WO2022270524A1 - 癌の治療及び／又は予防のための医薬品 - Google Patents

癌の治療及び／又は予防のための医薬品 Download PDF

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WO2022270524A1
WO2022270524A1 PCT/JP2022/024814 JP2022024814W WO2022270524A1 WO 2022270524 A1 WO2022270524 A1 WO 2022270524A1 JP 2022024814 W JP2022024814 W JP 2022024814W WO 2022270524 A1 WO2022270524 A1 WO 2022270524A1
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seq
chain variable
variable region
amino acid
acid sequence
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French (fr)
Japanese (ja)
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岡野文義
赤澤大輔
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Toray Industries Inc
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Toray Industries Inc
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Priority to AU2022298240A priority Critical patent/AU2022298240A1/en
Priority to BR112023026992A priority patent/BR112023026992A2/pt
Priority to US18/573,641 priority patent/US20250228937A1/en
Priority to CA3225422A priority patent/CA3225422A1/en
Priority to CN202280041252.1A priority patent/CN117460532A/zh
Priority to MX2023014500A priority patent/MX2023014500A/es
Priority to EP22828440.2A priority patent/EP4360649A4/en
Priority to KR1020237042093A priority patent/KR20240024803A/ko
Priority to JP2022542938A priority patent/JPWO2022270524A1/ja
Publication of WO2022270524A1 publication Critical patent/WO2022270524A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines

Definitions

  • the present invention relates to a drug for treating and/or preventing cancer using an antibody or fragment thereof against the CAPRIN-1 protein and a topoisomerase I inhibitor.
  • cytopasmic-activation-and-proliferation-associated protein 1 (CAPRIN-1) is expressed on the cell membrane surface of many solid tumors, and antibodies against this CAPRIN-1 protein are used for medical treatment and/or prevention of cancer. It is known to be promising as (Patent Document 1).
  • a treatment method that uses multiple cancer therapeutic drugs in combination has been used as a standard treatment method in order to increase the effectiveness of cancer therapeutic drugs.
  • cancer therapeutic drugs for example, irinotecan, folinic acid, and fluorouracil for colorectal cancer, doxorubicin and cyclophosphamide for breast cancer, or paclitaxel, trastuzumab, and pertuzumab for gastric cancer.
  • multiple anticancer agents such as cisplatin and fluorouracil.
  • a cancer therapeutic agent containing an anti-CAPRIN-1 antibody as an active ingredient has an excellent cancer therapeutic effect when used in combination with a chemotherapeutic agent (Patent Document 2).
  • cancer treatment with a combination of chemotherapeutic agents is not effective against all cancers for which it is applied. There are only a few substances that enhance the therapeutic effect of
  • a specific example of a cancer treatment method that uses multiple cancer therapeutic agents in combination is the combination of pyrimidine drugs (eg, gemcitabine) and carboplatin.
  • pyrimidine drugs eg, gemcitabine
  • carboplatin also called CBDCA+GEM
  • Ovarian cancer is cancer that has metastasized to the peritoneal cavity, cancer that has metastasized to the lymph nodes, and is likely to metastasize to the liver and lungs.
  • stage III and stage IV advanced ovarian cancer there are cases of recurrence within 2 years after initial treatment. It is a highly malignant cancer with an incidence of more than 50%.
  • GC carboplatin combination therapy
  • PFI Platinum-Free interval
  • patients have a response rate of 40% or more to treatment after recurrence, whereas patients with a PFI of less than 6 months from the end of chemotherapy to recurrence (so-called platinum-sensitive patients) susceptible patients), the response rate to treatment after recurrence is 10% or less, and the prognosis is extremely poor (Non-Patent Document 2).
  • GC-BEV platinum-sensitive ovarian cancer
  • platinum agents such as carboplatin cannot be used according to guidelines, and other treatment methods are selected.
  • chemotherapeutic agents such as the taxanes paclitaxel and docetaxel, the anthracyclines doxorubicin and its liposomal formulations, and the topoisomerase inhibitors etoposide and topotecan have been approved, although various dosing regimens are available. Although it has been verified, the response rate is 10 to 30%, and a satisfactory effect has not been obtained (Non-Patent Documents 4 to 7).
  • An object of the present invention is to provide pharmaceuticals for treating and/or preventing cancers that specifically express the CAPRIN-1 protein on the cell surface.
  • the present inventors have found that a combination of an antibody against CAPRIN-1 protein having immunological reactivity with cancer cells or a fragment thereof and a topoisomerase I inhibitor is superior to each single agent treatment. Exhibiting extremely strong antitumor effect, that the antitumor effect is a synergistic effect of regressing tumors, and that the effect is remarkably higher than the combined effect with other topoisomerase inhibitors. The discovery led to the completion of the present invention.
  • the present invention has the following features (1) to (13).
  • CAPRIN- wherein the antibody or fragment has an amino acid sequence represented by any of even-numbered SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence; (1) or (2), which is an antibody or fragment thereof having immunological reactivity with 1 protein.
  • the antibody or fragment thereof has an amino acid sequence represented by any of SEQ ID NOS: 31-35, 296-299, 308, and 309, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence;
  • the drug according to any one of (1) to (4), which has immunological reactivity with a partial polypeptide of CAPRIN-1 protein.
  • a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 36, 37 and 38 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 40, 41 and 42 (CDR1, CDR2 and CDR3, respectively).
