), SEQ ID NO: 650 (VL CDR3)
  • (1) to (4) correspond to 015-126 antibody; (5) and (20) correspond to 015-044 antibody; (6) and (21) correspond to 015-102 antibody; (7) and (22) correspond to 015-136 antibody; (8) and (23) correspond to 015-143 antibody; (9) and (24) correspond to 015-209 antibody; (10) and (25) correspond to 039-016 antibody; (11) and (26) correspond to 053-216 antibody; (12) and (27) correspond to 075-024 antibody; (13) and (28) correspond to 075-110 antibody; (14), (29) correspond to 086-032 antibody; (15) and (30) correspond to 086-035 antibody; (16) and (31) correspond to 086-036 antibody; (17) and (32) correspond to 086-061 antibody; (18) and (33) correspond to 086-138 antibody; as well as (19) and (34) correspond to 086-182 antibody. Therefore, the antibody of the present invention is expected to have high specificity to HER2.
  • the third embodiment of this aspect provides an isolated antibody having a specific binding property to CD46 antigen.
  • the antibody of this form includes the heavy chain variable region CDR3 and the light chain variable region CDR3 specified by the combination of SEQ ID NOs (SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR3, and SEQ ID NO showing the amino acid sequence of the light chain variable region CDR3) selected from the following the group consisting of (1) to (7).
  • the heavy chain variable regions CDR2 and CDR3 and the light chain variable regions CDR2 and CDR3 specified by the combination of SEQ ID NOs (SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR2, SEQ ID NO showing the amino acid sequence of the heavy chain variable region CDR3, SEQ ID NO showing the amino acid sequence of the light chain variable region CDR2, and SEQ ID NO showing the amino acid sequence of the light chain variable region CDR3) selected from the following the group consisting of (8) to (14).
  • SEQ ID NO: 34 SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40
  • SEQ ID NO: 42 SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48
  • SEQ ID NO: 50 SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56

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US20090177408A1 (en) * 2005-08-03 2009-07-09 Suresh Gopalan Methods and systems for high confidence utilization of datasets
US20090238834A1 (en) * 2006-08-29 2009-09-24 Christian Rohlff Identification of protein associated with hepatocellular carcinoma, glioblastoma and lung cancer
US20100297006A1 (en) * 2002-08-16 2010-11-25 Agensys, Inc. NUCLEIC ACIDS AND CORRESPONDING PROTEINS ENTITLED 191P4D12(b) USEFUL IN TREATMENT AND DETECTION OF CANCER
EP2374816A1 (en) * 2010-04-07 2011-10-12 Humalys Binding molecules against Chikungunya virus and uses thereof
WO2011124635A1 (en) * 2010-04-07 2011-10-13 Humalys Binding molecules against chikungunya virus and uses thereof
WO2012047724A1 (en) * 2010-09-29 2012-04-12 Agensys, Inc. Antibody drug conjugates (adc) that bind to 191p4d12 proteins
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EP2078732A4 (en) 2010-07-28
JP6063494B2 (ja) 2017-01-18
JP2015143226A (ja) 2015-08-06
JP2014027941A (ja) 2014-02-13
US20140235833A1 (en) 2014-08-21
US9388249B2 (en) 2016-07-12
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JP5382692B2 (ja) 2014-01-08
JP2017012181A (ja) 2017-01-19

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