WO2023033129A1 - 癌の治療及び／又は予防用医薬組成物 - Google Patents

癌の治療及び／又は予防用医薬組成物 Download PDF

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WO2023033129A1
WO2023033129A1 PCT/JP2022/033055 JP2022033055W WO2023033129A1 WO 2023033129 A1 WO2023033129 A1 WO 2023033129A1 JP 2022033055 W JP2022033055 W JP 2022033055W WO 2023033129 A1 WO2023033129 A1 WO 2023033129A1
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seq
chain variable
variable region
amino acid
acid sequence
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PCT/JP2022/033055
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French (fr)
Japanese (ja)
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岡野文義
齋藤孝則
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東レ株式会社
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Priority to KR1020247007544A priority Critical patent/KR20240051956A/ko
Priority to EP22864711.1A priority patent/EP4400121A1/en
Priority to CN202280070145.1A priority patent/CN118119409A/zh
Priority to AU2022338463A priority patent/AU2022338463A1/en
Priority to JP2022571749A priority patent/JPWO2023033129A1/ja
Priority to CA3230737A priority patent/CA3230737A1/en
Publication of WO2023033129A1 publication Critical patent/WO2023033129A1/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins

Definitions

  • the present invention relates to a conjugate of an antibody against the CAPRIN-1 protein and dolastatin 10 or a derivative thereof, and a medical use thereof for treating and/or preventing cancer.
  • an object of the present invention is to enhance the antitumor effect of ADCs using dolastatin 10 or its derivatives.
  • CAPRIN-1 protein having an amino acid sequence represented by any of even numbered SEQ ID NOs among SEQ ID NOs: 2 to 30 or an amino acid sequence having 80% or more sequence identity with said amino acid sequence, and immunology A conjugate comprising a reactive antibody or fragment thereof and dolastatin 10 or a derivative thereof.
  • 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).
  • 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 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.
  • 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: 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.
  • 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:122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:123.
  • a dolastatin 10 derivative is a compound in which a part of the amino acids constituting dolastatin 10 is substituted or deleted, a compound in which another amino acid is added to a pentapeptide, or a compound in which a pentapeptide is modified with a substituent.
  • Specific examples include peptide compounds in which valine (Val), drytholine (Dil), dolaproine (Dap), draphenin (Doe) are linked, drytholine (Dil), dolaproine (Dap), drafenin (Doe ), and those in which the pyrrolidine ring of the doraproline (Dap) moiety of dolastatin 10 is converted (eg, CT-P26).
  • the linker means a compound capable of binding the anti-CAPRIN-1 antibody and dolastatin 10 or its derivative.
  • Various known linkers may be used, or the structure on the activator side may be appropriately chemically modified and directly bound.
  • N-hydroxysuccinimide (NHS) esters imidoesters, pentafluorophenyl esters, hydroxymethylphosphines, isothiocyanates, isocyanates, acylazides, N-hydroxyl esters, sulfonyl chlorides, aldehydes, glyoxal, epoxides, which are reactive groups reactive to amines , oxiranes, carbonates, aryls, carbodiimides and carboxylic anhydrides.
  • NHS N-hydroxysuccinimide
  • Diazirine, arylazides, aryls, benzophenols, and diazo compounds as photoreactive reactive groups.