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125 an antibody or fragment thereof comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 127 (ai) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 128; and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129 or a fragment thereof (aj) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises SEQ ID NO: 131 an antibody or fragment thereof (ak) wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133 ( al) An antibody or fragment thereof, wherein the heavy chain variable region comprises the heavy chain variable region comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124
  • the cancer is ovarian cancer, cholangiocarcinoma, breast cancer, renal cancer, pancreatic cancer, colon cancer, melanoma, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial cancer, colorectal cancer, Esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mastocytoma, adrenocortical carcinoma, Ewing tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer of (1) to (10) A medicinal product according to any one of the above.
  • a drug efficacy enhancer for a pharmaceutical composition for treating and/or preventing cancer which comprises a topoisomerase I inhibitor as an active ingredient and an antibody or fragment thereof immunologically reactive with CAPRIN-1 protein as an active ingredient.
  • a drug efficacy enhancer for a pharmaceutical composition for the treatment and/or prevention of cancer comprising an antibody or fragment thereof immunologically reactive with CAPRIN-1 protein as an active ingredient, and comprising a topoisomerase I inhibitor as an active ingredient.
  • the combined use of an antibody against the CAPRIN-1 protein or a fragment thereof and a topoisomerase I inhibitor according to the present invention exhibits a stronger antitumor effect than the antibody against the CAPRIN-1 protein alone and the topoisomerase I inhibitor topotecan alone. Furthermore, the combined use of an antibody against CAPRIN-1 protein and a topoisomerase I inhibitor according to the present invention exhibits a stronger antitumor effect than the combined use of other topoisomerase inhibitors and an antibody against CAPRIN-1 protein. Therefore, combined use of an antibody against the CAPRIN-1 protein and a topoisomerase I inhibitor is effective in treating or preventing cancer.
  • FIG. 4 shows the anti-tumor effect of combined use of anti-CAPRIN-1 antibody and topotecan on NOD-SCID mice implanted with human cancer cell line BT474 expressing CAPRIN-1.
  • Ref 1 PBS administered instead of drug Ref 2; Topotecan low dose (3 mg/kg) administered Ref 3; Topotecan high dose (10 mg/kg) Ref 4; Anti-CAPRIN-1 Anti-CAPRIN-1 antibody and topotecan low dose (3 mg/kg) co-administration, reference number 6; Anti-CAPRIN-1 antibody and topotecan high dose (10 mg/kg) co-administration Shows tumor size in mice.
  • FIG. 4 shows the anti-tumor effect of combined use of anti-CAPRIN-1 antibody and topotecan on NOD-SCID mice implanted with human cancer cell line BT474 expressing CAPRIN-1.
  • Ref 1 PBS administered instead of drug Ref 2
  • Topotecan low dose (3 mg/kg) administered Ref 3
  • anti-CAPRIN-1 antibody an antibody against the CAPRIN-1 protein or a fragment thereof (hereinafter collectively referred to as "anti-CAPRIN-1 antibody") used in the present invention and a topoisomerase I inhibitor is as described below. It can be evaluated by examining inhibition of tumor growth in tumor-bearing animals in vivo.
  • the term “combination” or “combination” refers to the administration of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor to the same organism simultaneously or at predetermined intervals as independent active ingredients. .
  • the intervals may be co-administration, after 30 minutes, or after 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, 5 days, 7 days, 2 weeks, 3 After a week, it may be after 4 weeks.
  • Either the anti-CAPRIN-1 antibody or the topoisomerase I inhibitor may be administered when it exhibits its activity in vivo.
  • the anti-CAPRIN-1 antibody may be administered first, and the topoisomerase I inhibitor may be administered first.
  • the anti-CAPRIN-1 antibody according to the present invention may be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody, and any type of antibody as long as the antibody of the present invention can exhibit antitumor activity.
  • the antibody may be a recombinant antibody, human antibody, humanized antibody, chimeric antibody, non-human animal antibody.
  • subjects who are the targets of cancer treatment and/or prevention in the present invention are mammals such as humans, pet animals, domestic animals, and sports animals, and preferred subjects are humans.
  • anti-CAPRIN-1 antibody topotecan
  • pharmaceuticals containing them as active ingredients and cancer treatment and/or prevention methods related to the present invention are described below.
  • CAPRIN-1 having an amino acid sequence represented by any of even-numbered SEQ ID NOS: 2 to 30, which is a specific example of an antigen immunologically reactive with the anti-CAPRIN-1 antibody used in the present invention
  • the amino acid sequences represented by SEQ ID NOS: 6, 8, 10, 12 and 14 are the amino acid sequences of canine CAPRIN-1 protein
  • the amino acid sequences represented by SEQ ID NOS: 2 and 4 are of human CAPRIN-1 protein.
  • the amino acid sequence shown in SEQ ID NO: 16 is the amino acid sequence of bovine CAPRIN-1 protein
  • the amino acid sequence shown in SEQ ID NO: 18 is the amino acid sequence of equine CAPRIN-1 protein
  • SEQ ID NO: The amino acid sequences represented by 20 to 28 are the amino acid sequences of the mouse CAPRIN-1 protein
  • the amino acid sequence represented by SEQ ID NO: 30 is the amino acid sequence of the chicken CAPRIN-1 protein.
  • the anti-CAPRIN-1 antibody used in the present invention has an amino acid sequence represented by any of the even-numbered SEQ ID NOs of SEQ ID NOs: 2 to 30 above by 80% or more, preferably 90% or more, more preferably 95%. %, more preferably 99% or more, are immunologically reactive with variants of the CAPRIN-1 protein.
  • the "% sequence identity" as used herein refers to the number of amino acids (or bases) when two sequences are aligned with or without gaps to maximize similarity. Means the percentage (%) of identical amino acids (or bases) to the total number.
