WO2023062848A1 - Composition pharmaceutique comprenant un anticorps fnl4 anti-humain ou un fragment de liaison à l'antigène de celui-ci pour la prévention ou le traitement du cancer - Google Patents

Composition pharmaceutique comprenant un anticorps fnl4 anti-humain ou un fragment de liaison à l'antigène de celui-ci pour la prévention ou le traitement du cancer Download PDF

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WO2023062848A1
WO2023062848A1 PCT/JP2021/038847 JP2021038847W WO2023062848A1 WO 2023062848 A1 WO2023062848 A1 WO 2023062848A1 JP 2021038847 W JP2021038847 W JP 2021038847W WO 2023062848 A1 WO2023062848 A1 WO 2023062848A1
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amino acid
seq
acid sequence
antigen
antibody
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PCT/JP2021/038847
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English (en)
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Masakatsu Kawakami
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Astellas Pharma Inc.
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Priority to PCT/JP2021/038847 priority Critical patent/WO2023062848A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer, and so on.
  • Fibroblast growth factor-inducible 14 (also referred to as TNFRSF12A) is a member of tumor necrosis factor receptor family. Fnl4 is also known as a Tweak receptor, which binds to a TNF-like weak inducer of apoptosis (Tweak). Tweak-dependent or independent activation of Fnl4 is known to activate the NFkB signaling pathway and to control cell proliferation, migration, differentiation, and apoptosis, as well as inflammation involved in angiogenesis, tissue damage, and regeneration (Non-Patent Document 1).
  • Non-Patent Document 2 Fnl4 is overexpressed in various solid cancers
  • Non-Patent Document 3 Fnl4 is involved in tumor progression and metastasis
  • an anti-Fnl4 antibody is effective in improving the symptoms of cachexia, and the action thereof is due to Fnl4 inhibition in the tumor (Non-Patent Document 4).
  • Enavatuzumab (Patent Document 1), that is under clinical development, has been reported as an agonist antibody against human Fnl4. Hepatotoxicity has been reported in phase I clinical trial of Enavatuzumab (Non-Patent Document 5), and it has been suggested that inflammation may be caused by Enavatuzumab treatment (Non-Patent Document 6).
  • a mouse monoclonal antibody CRCBT-06-002 has been reported as an antibody which binds to human Fnl4 and has antagonist activity, but does not have agonist activity under specific conditions (Patent Document 2).
  • CRCBT-06-002 has been reported to have antagonist activity that inhibits IL- 8 production induced by Tweak stimulation in a human malignant melanoma-derived cell line A375 cell and to have effectiveness in a mouse model of cancer cachexia.
  • agonist activity that induces IL-8 production from A375 cells in the absence of Tweak remains (Patent Document 2).
  • Patent Document 1 WO 2009/020933
  • Patent Document 2 WO 2013/026099
  • Patent Document 3 WO 2020/090892
  • Non-Patent Document 1 Winkles JA, Nat Rev Drug Discov. 2008, Vol. 7, p. 411-425
  • Non-Patent Document 2 Culp PA et al., Clin Cancer Res. 2010, Vol. 16, p. 497-508
  • Non-Patent Document 3 HU G et al., Tumor Biol. 2017, Vol. 39 June, p. 1-9
  • Non-Patent Document 4 Johnston A J et al., Cell. 2015, Vol. 162, p. 1365-1378
  • Non-Patent Document 5 Lam ET et al., Mol Cancer Ther. 2018, Vol. 17, p. 215-221
  • Non-Patent Document 6 Choi D et al., Am J Pharmacol Toxicol. 2017, Vol. 12, p. 18-38 Disclosure of Invention
  • An object of the present invention is to provide a pharmaceutical composition comprising an anti -human Fnl4 antibody or an antigen-binding fragment thereof, as an active ingredient, for preventing or treating cancer. More specifically, an object of the present invention is to provide a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof, as an active ingredient, for preventing or treating cancer. More specifically, an object of the present invention is to provide a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof, as an active ingredient, for preventing or treating cancer. More specifically, an object of the present invention is to provide a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof, as an active ingredient, for preventing or treating cancer. More specifically, an object of the present invention is to provide a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof, as an active ingredient, for preventing or treating cancer. More specifically, an object of the present invention is to
  • Fnl4 antibody or an antigen-binding fragment thereof retaining high antagonist activity and having reduced agonist activity as compared to conventional antibodies, as an active ingredient, for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent.