  • a linker having an N-hydroxysuccinimide ester as a reactive group e.g., Disuccinimidyl Glutarate (DSG), Discuccinimidyl Suberate (DSS), Bis (sulfosuccinimidyl) Suberate (BS3), Tris-( Succinimidyl)Aminotriacetate(TSAT) ⁇ PEGylated Bis(Sulfosuccinimidyl)Suberate(BS(PEG) 5 ⁇ BS(PEG) 9 ) ⁇ Dithiobis(Succinimidyl Propionate)(DSP) ⁇ 3,3'-dithiobis(sulfosuccinimidyl propionate)(DTSSP) ⁇ ethylene glycol bis(succinimidyl succinate)(EGS) ⁇ Sulfo-ethylene glycol bis(succinimidyl succinate(Sulfo-EGS) ⁇ Di
  • Main linkers with different reactive group ends include linkers with NHS ester and maleimide as reactive groups (e.g., AMAS, BMPS, GMBS, Sulfo-MBS, MBS, Sulfo-MBS, SMCC, Sulfo-SMCC, EMCS, Sulfo - EMCS, SMPB, Sulfo-SMPB, SMPH, LC-SMCC, Sulfo-KMUS, SM(PEG) 2 , SM(PEG) 4 , SM(PEG) 6 , SM(PEG) 8 , SM(PEG) i2 , SM (PEG) 24 ), linkers having NHS esters and pyridyldithiols as reactive groups (e.g., SPDP, LC-SPDP, Sulfo-LC-SPDP, SMPT, (PEG) 4 SPDP, PEG12-SPDP), NHS esters and haloacetyl.
  • reactive groups e
  • Linkers with reactive groups e.g., SIA, SBAP, SIAB, Sulfo-SIAB
  • linkers with NHS esters and arylazides as reactive groups e.g., ANB-NOS, Sulfo-SANPAH, ATFB
  • reacting NHS esters with diazirine base linkers e.g., SDA, Sulfo-SDA, LC-SDA, SDAD, Sulfo-SDAD
  • carbodiimide-reactive linkers e.g., DCC, EDC, EDAC, NHS, Sulfo-NHS
  • maleimide and hydrazide a linker with a reactive group e.g., BMPH, EMCH, MPBH, KMUH
  • a linker with pyridyldithiol and hydrazide as a reactive group e.g., PDPH
  • a linker with an isocyanate and maleimide as a reactive group e.g
  • linkers include linkers containing polypeptides, such as Fmoc-Ala-Ala-Asn-PAB, Fmoc-Ala-Ala-Asn(Trt)-PAB, Fmoc-PEG 3 -Ala-Ala-Asn(Trt)-PAB , Fmoc-PEG 4 -Ala-Ala-Asn(Trt)-PAB, Fmoc-Ala-Ala-Asn-PAB-PNP, Fmoc-Ala-Ala-Asn(Trt)-PAB-PNP, Fmoc-PEG 3 -Ala -Ala-Asn(Trt)-PAB-PNP, Azide-PEG 4 -Ala-Ala-Asn(Trt)-PAB-PNP, Mal-PEG 4 -Ala-Ala-Asn(Trt)-PAB-PNP, Fmoc- Val
  • the disulfide bond on the antibody is converted to maleimide or ⁇ -haloamide by using a reducing agent such as mercaptoethanol to generate a thiol.
  • a reaction method is used.
  • the amount of thiol added to the antibody can be determined, for example, by mixing a sample solution containing 5,5′-Dithiobis (2-nitrobenzoic acid) (DTNB) and an SH group with phosphate buffer (pH 8.0) and distilled water, After adding a DTNB solution dissolved in an acid buffer, Good's buffer or Tris buffer and incubating for a certain period of time, it can be quantified by measuring the absorbance at 412 nm (GL Ellman, Arch. Biochem. Biophys., 82, 70 (1959)).
  • DTNB 5,5′-Dithiobis (2-nitrobenzoic acid)
  • SH group phosphate buffer
  • distilled water distilled water
  • the thiol groups added by cutting the disulfide bonds of the antibody by reduction treatment are preferably treated (capping) to prevent re-formation of disulfide bonds.
  • capping for example, N-ethylmaleimide (NEM) or iodoacetamide (2-iodoacetamide (IAA)) can be used.
  • an amide bond is first formed on an amino group present in the activator using SMCC, and then a thiol group added to the antibody side and a maleimide group of SMCC to which dolastatin 10 or a derivative thereof is bound. can be reacted to give a conjugate.
  • conjugates of antibodies and dolastatin 10 or derivatives thereof are prepared using, for example, maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-Val-Cit-PAB) as a linker.
  • mc-val-Cit-PAB mc-vc-PAB
  • a thiol group is added to an antibody dissolved in a phosphate buffer using DTT or the like.