  • an anti-CAPRIN-1 antibody means an antibody or a fragment thereof that has immunological reactivity with the full-length CAPRIN-1 protein or a fragment thereof.
  • immunological reactivity refers to the property of binding between an antibody and a CAPRIN-1 protein or a partial polypeptide thereof in vivo.
  • the anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.
  • a polyclonal antibody immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof is, for example, a natural CAPRIN-1 protein, a fusion protein with GST or the like, or a partial peptide thereof.
  • Mice, human antibody-producing mice, rats, rabbits, chickens, etc. are immunized to obtain sera.
  • the obtained serum can be obtained by ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column bound with CAPRIN-1 protein or partial peptide, or the like.
  • the full-length CAPRIN-1 protein or a fragment thereof used for immunization, the base sequence and amino acid sequence of CAPRIN-1 and its homologues can be obtained by accessing, for example, GenBank (NCBI, USA) and using algorithms such as BLAST and FASTA (Karlin and Altschul USA, 90:5873-5877, 1993; Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997). Also, the method for producing the CAPRIN-1 protein can be obtained by referring to WO2014/012479, and cells expressing the CAPRIN-1 protein can also be used.
  • a monoclonal antibody (anti-CAPRIN-1 monoclonal antibody) having immunological reactivity with the full-length CAPRIN-1 protein or a fragment thereof is, for example, breast cancer cell SK-BR-3 expressing CAPRIN-1 or CAPRIN-1 protein.
  • the full length or a fragment thereof is administered to mice for immunization, spleen cells isolated from the mice are fused with myeloma cells, and clones producing anti-CAPRIN-1 monoclonal antibodies are selected from the resulting fused cells (hybridomas).
  • Hybridomas can be obtained by
  • Antibodies produced from the selected hybridomas can be obtained by the same method as the polyclonal antibody purification method described above.
  • Antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.
  • Human antibodies sensitize human lymphocytes infected with EB virus with proteins, protein-expressing cells, or lysates thereof, fuse the sensitized lymphocytes with myeloma cells such as human-derived U266 cells, and obtain fusion Antibodies immunologically reactive with the full-length CAPRIN-1 protein or fragments thereof can be obtained from the cells.
  • a humanized antibody is a modified antibody, also called a reshaped human antibody.
  • Humanized antibodies are constructed by grafting the complementarity determining regions of an antibody from an immunized animal onto the complementarity determining regions of a human antibody.
  • the gene recombination technique as the general technique is also a well-known technique. Specifically, for example, several DNA sequences designed to link the complementarity-determining region of a mouse antibody or rabbit antibody and the framework region of a human antibody are prepared so as to have overlapping portions at their ends.
  • the resulting DNA is ligated with a DNA encoding a constant region of a human antibody, incorporated into an expression vector, and introduced into a host for production (European Patent Application Publication No. EP239400, International Publication No. See WO96/02576).
  • the framework regions of the human antibody to be linked via the complementarity determining regions are selected so that the complementarity determining regions form good antigen-binding sites. If necessary, amino acids in the framework region of the antibody variable region may be substituted so that the complementarity-determining region of the reshaped human antibody forms an appropriate antigen-binding site (Sato K. et al., Cancer Research 1993, 53:851-856). Also, framework regions from various human antibodies may be substituted (see WO99/51743).
  • Antibodies are heteromultimeric glycoproteins, usually containing at least two heavy chains and two light chains. Antibodies are composed of two identical light chains and two identical heavy chains. A heavy chain has at one end a heavy chain variable region followed by a number of constant regions. A light chain has at one end a light chain variable region followed by a number of constant regions. The variable region exhibits specific variable regions, called complementarity determining regions (CDRs), that confer binding specificity on the antibody. Portions that are relatively conserved in the variable region are called framework regions (FR). Complete heavy and light chain variable regions each contain four FRs joined by three CDRs (CDR1-CDR3).
  • CDRs complementarity determining regions
  • accession numbers J00230 for the heavy chain constant region of human IgG2 accession numbers V00557, X64135, X64133, etc. for the human light chain ⁇ constant region, accession numbers X64132, X64134, etc. for the human light chain ⁇ constant region. be able to.
  • a chimeric antibody is an antibody produced by combining sequences derived from different animals, for example, the constant regions of heavy and light chain variable regions of a mouse antibody and heavy and light chain variable regions of a human antibody Antibodies, etc.
  • a chimeric antibody can be produced using a known method. For example, DNA encoding an antibody V region and DNA encoding a human antibody C region are ligated, and this is incorporated into an expression vector and introduced into a host. obtained by producing
  • Non-human animal antibodies are obtained by immunizing an animal with a sensitizing antigen according to known methods, generally by injecting the sensitizing antigen intraperitoneally, intradermally, or subcutaneously into an animal such as a mouse. .
  • the sensitizing antigen is injected, it is mixed with an appropriate amount of various adjuvants such as CFA (complete Freund's adjuvant) and administered to the animal multiple times.
  • Animals were immunized, serum was obtained after confirming that the serum contained anti-CAPRIN-1 antibodies, and ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, CAPRIN-1 protein were obtained as described above. or an affinity column to which a partial peptide is bound.
  • a monoclonal antibody from a non-human animal when obtaining a monoclonal antibody from a non-human animal, it can be obtained by collecting immune cells from the immunized animal and subjecting them to cell fusion with myeloma cells. Cell fusion between the immune cells and myeloma cells can be performed according to known methods (see Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).