  • an anti-human Fnl4 antibody which comprises: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and
  • CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103 of SEQ ID NO: 4 (Examples 1 to 5), and confirmed to bind to human Fnl4 (Example 6). Further, the inventors conducted intensive studies, and as a result found that an antibody formed by murinizing the above antibody (Example 4) suppresses tumor growth in a mouse model of cancer (Examples 7 and 8), and the present invention was completed.
  • a pharmaceutical composition comprising an anti -human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103
  • an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers
  • Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • composition according to [2], wherein the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain.
  • Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • an anti-human Fnl4 antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4;
  • an anti -human Fnl4 antibody being an antibody formed by posttranslational modification of the antibody of (3).
  • anti-human Fnl4 antibody is an anti-human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • composition according to [6] wherein the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain and/or deletion of lysine at the C terminal of the heavy chain.
  • composition according to any one of [1] to [5], wherein the antigen-binding fragment is scFv, Fab, Fab', or F(ab')2.
  • composition according to any one of [1] to [10], further comprising a pharmaceutically acceptable excipient.
  • composition according to any one of [1] to [11], wherein the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • composition according to any one of [1] to [11], wherein the cancer is lung cancer, renal cancer, or gastric cancer.
  • an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to
  • a pharmaceutical composition comprising an anti -human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103 of SEQ ID NO: 4.
  • a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers
  • An anti-human Fnl4 antibody comprised in the pharmaceutical composition of the present invention exhibits an effect to suppress tumor growth, and hence the pharmaceutical composition of the present invention, which comprises the anti-human Fnl4 antibody, can be used for preventing or treating cancer.
  • the effect of the anti-human Fnl4 antibody to suppress tumor growth is obtained through single administration of the antibody, which allows use of the antibody for pharmaceutical compositions for preventing or treating cancer that are not to be used in combination with an additional anticancer agent.
  • FIG. 1 shows antitumor effects of a control antibody, a commercially available anti-Fnl4 antibody (ITEM-4), and a 4-lh surrogate antibody in a mouse B16-F10 tumor-bearing model.
  • the vertical axis represents tumor volume (mm 3 ).
  • the P values for significance probability were determined by comparing with the antitumor effect of a control antibody group on the basis of Student T-test.
  • "NS" indicates that there is no significant difference, and indicates that the P value is smaller than a significance level of 0.05.
  • FIG. 2 shows antitumor effects of a control antibody and a 4-lh surrogate antibody in a mouse CT26.WT tumor-bearing model.
  • the vertical axis represents tumor volume (mm 3 ).
  • the P value for significance probability was determined by comparing with the antitumor effect of a control antibody group on the basis of Student T-test.
  • "*" indicates that the P value is smaller than a significance level of 0.05.
  • the present invention is a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer.
  • the anti -human Fnl4 antibody or antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention includes an anti-human
  • the present invention is a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent.
  • IgG There are five classes of IgG, IgM, IgA, IgD, and IgE in an antibody.
  • the basic structure of an antibody molecule is configured of heavy chains having a molecular weight of 50000 to 70000 and light chains having a molecular weight of 20000 to 30000 in each of the classes in common.
  • Heavy chain usually consists of a polypeptide chain comprising approximately 440 amino acids, has a distinctive structure for each of the classes, and is referred to as Igy, Igp, Iga, Ig8, and Igs corresponding to IgG, IgM, IgA, IgD, and IgE, respectively.
  • IgG 1 , Igy2, Igy3, and Igy4 are present in IgG, and the heavy chains respectively corresponding thereto are referred to as Igy 1 , Igy2, Igy3, and Igy4.