  • dolastatin or a dolastatin derivative having an amino group is reacted with benzyloxycarbonyl (PAB) in mc-Val-Cit-PAB to prepare dolastatin 10 or a derivative thereof bound to mc-val-Cit-PAB
  • Conjugates can be obtained by reacting with the aforementioned thiol-tagged antibodies.
  • mc-val-Cit-PAB-MMAE in which MMAE, which is one of the dolastatin derivatives, is linked to mc-val-Cit-PAB by a predetermined method.
  • it is Vedotin conjugated with MMAE or mafadotin conjugated with MMAF.
  • succinimidyl 3-(2-pyridyldithio)propionate is added to primary amino groups on lysine residues of the antibody by attaching SATA to attach the thiol group to the amino group. and dolastatin 10 or a derivative thereof to form an amide bond with the N-succinimide group in SPDP.
  • the linker used in the present invention can be cleaved under intracellular conditions, and a substance having antitumor activity containing dolastatin 10 or its derivative or dolastatin 10 or its derivative and part of the linker is released intracellularly.
  • linkers that are cleaved by intracellular peptidases and proteases Preferred are linkers that are cleaved by lysosomes, endosomal proteases, cathepsin B, cathepsin D, plasmin.
  • Examples include linkers containing polypeptides cleavable by cathepsin B (Val-Cit, Phe-Leu or Gly-Phe-Leu-Gly). More specifically, the linkers described in US Pat. No. 6,214,345 can be used.
  • a linker with glucuronic acid as described in WO2007/0711968 can be used.
  • the means described in WO2013/173337, WO2015/095755, WO2015/123679, and WO2018/031690 can be used.
  • a conjugate of two or more drugs including dolastatin 10 or a dolastatin 10 derivative with an anti-CAPRIN-1 antibody can be obtained by the method described in WO2018/112253.
  • one of said two or more drugs is MMAE or MMAF.
  • the ability of the conjugates of the present invention to bind to CAPRIN-1 can be determined using binding assays such as surface plasmon resonance (SPR), ELISA, Western blotting, immunofluorescence and flow cytometry. can be specified.
  • binding assays such as surface plasmon resonance (SPR), ELISA, Western blotting, immunofluorescence and flow cytometry.
  • the conjugate of the present invention enhances the antitumor effect more than the anti-CAPRIN-1 antibody alone, and the enhancement rate is preferably 30% or more, more preferably 40% or more, and still more preferably 50% or more. , still more preferably 55% or more, still more preferably 60% or more, still more preferably 65% or more, and most preferably 70% or more.
  • the enhancement rate of the anti-tumor effect of the conjugate of the present invention relative to the anti-CAPRIN-1 antibody alone can be evaluated by administering an effective amount of each to tumor-bearing mice under the same conditions, and comparing the tumor volume after 10 days from the start of administration. can be calculated by
  • the target of the pharmaceutical composition for treating and/or preventing cancer of the present invention is not particularly limited as long as it is a cancer (cell) that expresses the CAPRIN-1 protein.
  • tumor and cancer refer to malignant neoplasms and are used interchangeably.
  • renal pelvic tract cancer bladder cancer, urethral cancer, testicular tumor, malignant pleural mesothelioma, malignant osteosarcoma, pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, medulloblastoma, renal blastoma, retinoblastoma, central nervous system germ cell tumors, Ewing's sarcoma family tumors), etc., but are not limited thereto.
  • 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 conjugate used in the present invention when used as a pharmaceutical composition, it can be formulated by a method known to those skilled in the art. For example, they can be used parenterally in the form of injections of sterile solutions or suspensions with water or other pharmaceutically acceptable liquids.
  • pharmacologically acceptable carriers or media specifically sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, fragrances, excipients, binders, etc. It is conceivable to formulate by combining appropriately with and admixing in a unit dosage form required for 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.
  • the administration method can be appropriately selected according to the patient's age, weight, sex, symptoms, etc.