  • Antibodies used in the present invention can also be obtained as recombinant antibodies produced by cloning antibody genes from hybridomas, incorporating them into appropriate vectors, introducing them into hosts, and producing them using genetic recombination techniques. (See Carl, AK Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODYS, Published in the United Kingdom by MILLAN PUBLISHERS LTD, 1990).
  • the anti-CAPRIN-1 antibody used in the present invention may have amino acids in the variable region (eg, FR) or constant region substituted with other amino acids.
  • Amino acid substitutions are substitutions of one or more, such as less than 15, less than 10, 8 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less amino acids, preferably 1 to 9 amino acids, and
  • the modified antibody should have antigen-specific binding properties and antigen-binding affinity equal to or higher than those of unsubstituted antibodies, and should not cause rejection when applied to humans.
  • Amino acid substitutions are preferably conservative amino acid substitutions, which are substitutions between amino acids with similar properties such as charge, side chain, polarity, and aromaticity.
  • Amino acids with similar properties are, for example, basic amino acids (arginine, lysine, histidine), acidic amino acids (aspartic acid, glutamic acid), uncharged polar amino acids (glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine), non-polar amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched-chain amino acids (threonine, valine, isoleucine), aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine), and the like.
  • basic amino acids arginine, lysine, histidine
  • acidic amino acids aspartic acid, glutamic acid
  • uncharged polar amino acids glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine
  • the anti-CAPRIN-1 antibody used in the present invention can be expected to have a stronger anti-tumor effect when it has a higher binding affinity to the CAPRIN-1 protein on the surface of cancer cells.
  • the binding constant (affinity constant) Ka (kon/koff) is preferably at least 10 7 M ⁇ 1 , at least 10 8 M ⁇ 1 , at least 5 ⁇ 10 8 M ⁇ 1 , at least 10 9 M ⁇ 1 , at least 5 ⁇ 10 9 M ⁇ 1 , at least 10 10 M ⁇ 1 , at least 5 ⁇ 10 10 M ⁇ 1 , at least 10 11 M ⁇ 1 , at least 5 ⁇ 10 11 M ⁇ 1 , at least 10 12 M ⁇ 1 , or at least 10 13 M ⁇ 1 is desirable.
  • the anti-CAPRIN-1 antibody used in the present invention may be chemically modified, and examples of such antibody modifications include polyethylene glycol (PEG), antitumor compounds (e.g., antitumor compounds exemplified below). Antibodies bound to various molecules such as tumor agents) can be mentioned.
  • the substance to be bound is not limited.
  • modified antibodies can be obtained by chemically modifying the obtained antibodies. These methods are already established in this field.
  • the anti-CAPRIN-1 antibody used in the present invention has one, two or several amino acid substitutions in the heavy chain constant region of the antibody, or N- By removing fucose bound to acetylglucosamine, the binding strength of the anti-CAPRIN-1 antibody to effector cells can be improved.
  • the above amino acid substitution may be performed alone, or may be a composition with an antibody to which fucose is bound.
  • Antibodies with one, two, or several amino acid substitutions in the heavy chain constant region are prepared by referring to, for example, WO2004/063351, WO2011/120135, US Pat. can do.
  • Antibodies in which fucose attached to N-acetylglucosamine in the N-glycoside-linked sugar chain in the heavy chain constant region has been removed, or cells producing the antibody see US Pat.
  • Anti-CAPRIN-1 polyclonal antibodies, anti-CAPRIN-1 monoclonal antibodies, methods for producing antibodies, methods for purifying antibodies, and methods for producing CAPRIN-1 proteins or partial polypeptides thereof used for immunization used in the present invention are described in WO2010/016526, WO2011/ 096517 ⁇ WO2011/096528 ⁇ WO2011/096519 ⁇ WO2011/096533 ⁇ WO2011/096534 ⁇ WO2011/096535 ⁇ WO2013/018886 ⁇ WO2013/018894 ⁇ WO2013/018892 ⁇ WO2013/018891 ⁇ WO2013/018889 ⁇ WO2013/018883 ⁇ WO2013/125636 ⁇ WO2013/125654, WO2013/125630, WO2013/125640, WO2013/147169, WO2013/147176 and WO2015/020212.
  • anti-CAPRIN-1 antibody in the present invention examples include the aforementioned WO2010/016526, WO2011/096517, WO2011/096528, WO2011/096519, WO2011/096533, WO2011/096534, WO2011/096535, WO2013/0188 018894 ⁇ WO2013/018892 ⁇ WO2013/018891 ⁇ WO2013/018889 ⁇ WO2013/018883 ⁇ WO2013/125636 ⁇ WO2013/125654 ⁇ WO2013/125630 ⁇ WO2013/125640 ⁇ WO2013/147169 ⁇ WO2013/147176 ⁇ WO2015/020212 ⁇ CAPRIN -1 antibodies, preferred anti-CAPRIN-1 antibodies include:
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 31 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 36, 37 and 38 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 40, 41 and 42 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region and immunologically reactive with the CAPRIN-1 protein, or the complementarity determining regions of SEQ ID NOS: 140, 141 and 142 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOS: 143, 144 and 145 (CDR1, CDR2 and CDR3, respectively), and immunologically reactive with CAPRIN-1 protein or a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 164, 165 and 166 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 167, 168 and 169 (
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 33 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 60, 61 and 62 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 64, 65 and 66 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region comprising and immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:67.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 32 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 52, 53 and 54 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 56, 57 and 58 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region comprising and immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:55 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:59.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 34 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 170, 171 and 172 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 173, 174 and 175 (CDR1, CDR2 and CDR3, respectively) and an antibody or fragment thereof that is immunologically reactive with the CAPRIN-1 protein, or the complementarity determining regions of SEQ ID NOs: 176, 177 and 178 (CDR1, CDR2 and CDR3, respectively).