  • Light chain usually consists of a polypeptide chain comprising 220 amino acids, two types of which, type L and type K are known, and are referred to as IgA, and IgK.
  • S-S bond disulfide bonds
  • non-covalent bonds the molecular weight thereof is 150000 to 190000.
  • Two kinds of light chains can be paired with any heavy chain.
  • the respective antibody molecules typically consist of two identical light chains and two identical heavy chains.
  • intrachain S-S bonds With regard to intrachain S-S bonds, four of the S-S bonds are present in the heavy chain (five in Igp and Ig8 chains) and two of them are present in the light chain; one loop is formed per 100 to 110 amino acid residues, and this steric structure is similar among the loops and are referred to as a structural unit or a domain.
  • the domain located at the N terminal side in both of the heavy chain and the light chain, whose amino acid sequence is not constant even in a case of a sample from the same class (sub class) of the same kind of animal is referred to as a variable region, and respective domains are referred to as a heavy chain variable region (VH) and a light chain variable region (VL).
  • VH heavy chain variable region
  • VL light chain variable region
  • the amino acid sequence of the C terminal side from the variable region is nearly constant in each class or subclass and is referred to as a constant region (respective domains are represented as CHI, CH2, CH3, or CL, respectively
  • An antigenic binding site of an antibody is configured of VH and VL, and the binding specificity depends on the amino acid sequence of this site.
  • biological activities such as binding to complements and various Fc receptor expression cells reflect differences in the constant region structures among each class Ig. It is understood that the variability of variable regions of the light chains and the heavy chains is mostly limited to three small hypervariable regions present in both chains and these regions are referred to as complementarity determining regions (CDR: CDR1, CDR2, and CDR3 from the N terminal side). The remaining portion of the variable region is referred to as a framework region (FR) and is relatively constant.
  • CDR complementarity determining regions
  • Various antigen-binding fragments comprising VH and VL of an antibody also have antigen-binding activities, and representative examples of such an antigen-binding fragment include a single chain variable region fragment (scFv), Fab, Fab', and F(ab')2.
  • scFv is a monovalent antibody fragment which is configured of VH and VL connected to each other via a linker.
  • Fab is a monovalent antibody fragment which is configured of a light chain and a heavy chain fragment comprising VH, a CHI domain, and a portion of a hinge region.
  • Fab' is a monovalent antibody fragment which is configured of a light chain and a heavy chain fragment comprising VH, a CHI domain, and a portion of a hinge region, and the portion of the hinge region includes cysteine residues configuring the S-S bond between heavy chains.
  • F(ab')2 fragment is a divalent antibody fragment in which two Fab' fragments are bound by an S-S bond between heavy chains in the hinge region.
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103 of SEQ ID NO: 4.
  • a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2
  • CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention has the above-described characteristics, and further comprises a heavy chain constant region and a light chain constant region.
  • the constant region any subclass constant region (for example, Igyl, Igy2, Igy3, or Igy4 as a heavy chain constant region, and IgA. or IgK as a light chain constant region) can be selected.
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof used for the present invention comprises a human Igyl constant region as a heavy chain constant region and a human IgK constant region as a light chain constant region.
  • the residue number related to the introduction of amino acid mutations in the constant region of the antibody used in the present specification can be defined according to the EU index (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institute of Health, Bethesda).
  • L234A and L235A are substitutions of leucine at the amino acid 234 position and the amino acid 235 position with alanine in the human Igyl constant region according to the EU index of Kabat et al., respectively.
  • Examples of the human Igyl constant region having amino acid mutations of L234A and L235A include a human Igyl constant region consisting of the amino acid sequence of amino acid numbers 126 to 455 of SEQ ID NO: 2.
  • the amino acid 234 position and the amino acid 235 position in the human Igyl constant region according to the EU index of Kabat et al. correspond to amino acid numbers 242 and 243, respectively, in the amino acid sequence of SEQ ID NO: 2.
  • the antibody or the antigen-binding fragment thereof is modified after translation of it.