  • the dose of the antibody or the pharmaceutical composition containing the polynucleotide encoding the antibody is, for example, in the range of 0.0001 mg to 1000 mg per kg of body weight per dose, for example, 0.5 mg, 1 mg per kg of body weight per dose, A dose of 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 50 mg, 75 mg, 100 mg, 200 mg, 500 mg or 1000 mg can be chosen.
  • the dose can be selected in the range of 0.001 to 100000 mg/body per patient, but is not necessarily limited to these numerical values.
  • cancer expressing CAPRIN-1 on the surface of the cell membrane preferably breast cancer and renal cancer.
  • Example 2 Anti-CAPRIN-1 monoclonal antibody The following anti-CAPRIN-1 monoclonal antibody was used for the conjugate of the present invention.
  • a monoclonal antibody against CAPRIN-1 described in WO2011/096528 which has a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 70 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 71 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 72 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 73;
  • a monoclonal antibody against CAPRIN-1 described in WO2011/096533 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:80 and a light chain variable region represented by the amino acid sequence of SEQ ID NO:81 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:82 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:83;
  • a monoclonal antibody against CAPRIN-1 described in WO2010/016526 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:88 and a light chain variable region represented by the amino acid sequence of SEQ ID NO:89 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:90 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:91;
  • a monoclonal antibody against CAPRIN-1 described in WO2013/018894 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 102 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 103 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:104 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:105;
  • a monoclonal antibody against CAPRIN-1 described in WO2013/018892 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 106 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 107 an antibody comprising the amino acid sequence of the region;
  • a monoclonal antibody against CAPRIN-1 described in WO2013/125636 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 114 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 115 an antibody comprising the amino acid sequence of the region;
  • a monoclonal antibody against CAPRIN-1 described in WO2013/125654 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 116 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 117 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:118 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:119;
  • a monoclonal antibody against CAPRIN-1 described in WO2013/125630 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 120 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 121 an antibody comprising the amino acid sequence of the region;
  • a monoclonal antibody against CAPRIN-1 described in WO2015/020212 comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 122 and a light chain variable region represented by the amino acid sequence of SEQ ID NO: 123 an antibody comprising a heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 124 and a light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO: 125;
  • a heavy chain comprising the above anti-CAPRIN-1 monoclonal antibody, wherein the CDRs 1 to 3 of the heavy chain variable region consist of the amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, respectively, and the framework region comprises the sequence of a human antibody
  • a nucleotide sequence was designed so that the variable region could be expressed, and this was inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 had been inserted.
  • CDRs 1 to 3 of the light chain variable region consist of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively, and the base sequence is such that the framework region can express the light chain variable region containing the sequence of a human antibody. was designed and inserted into a mammalian expression vector into which the light chain constant region of human IgG1 was inserted.
  • the above two recombinant expression vectors are introduced into mammalian cells according to a conventional method, and CDRs 1 to 3 of the heavy chain variable region consist of the amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, respectively, and the light chain variable region A culture supernatant containing humanized monoclonal antibody #1 (humanized antibody #1) against CAPRIN-1, whose CDRs 1 to 3 consist of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively, was obtained.
  • a nucleotide sequence was designed so that the variable region could be expressed, and this was inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 had been inserted.
  • a nucleotide sequence is designed so that the variable region can be expressed, this is inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 has been inserted, and the above two recombinant expression vectors are introduced into mammalian cells according to a conventional method.
  • CDRs 1 to 3 of the heavy chain variable region consist of the amino acid sequences of SEQ ID NO: 44, SEQ ID NO: 45 and SEQ ID NO: 46, and CDRs 1 to 3 of the light chain variable region consist of SEQ ID NO: 48, SEQ ID NO: 49 and SEQ ID NO: 50, respectively.
  • CDR1-3 of the heavy chain variable region consist of the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively
  • CDR1-3 of the light chain variable region consist of SEQ ID NO:56, SEQ ID NO:57 and SEQ ID NO:57, respectively.
  • a culture supernatant containing humanized anti-CAPRIN-1 monoclonal antibody #3 (humanized antibody #3) consisting of #58 was obtained.