  • an antibody or fragment thereof having More preferably, an antibody or fragment thereof in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:81, or the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:83.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 35 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 182, 183 and 184 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 185, 186 and 187 (CDR1, CDR2 and CDR3, respectively) and an antibody or fragment thereof that is immunologically reactive with the CAPRIN-1 protein, or the complementarity determining regions of SEQ ID NOS: 188, 189 and 190 (CDR1, CDR2 and CDR3, respectively).
  • an antibody or fragment thereof having More preferably, an antibody or fragment thereof in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:85, or the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:87.
  • a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 44, 45 and 46 (CDR1, CDR2 and CDR3, respectively) and a light chain comprising the complementarity determining regions of SEQ ID NOS: 48, 49 and 50 (CDR1, CDR2 and CDR3, respectively).
  • chain variable region and immunologically reactive with the CAPRIN-1 protein.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 296 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 146, 147 and 148 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 149, 150 and 151 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:73.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 297 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 272, 273 and 274 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 275, 276 and 277 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:115.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 298 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 290, 291 and 292 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 293, 294 and 295 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:121.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 299 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 301, 302 and 303 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 305, 306 and 307 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:304.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 308 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 134, 135 and 136 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 137, 138 and 139 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:69.
  • CAPRIN- having an amino acid sequence represented by SEQ ID NO: 309 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) sequence identity with the amino acid sequence
  • An antibody or fragment thereof having immunological reactivity with a partial polypeptide of 1 protein Preferably, a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 134, 135 and 136 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 137, 138 and 139 (CDR1, CDR2 and CDR3, respectively) and a light chain variable region, and is immunologically reactive with CAPRIN-1 protein. More preferably, an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:69.
  • anti-CAPRIN-1 antibodies are also preferably used.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:69.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:71.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:73.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:75.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:77.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:79.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:81.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:83.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:85.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:87.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:89.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:91.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:93.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:95.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:97.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:99.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:101.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:111.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:115.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:117.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:119.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:121.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:123.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:127.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:129.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:131.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133.
  • an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:304.
  • topoisomerase I inhibitor selectively binds to type I topoisomerase complexed with DNA to stabilize its structure, inhibits relaxation of the DNA helical structure, causes DNA fragmentation, and terminates cell division. Induces cell death.
  • it may contain a suitable tonicity agent or pH or a suitable dosage form.
  • Specific examples of topoisomerase I inhibitors are topotecan (topotecan) or irinotecan.
  • a topoisomerase I inhibitor can be obtained by chemical synthesis by a technique known to those skilled in the art.
  • Topoisomerase I Topoisomerase I ⁇ Topotecan> Topotecan is a semi-synthetic derivative of camptothecin, a natural product extracted from the bark of the kanrenboku tree, and has a molecular weight of about 421.4, represented by CAS number 123948-87-8 (hydrate is 119413-54-6). It is a type I topoisomerase inhibitor. In the present specification, simply referring to "topotecan” includes topotecan hydrochloride and topotecan hydrochloride hydrate unless otherwise specified.
  • topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2- b]quinoline-3,14(4H,12H)-dione monohydrochloride, alternatively represented by Nogitecan hydrochloride.
  • "Hycamtin (registered trademark)” and “Potactasol (registered trademark)” are commercially available as pharmaceuticals containing topotecan hydrochloride as an active ingredient, and these pharmaceuticals are appropriately used when topotecan is used in the present invention. be able to.
  • Irinotecan is a type I topoisomerase inhibitor with a molecular weight of about 586.678 represented by CAS number 100286-90-6 (136572-09-3 for hydrate).
  • irinotecan includes irinotecan hydrochloride and irinotecan hydrochloride hydrate unless otherwise specified.
  • pharmaceuticals containing irinotecan hydrochloride as an active ingredient “Campto (registered trademark)", “Topotecin” (registered trademark), “Onivyde (registered trademark)” and the like have been marketed. can use these drugs as appropriate.
  • the active ingredients of the drug of the present invention include anti-tumor agents known in literature etc., as long as they do not inhibit the effects of the drug of the present invention.
  • antitumor agents are not particularly limited, but specific examples include paclitaxel, doxorubicin, daunorubicin, cyclophosphamide, methotrexate, 5-fluorouracil, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carbocone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, bratacin, bratacinone, bryo statins, callystatin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleuterobin, pancratistatin, sarcodictyin, spongestatin, chlorambucil, chloRNAphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechloreth
  • the combination of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor of the invention has cytotoxic activity in vivo. Therefore, the antitumor effect of the present invention can be known by examining its cytotoxic activity against cancer. Cytotoxic activity can be evaluated by administering anti-CAPRIN-1 and a topoisomerase I inhibitor to a cancer-bearing organism, measuring the size of the tumor after administration, and examining the size of the cancer over time. Moreover, the anti-tumor effect of the present invention can also be evaluated by examining the survival rate. It can also be evaluated by examining the ability to produce cytokines or chemokines. The anti-tumor effect of the combination of the anti-CAPRIN-1 antibody and topoisomerase I inhibitor of the present invention can be further determined by examining cancer prevention, metastasis prevention, or recurrence prevention.
  • the anti-CAPRIN-1 antibody used in the present invention can be expected to have a stronger anti-tumor effect when it has a higher binding affinity to the CAPRIN-1 protein on the surface of cancer cells.