  • the posttranslational modification include deletion of lysine at the C terminal of the heavy chain by a carboxypeptidase, modification of glutamine or glutamic acid at the N terminal of the heavy chain and the light chain to pyroglutamic acid by pyroglutamylation, glycosylation, oxidation, deamidation, and glycation, and it is known that such posttranslational modifications occur in various antibodies (Liu H et al., J Phar Sci. 2008, Vol. 97 No. 7, p. 2426-2447).
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody or an antigen-binding fragment thereof formed by posttranslational modification.
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody or an antigen-binding fragment thereof subjected to pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain. It is known in the field that such posttranslational modification due to pyroglutamylation at the N terminal or deletion of lysine at the C terminal does not have any influence on the activity of the antibody (Lyubarskaya Y et aL, Anal Biochem. 2006, Vol. 348, p. 24-39).
  • the pharmaceutical composition of the present invention comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification of an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody formed by posttranslational modification.
  • the pharmaceutical composition of the present invention comprises an anti -human Fnl4 antibody subjected to pyroglutamylation at the N terminal of the heavy chain and/or deletion of lysine at the C terminal of the heavy chain.
  • the pharmaceutical composition of the present invention comprises an anti-human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 454 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the antigen-binding fragment comprised in the pharmaceutical composition of the present invention is scFv, Fab, Fab', or F(ab')2.
  • examples of the antigen-binding fragment comprised in the pharmaceutical composition of the present invention include a 4-lh antibody described in Examples below.
  • any person skilled in the art can prepare a fused form in which the antibody or the antigen-binding fragment thereof is fused with another peptide or protein, or also can prepare a modified form to which a modifying agent is bound on the basis of the contents disclosed in the present specification, and the antibody or the antigen-binding fragment comprised in the pharmaceutical composition of the present invention also includes these forms of antibodies or antigen-binding fragments thereof.
  • peptides or proteins used for the fusion are not particularly limited as long as the fused form binds to Fnl4, and examples thereof include human serum albumin, various tag peptides, artificial helix motif peptide, maltose-binding proteins, glutathione S transferase, various toxins, and other peptides or proteins capable of promoting multimerization.
  • the modifying agent used for the modification is not particularly limited as long as the modified form binds to Fnl4, and examples thereof include polyethylene glycol, sugar chains, phospholipids, liposomes, and low-molecular compounds.
  • the modifying agent used for the modification of the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention is polyethylene glycol.
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof in the present specification means an antibody or antigen-binding fragment thereof that binds to human Fnl4. Whether the anti-human Fnl4 antibody binds to human Fnl4 can be confirmed by using a known binding activity measurement method. Examples of the binding activity measurement method include an Enzyme-Linked ImmunoSorbent Assay (ELISA). In a case of using the ELISA, for example, a human Fnl 4 protein is immobilized on an ELISA plate and a test antibody is added thereto to be reacted.
  • ELISA Enzyme-Linked ImmunoSorbent Assay
  • a secondary antibody such as an anti-IgG antibody, labeled with an enzyme such as horseradish peroxidase (HRP), is reacted.
  • HRP horseradish peroxidase
  • washing is performed, and then it is possible to confirm whether the test antibody binds to the human Fnl 4 by identifying binding of the secondary antibody through activity measurement using a reagent detecting the activity (for example, in a case of HRP labeling, TMB Microwell Peroxidase Substrate (Kirkegaard & Perry Laboratories, Inc., 50-76-03)).
  • HRP labeling for example, in a case of HRP labeling, TMB Microwell Peroxidase Substrate (Kirkegaard & Perry Laboratories, Inc., 50-76-03).
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention includes, in addition to binding to human Fnl4, an antibody or antigen-binding fragment thereof that binds to Fnl4 derived from other animals (for example, mouse Fnl4), as long as the antibody or the antigen-binding fragment thereof binds to human Fnl 4.
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention can be prepared by a person skilled in the art using a known method in the field.
  • the anti-human Fnl 4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention can be prepared by a person skilled in the art using a known method in the field, based on sequence information on the heavy chain and the light chain of the anti-human Fnl 4 antibody disclosed in the present specification.