  • CDR1-3 of the heavy chain variable region consist of the amino acid sequences of SEQ ID NO:60, SEQ ID NO:61 and SEQ ID NO:62, respectively
  • CDR1-3 of the light chain variable region consist of SEQ ID NO:64, SEQ ID NO:65 and sequence
  • a culture supernatant containing humanized anti-CAPRIN-1 monoclonal antibody #4 (humanized antibody #4) consisting of #66 was obtained.
  • culture supernatants containing the following humanized anti-CAPRIN-1 monoclonal antibodies #9 to #41 were obtained.
  • Humanized monoclonal antibody #9 comprising the heavy chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:68 and the light chain variable region amino acid sequence represented by the amino acid sequence of SEQ ID NO:69 9).
  • Humanized monoclonal antibody #10 (humanized antibody # 10).
  • Humanized monoclonal antibody #11 (humanized antibody # 11).
  • Humanized monoclonal antibody #13 (humanized antibody # 13).
  • Humanized monoclonal antibody #15 (humanized antibody # 15).
  • Humanized monoclonal antibody #16 (humanized antibody # 16).
  • Antibody humanized monoclonal antibody #19 (humanized antibody #19).
  • Humanized monoclonal antibody #33 (humanized antibody # 33).
  • Humanized monoclonal antibody #34 (humanized antibody # 34).
  • Humanized monoclonal antibody #36 (humanized antibody # 36).
  • Humanized monoclonal antibody #38 (humanized antibody # 38).
  • the CDRs 1 to 3 of the heavy chain variable region of the humanized antibody #1 consist of the amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, respectively,
  • a nucleotide sequence is designed so that the framework region can express a heavy chain variable region containing the sequence of a human antibody, and the serine (Ser), which is the 239th amino acid in EU numbering, is replaced with aspartic acid (Asp).
  • the heavy chain constant region of human IgG1 in which isoleucine (Ile), which is the 332nd EU numbering amino acid, was replaced with glutamic acid (Glu) was inserted into a mammalian expression vector.
  • humanized anti-CAPRIN-1 monoclonal antibody #6 (humanized antibody #6) consisting of the amino acid sequence of the heavy chain variable region and the amino acid sequence of the light chain variable region of humanized antibody #2 prepared above A culture supernatant containing
  • the MMAE-conjugated anti-CAPRIN-1 polyclonal antibody #1 (conjugated) of the present invention was filtered using a 0.22 ⁇ m sterile filtration membrane. A solution containing gate 81) was obtained.
  • CAPRIN-1 protein The specific reactivity to the CAPRIN-1 protein was confirmed using the ELISA method. 100 ⁇ L of 1 ⁇ g/mL of CAPRIN-1 protein solution 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 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 solutions containing conjugates 1 to 6, conjugates 81 to 86, and control conjugates 1 and 2 were added to each well. and allowed to stand at room temperature for 2 hours.
  • BSA Bovine Serum Albumin
  • conjugates 1 to 6 and conjugates 81 to 86 which are conjugates of the anti-CAPRIN-1 polyclonal antibody and MMAE, had higher fluorescence intensities than the negative control conjugates 1 and 2, that is, CAPRIN -1 was confirmed to strongly react with the cell surface of human cancer cells BT474 expressing.
  • conjugates 7-80 and conjugates 87-160 which are conjugates of anti-CAPRIN-1 monoclonal antibody and MMAE
  • human CAPRIN-1-expressing cancer cells were treated with Alexa488-labeled anti-human IgG (H + L) antibody.
  • Specific reactivity to cancer cell BT474 and mouse cancer cell 4T1 was detected.
  • conjugates 7 to 80 and conjugates 87 to 160 which are conjugates of the anti-CAPRIN-1 polyclonal antibody and MMAE, had higher fluorescence intensities than the negative control conjugates 3 and 4, ie, CAPRIN -1 was confirmed to strongly react with the cell surface of human cancer cells BT474 expressing.