  • the binding constant (affinity constant) Ka (kon/koff) is preferably at least 10 7 M ⁇ 1 , at least 10 8 M ⁇ 1 , at least 5 ⁇ 10 8 M ⁇ 1 , at least 10 9 M ⁇ 1 , at least 5 ⁇ 10 9 M ⁇ 1 , at least 10 10 M ⁇ 1 , at least 5 ⁇ 10 10 M ⁇ 1 , at least 10 11 M ⁇ 1 , at least 5 ⁇ 10 11 M ⁇ 1 , at least 10 12 M ⁇ 1 , or at least 10 13 M ⁇ 1 is desirable.
  • the ability of the anti-CAPRIN-1 antibody used in the present invention to bind to CAPRIN-1 can be determined using binding assays such as ELISA, Western blotting, immunofluorescence and flow cytometry. can.
  • a combination of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor according to the present invention into a cancer body enhances the antitumor effect more than the anti-CAPRIN-1 antibody alone, as described above.
  • 30% or more, more preferably 40% or more, still more preferably 50% or more, still more preferably 55% or more, still more preferably 60% or more, still more preferably 65% or more, most preferably 70% or more is.
  • the enhancement rate of the antitumor effect of the combined administration of the anti-CAPRIN-1 antibody and topoisomerase I inhibitor of the present invention relative to the administration of the anti-CAPRIN-1 antibody alone was evaluated by administering an effective amount of each to tumor-bearing mice under the same conditions. It can be calculated by comparing the tumor volume after 7 days after initiation.
  • the medicament of the present invention is intended for the treatment and/or prevention of cancer.
  • the cancer targeted by the drug of the present invention is not particularly limited as long as it is a cancer (cell) that expresses the CAPRIN-1 protein.
  • Treatment means treatment of cancer based on the aforementioned antitumor effect.
  • prevention means not only prevention of cancer development but also prevention of metastasis or recurrence of cancer.
  • tumor and cancer refer to malignant neoplasms and are used interchangeably.
  • the target cancer in the present invention may be any cancer that expresses the CAPRIN-1 protein on the cell membrane surface.
  • ovarian cancer cholangiocarcinoma, breast cancer, renal cancer, pancreatic cancer, colon cancer, melanoma (including postoperative melanoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), renal cell carcinoma, Hodgkin's lymphoma , head and neck cancer, gastric cancer, mesothelial cancer (including malignant pleural mesothelioma), colorectal cancer (e.g.
  • colorectal cancer with MSI-high esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, Glioblastoma, urothelial cancer, bladder cancer, uterine cancer (including cervical cancer, endometrial cancer), primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer , sarcoma, fibrosarcoma, mastocytoma, adrenocortical carcinoma, Ewing tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer.
  • uterine cancer including cervical cancer, endometrial cancer
  • primary central nervous system lymphoma primary testicular lymphoma, biliary tract cancer
  • brain tumor prostate cancer
  • leukemia lymphoma
  • liver cancer sarcoma
  • fibrosarcoma fibrosarcoma
  • these cancers may be primary cancers, metastatic cancers, metastatic cancers or recurrent cancers, postoperative cancers, or unresectable cancers.
  • melanoma is often used synonymously with malignant melanoma or malignant melanoma.
  • cancers to be targeted in the present invention include cancers that are resistant to known treatment methods.
  • the cancer with resistance is not particularly limited even if it is a cancer derived from a patient with any history of treatment, for example, a cancer derived from a patient with a history of treatment with a platinum agent or 5-FU, after administration , resistant cancer, metastatic cancer or recurrent cancer.
  • the cancer is, for example, Bowen's disease, melanoma, squamous cell carcinoma, extramammary Paget's disease, mycosis fungoides, Sezary syndrome, cutaneous T/NK cell lymphoma, T cells with lesions only in the skin Leukemia/lymphoma, cutaneous B-cell lymphoma (indolent group), cutaneous T-cell lymphoma mammary carcinoma, combined breast adenocarcinoma, malignant mixed tumor of the breast, intraductal papillary adenocarcinoma, lung adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, neuroepithelial tissue tumor glioma, glioblastoma, neuroblastoma, ventricular ependymoma, neurocellular tumor, embryonic neuroectodermal tumor, schwannoma, neurofibroma, meningioma, chronic lymphocytic leukemia, lymph
  • cancer that can be palpated from the above cancers cancer that exists under the skin, cancer that exists in the skin, cancer that is superficial, cancer that exists in the dermis, cancer that exists in non-parenchymal organs, and advanced cancer. subsumed.
  • metastasis or recurrence of the above cancer as a primary source can result in palpable cancer, cancer existing under the skin, cancer existing in the skin, cancer existing in the dermis, or cancer existing in non-parenchymal organs. Cancer is included.
  • Preferred subjects (patients) to be treated are mammals, for example, mammals including primates, pet animals, domestic animals, sports animals, and the like, with humans, dogs and cats being particularly preferred.
  • the drug of the present invention can be formulated by methods known to those skilled in the art.
  • the medicaments of the present invention can be used parenterally, for example, in the form of injections of sterile solutions or suspensions in water or other pharmaceutically acceptable liquids.
  • the active ingredients are added to each formulation or pharmaceutical composition, for example, a pharmacologically acceptable carrier or medium, specifically sterilized Water, saline, isotonic solutions, buffers (buffers, etc.), vegetable oils, oily oils, antioxidants, solubilizers, emulsifiers, suspending agents, surfactants, stabilizers, fragrances, excipients , binders and the like as appropriate, and preferably formulated by admixing them in unit dosage forms required in generally accepted pharmaceutical practice.