  • the anti-human Fnl4 antibody comprised in the pharmaceutical composition of the present invention can be prepared by (i) synthesizing a polynucleotide containing a base sequence encoding the heavy chain of the anti-human Fnl4 antibody and a polynucleotide containing a base sequence encoding the light chain of the anti-human Fnl4 antibody, followed by linking them to an appropriate expression vector, (ii) introducing the expression vector into cultured cells, and (iii) culturing the cultured cells and obtaining and purifying the antibody from the culture supernatant.
  • Such synthesis of polynucleotides, introduction of the polynucleotides into an expression vector, introduction of the expression vector into cultured cells, culture of the cultured cells, purification or the like of the antibody can be carried out by using various methods known in the field, and, for example, a method described in WO 2020/090892 can be used.
  • the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention can be prepared in accordance with a method described in WO 2020/090892.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable additive or carrier or the like.
  • the type of the pharmaceutically acceptable additive or carrier or the like is not particularly limited, and any additive or carrier or the like well-known to persons skilled in the art can be used.
  • the additive that can be comprised in the pharmaceutical composition of the present invention include isotonic agents, buffers, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, and solubilizers
  • examples of the carrier that can be comprised in the pharmaceutical composition of the present invention include distilled water for injection and physiological saline.
  • the pharmaceutical composition of the present invention can be prepared by a method being generally used with excipients or carriers or the like being generally used in the field.
  • the pharmaceutical composition of the present invention can be sterilized, for example, by blending a microbicide or irradiation. After being produced as a sterile solid composition, the pharmaceutical composition of the present invention can be used in a state dissolved or suspended in advance in sterile water or sterile solvent for injection.
  • Examples of dosage forms of the pharmaceutical composition of the present invention include parenteral drugs such as an injection drug, a drip infusion drug, and a depot drug.
  • the pharmaceutical composition of the present invention may be a sterile aqueous or non-aqueous solution, suspension, or emulsion.
  • aqueous solvents include distilled water for injection and physiological saline.
  • non-aqueous solvents include alcohols such as ethanol.
  • the form of administration of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition of the present invention can be administered, for example, by intravenous administration, subcutaneous administration, intramuscular administration, or the like.
  • the dose of the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention varies depending on the age and body weight of a subject for administration, the degree of his or her symptoms, the dosage form of the drug to be used, the form of administration, the binding titer of the antibody, or the like, and the pharmaceutical composition of the present invention can be used, for example, in an amount of approximately 0.001 mg/kg to 100 mg/kg as the amount of the antibody.
  • the subject for administration of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include humans.
  • the pharmaceutical composition of the present invention can be used for preventing or treating cancer.
  • the "cancer” is a term including brain tumor, head and neck cancer, salivary gland cancer, thyroid cancer, lung cancer, small cell lung cancer, breast cancer, mesothelioma, pancreatic cancer, liver cancer, biliary cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, small intestine cancer, colorectal cancer, renal cancer, renal pelvis cancer, ureter cancer, bladder cancer, prostate cancer, cervical cancer, ovarian cancer, uterine sarcoma, testicular tumor, malignant lymphoma, leukemia, chronic lymphocytic leukemia, multiple myeloma, skin cancer, melanoma, and sarcoma.
  • the cancer prevented or treated by the pharmaceutical composition of the present invention is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the cancer prevented or treated by the pharmaceutical composition of the present invention is lung cancer, renal cancer, gastric cancer, head and neck cancer, or esophageal cancer. That is, in one mode, the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating lung cancer, renal cancer, gastric cancer, head and neck cancer, or esophageal cancer.
  • the cancer prevented or treated by the pharmaceutical composition of the present invention is lung cancer, renal cancer, or gastric cancer. That is, in one mode, the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating lung cancer, renal cancer, or gastric cancer.
  • the cancer prevented or treated by the pharmaceutical composition of the present invention is cancer expressing Fnl4. That is, in one mode, the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating cancer expressing Fnl4.