  • Cancer cells (BT-474), colon cancer cells (HT-29), lung cancer cells (A549) which are human cancer cells confirmed to express CAPRIN-1 on the cell membrane surface of cancer cells in Example 5 ), gastric cancer cells (NCI-N87), uterine cancer cells (HEC-1-A), prostate cancer cells (22Rv1), pancreatic cancer cells (Panc10.5), liver cancer cells (Hep3B), ovarian cancer cells (SKOV3) , kidney cancer cells (Caki-2), brain tumor cells (U-87MG), bladder cancer cells (T24), bile duct cancer cells (KKU213), fibrosarcoma cells (HT-1080), esophageal cancer cells (OE33), leukemia cells (OCI-AML5), lymphoma cells (Ramos), gallbladder cancer cells (TGBC14TKB), melanoma cells (Malme-3M), mouse kidney cancer cells (Renca) in which expression of CAPRIN-1 gene has been confirmed, mouse breast cancer cells (4T1) was assessed for anti
  • cell viability was measured using Cell Titer Glow Luminescent Cell Viability Assay (#7573, Promega). Add 100 ⁇ L of substrate per well, shake for 2 minutes using a plate shaker, allow to stand for 10 minutes, and measure the luminescence signal intensity using SpectraMax (registered trademark) iD3 (MOLECULAR DEVICE). The ATP content of the cells containing the cells was calculated.
  • conjugates 1 to 6 and conjugates 81 to 86 which are conjugates of the antibody against CAPRIN-1 according to the present invention and MMAE, were obtained using a control antibody showing no reactivity to the CAPRIN-1 protein. It showed stronger anti-tumor activity compared to the control conjugates 1 and 2 made.
  • conjugates 7 and 11, which are conjugates of the antibody against CAPRIN-1 according to the present invention and MMAE were set to 100% for the negative control (conjugate non-addition group) for any cancer cells. In that case, less than 60% of cancer cells survived.
  • conjugates 8-80, conjugates 12-80, and conjugates 87-160 gave similar results to conjugates 7 and 11.
  • HT29 expresses the CAPRIN-1 protein on the cell membrane surface, and as shown in Example 5, conjugates 1 to 6 and conjugate 81 prepared using anti-CAPRIN-1 polyclonal antibodies #1 to #6 ⁇ 86, conjugates 7-80 and conjugates 87-160 prepared using an anti-CAPRIN-1 monoclonal antibody bind specifically to the cell membrane surface.
  • conjugates 1 to 6 and conjugate 81 prepared using anti-CAPRIN-1 polyclonal antibodies #1 to #6 ⁇ 86, conjugates 7-80 and conjugates 87-160 prepared using an anti-CAPRIN-1 monoclonal antibody bind specifically to the cell membrane surface.
  • Each of the above conjugates was administered at 10 mg/kg into the tail vein of 10 tumor-bearing mice.
  • a solution containing a conjugate of trastuzumab (Chugai Pharmaceutical Co., Ltd.) and MMAE was prepared using an antibody against CAPRIN-1 so that the same amount of drug as that of the conjugate was prepared.
  • the same dose was administered to the above tumor-bearing mice.
  • HT29 expresses the HER2 protein, which is the target antigen of trastuzumab, on the cell membrane surface, and the conjugate of trastuzumab and MMAE described above specifically binds to it.
  • Administration to tumor-bearing mice was performed twice a week.
  • PBS (-) was administered to the negative control tumor-bearing mice.
  • the tumor volume of mice administered a solution containing a trastuzumab and MMAE conjugate as a comparison control was 65% or more compared to the negative control. Furthermore, when the tumor volume of tumor-bearing mice administered with trastuzumab alone was taken as 100%, the tumor volume of tumor-bearing mice administered with the conjugate was less than 81%.
  • conjugates 7 to 80 and conjugates 87 to 160 prepared in Examples 3 and 4 using an antibody against CAPRIN-1 were significantly higher than the negative control (untreated control group). It was shown to exert a strong antitumor effect.
  • conjugates 7-80 and conjugates 87-160 were shown to have significantly stronger antitumor effects than the conjugate of trastuzumab and MMAE prepared as a control.

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