  • the amount of active ingredient in these formulations is such that a suitable dosage in the range indicated will be obtained.
  • a sterile composition for injection can be formulated according to normal pharmaceutical practice using a vehicle such as distilled water for injection.
  • Aqueous solutions for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride.
  • Alcohols, particularly ethanol, polyalcohols such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80(TM), HCO-60 may be used in combination.
  • Oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate and benzyl alcohol as solubilizers.
  • buffers such as phosphate buffers, sodium acetate buffers, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants.
  • a prepared injection solution is usually filled into a suitable ampoule.
  • Administration is oral or parenteral, preferably parenteral, and specific examples include injection, nasal, pulmonary, and transdermal administration.
  • injection dosage forms include systemic or local administration by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intratumoral injection, and the like.
  • transdermal administration forms are those called liniments or topical drugs.
  • External medicines include solids, liquids, sprays, ointments, creams, and gels.
  • the administration method can be appropriately selected according to the patient's age, weight, sex, symptoms, etc.
  • the dosage of the pharmaceutical composition containing at least one of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor is the amount of each active ingredient, for example, selected in the range of 0.0001 mg to 1000 mg per kg of body weight per dose. It is possible. Alternatively, for example, the dose can be selected in the range of 0.001 to 100000 mg/body per patient, or in the range of 1 mg to 30 mg per kg of patient weight, but is not necessarily limited to these figures.
  • the dose and administration method vary depending on the body weight, age, sex, symptoms, etc. of the patient, but can be appropriately selected by those skilled in the art.
  • the treatment and/or prevention of cancer with the drug for treatment and/or prevention of cancer of the present invention includes various forms in addition to administration as the drug described above.
  • each active ingredient of the medicament of the present invention can be administered simultaneously or separately in order.
  • the second active ingredient can be administered within a time interval of up to about three weeks, ie immediately after administration of the first active ingredient and up to about three weeks later.
  • the surgical treatment may be performed subsequently, or the surgical treatment may be performed between administrations of the first drug and the second drug.
  • the cancer therapeutic and/or preventive agent of the present invention may be administered according to multiple administration cycles.
  • a pharmaceutical composition containing both active ingredients is administered for about 2 days to about 3 weeks as one cycle. Thereafter, the treatment cycle can be repeated as necessary according to the judgment of the doctor in charge.
  • the duration of administration of each individual agent is adjusted to span the same period. The interval between cycles can vary from 0-2 months.
  • the dose of each active ingredient in the agent for treating and/or preventing cancer of the present invention can be set in the same manner as the dose of each active ingredient in the pharmaceutical composition.
  • the medicament for treating and/or preventing cancer of the present invention may be in the form of a pharmaceutical kit.
  • a pharmaceutical kit is a package for the use of active ingredients in the form of separate pharmaceutical compositions in a method for treating and/or preventing cancer, the package including instructions for administering each active ingredient. included.
  • Each active ingredient of the pharmaceutical composition for treating and/or preventing cancer contained in the pharmaceutical kit is a pharmaceutical composition formulated as described above so that each active ingredient can be administered together or separately. can be in the form Pharmaceutical kits also contain active ingredients in sufficient quantity for one or more doses so that each active ingredient can be administered according to the methods of administration described above.
  • the present invention further provides a method for treating and/or preventing cancer, which comprises administering the pharmaceutical agent of the present invention to a subject suspected of having cancer. offer. Also, in that embodiment, the antibody or fragment thereof and the antitumor agent contained in the medicament are administered to the subject, either simultaneously or separately.
  • polyclonal antibody 1 mg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010/016526 was mixed with an equal volume of incomplete Freund's adjuvant (IFA) solution, and this was subcutaneously administered to rabbits four times every two weeks. rice field. Blood was then collected to obtain antiserum containing polyclonal antibodies. Further, this antiserum was purified using a protein G carrier (manufactured by GE Healthcare Bioscience), substituted with PBS (-), and a polyclonal antibody against the CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody #1) was generated. Obtained.
  • IFA incomplete Freund's adjuvant
  • Hybridomas were selected using the binding affinity of antibodies produced by the prepared hybridomas to the CAPRIN-1 protein as an index.
  • 100 ⁇ l of a CAPRIN-1 protein solution of 1 ⁇ g/ml was added per well of a 96-well plate and allowed to stand at 4° C. for 18 hours. After each well was washed with PBS-T three times, 400 ⁇ l of 0.5% Bovine Serum Albumin (BSA) solution (manufactured by Sigma) was added per well and allowed to stand at room temperature for 3 hours.
  • BSA Bovine Serum Albumin
  • a CAPRIN-1 protein solution of 1 ⁇ g/ml was added in an amount of 100 ⁇ l per well of a 96-well plate and allowed to stand at 4° C. for 18 hours. After each well was washed with PBS-T three times, 400 ⁇ l of 0.5% BSA solution was added per well and allowed to stand at room temperature for 3 hours. After removing the solution and washing the wells three times with 400 ⁇ l of PBS-T per well, 100 ⁇ l of each culture supernatant of the hybridomas obtained above was added per well and allowed to stand at room temperature for 2 hours.
  • the CDRs 1 to 3 of the heavy chain variable region of the selected antibody are identified, the nucleotide sequence is designed so that the framework region can express the heavy chain variable region containing the sequence of the human antibody, and this is used as the heavy chain definition of human IgG1. It was inserted into a mammalian expression vector into which a constant region had been inserted.
  • the CDRs 1 to 3 of the light chain variable region were identified, the base sequence was designed so that the framework region could express the light chain variable region containing the sequence of a human antibody, and this was used as the light chain constant of human IgG1. It was inserted into a mammalian expression vector into which the region had been inserted.
  • the above two recombinant expression vectors were introduced into mammalian cells according to a standard method to obtain a culture supernatant containing humanized monoclonal antibody #1 against CAPRIN-1 (humanized antibody #1).
  • the resulting culture supernatant containing the humanized anti-CAPRIN-1 monoclonal antibody #1 was purified using Hitrap Protein A Sepharose FF (manufactured by GE Healthcare) in accordance with a conventional method, and was replaced with PBS (-) to a concentration of 0.22 ⁇ m. was filtered through a filter (manufactured by Millipore).
  • the specific reactivity of the anti-CAPRIN-1 antibody to the CAPRIN-1 protein was confirmed by immobilizing the CAPRIN-1 protein on a plate and detecting it using the ELISA method.
  • Example 2 Anti-tumor effect of combined use of anti-CAPRIN-1 antibody and topotecan Tumor bearing by combined use of anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 and topotecan Antitumor effects were evaluated in vivo in mice.
  • BT474 is a cancer cell in which the CAPRIN-1 protein is expressed on the cell membrane surface, and it has been confirmed that the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a portion of CAPRIN-1 on the cell membrane surface.
  • the anti-CAPRIN-1 antibody prepared in Example 1 was administered to each of the above tumor-bearing mice at a dose of 10 mg/kg into the tail vein of each of the above-mentioned tumor-bearing mice, 4 times a total of 4 times, once a week.
  • the same mice were given a low (3 mg/kg) or high (10 mg/kg) dose of topotecan once every four days for a total of four doses.
  • the same anti-CAPRIN-1 antibody as above was administered to tumor-bearing mice at the same dose once a week.
  • low-dose (3 mg/kg) or high-dose (10 mg/kg) topotecan was administered to other tumor-bearing mice at similar administration intervals.
  • untreated tumor-bearing mice were used as a negative control.
  • the size of the cancer in the tumor-bearing mice was measured over time using a vernier caliper, and the tumor volume was calculated according to a standard method using the formula: (length of major axis of cancer) x (length of minor axis of cancer). ) 2 ⁇ 0.5 was calculated for each individual, and the average value of the administration group was calculated.
  • the humanized anti-CAPRIN-1 produced in Example 1 which is the comparison group
  • the tumor volume in the Antibody #1 administration group was 38%
  • the topotecan low dose administration group was 33%
  • the topotecan high dose administration group was 16%
  • the tumor volume was increased from the beginning of administration.
  • the tumor volume of the group administered with humanized antibody #1 prepared in Example 1 and low dose topotecan was 6%
  • humanized antibody #1 prepared in Example 1 and high dose topotecan were administered together.
  • the tumor volume in the treated group was 0% (tumor regression in all individuals), which was smaller than at the start of administration.
  • NOD-SCID mice subcutaneously implanted with human-derived cancer cells expressing the CAPRIN-1 protein were used to examine the antitumor effect of the combined use of an anti-CAPRIN-1 antibody and etoposide.
  • 2 ⁇ 10 7 human breast cancer cells BT474 per mouse were mixed with Matrigel (SIGMA) and implanted subcutaneously to prepare tumor-bearing mice in which tumors were allowed to grow to approximately 190-192 mm 3 .
  • BT474 is a cancer cell in which the CAPRIN-1 protein is expressed on the cell membrane surface, and it has been confirmed that the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a portion of CAPRIN-1 on the cell membrane surface. .
  • the anti-CAPRIN-1 antibody prepared in Example 1 was administered to each of the above tumor-bearing mice at a dose of 10 mg/kg into the tail vein of each of the above-mentioned tumor-bearing mice, 4 times a total of 4 times, once a week.
  • the same mice were given a low (5 mg/kg) or high (15 mg/kg) dose of etoposide once every four days for a total of four doses.
  • the same anti-CAPRIN-1 antibody as above was administered to tumor-bearing mice at the same dose once a week.
  • low dose (5 mg/kg) or high dose (15 mg/kg) of etoposide was administered to other tumor-bearing mice at similar administration intervals.
  • untreated tumor-bearing mice were used as a negative control.
  • the size of the cancer in the tumor-bearing mice was measured over time using a vernier caliper, and the tumor volume was calculated according to a standard method using the formula: (length of major axis of cancer) x (length of minor axis of cancer). ) 2 ⁇ 0.5 was calculated for each individual, and the average value of the administration group was calculated.
  • Example 1 As a result of the evaluation, about 2 weeks after the end of drug administration (55 days after bearing cancer), when the tumor volume of the negative control was set to 100%, the humanized anti-CAPRIN-1 produced in Example 1, which is the comparison group, The tumor volume of the antibody #1 administration group was 35%, the etoposide low dose administration group was 92%, and the etoposide high dose administration group was 79%. The tumor volume of the group was 18%, and the tumor volume of the group co-administered with humanized antibody #1 prepared in Example 1 and a high dose of etoposide was 30%. increased from when it started.
  • Example 2 Compared to the results of evaluating the antitumor effect in combination with topotecan shown in Example 2, the antitumor effect when treated with a combination of an antibody against CAPRIN-1 and etoposide is low, and the antibody against CAPRIN-1 and topoisomerase I inhibition Combination treatment with the agents topotecan was shown to have a remarkably strong synergistic anti-tumor effect.

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