  • the cancer prevented or treated by the pharmaceutical composition of the present invention is cancer sensitive to the anti-Fnl4 antibody. That is, in one mode, the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating cancer sensitive to the anti-Fnl4 antibody.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti -human Fnl4 antibody or the antigen-binding fragment thereof is at least one anti-human Fnl4 antibody or antigen-binding fragment thereof selected from the group consisting of the following (1) and (2):
  • an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is use of an anti -human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticanCer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti -human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody is at least one anti-human Fnl4 antibody selected from the group consisting of the following (3) and (4):
  • an anti-human Fnl4 antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4;
  • an anti -human Fnl4 antibody being an antibody formed by posttranslational modification of the antibody of (3).
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody is an anti-human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is use of an anti -human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 454 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the antigen-binding fragment is scFv, Fab, Fab', or F(ab')2.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable additive and/or carrier.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the cancer is lung cancer, renal cancer, gastric cancer, head and neck cancer, or esophageal cancer.
  • the present invention is use of an anti-human Fnl4 antibody or an antigen-binding fragment thereof for the manufacturing of a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition being not to be used in combination with an additional anticancer agent, wherein the cancer is lung cancer, renal cancer, or gastric cancer.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti -human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is at least one anti-human Fnl4 antibody or antigen-binding fragment thereof selected from the group consisting of the following (1) and (2):
  • an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody is at least one anti-human Fn 14 antibody selected from the group consisting of the following (3) and (4):
  • an anti-human Fnl4 antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4;
  • an anti-human Fnl4 antibody being an antibody formed by posttranslational modification of the antibody of (3).
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody is an anti-human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is use of a pharmaceutical composition comprising an anti -human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is use of a pharmaceutical composition comprising an anti -human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 454 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the antigen-binding fragment is scFv, Fab, Fab', or F(ab')2.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable additive and/or carrier.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the cancer is lung cancer, renal cancer, gastric cancer, head and neck cancer, or esophageal cancer.
  • the present invention is use of a pharmaceutical composition comprising an anti-human Fnl4 antibody or an antigen-binding fragment thereof for preventing or treating cancer without using an additional anticancer agent in combination, wherein the cancer is lung cancer, renal cancer, or gastric cancer.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti -human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid numbers 98 to 114 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 40 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid numbers 56 to 62 of SEQ ID NO: 4, and
  • CDR3 consisting of the amino acid sequence of amino acid numbers 95 to 103 of SEQ ID NO: 4.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is at least one anti-human Fnl4 antibody or antigen-binding fragment thereof selected from the group consisting of the following (1) and (2):
  • an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain variable region and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti -human Fnl4 antibody or the antigen-binding fragment thereof is an anti-human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody is at least one anti-human Fnl4 antibody selected from the group consisting of the following (3) and (4):
  • an anti-human Fnl4 antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4;
  • an anti-human Fnl4 antibody being an antibody formed by posttranslational modification of the antibody of (3).
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti -human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody is an anti -human Fnl4 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti -human Fnl4 antibody or the antigen-binding fragment thereof comprises an antibody or an antigen-binding fragment thereof formed by posttranslational modification, and the posttranslational modification is pyroglutamylation at the N terminal of the heavy chain and/or deletion of lysine at the C terminal of the heavy chain.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the anti-human Fnl4 antibody or the antigen-binding fragment thereof is an anti -human Fnl4 antibody or an antigen-binding fragment thereof comprising: a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 454 of SEQ ID NO: 2, in which glutamine of amino acid number 1 of SEQ ID NO: 2 is modified to pyroglutamic acid; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the antigen-binding fragment is scFv, Fab, Fab', or F(ab')2.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable additive and/or carrier.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti -human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the cancer is melanoma, colorectal cancer, lung cancer, renal cancer, gastric cancer, esophageal cancer, head and neck cancer, mesothelioma, bile duct cancer, pancreatic cancer, bladder cancer, breast cancer, liver cancer, ovarian cancer, or cervical cancer.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the cancer is lung cancer, renal cancer, gastric cancer, head and neck cancer, or esophageal cancer.
  • the present invention is a method for preventing or treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an anti-human Fnl4 antibody or an antigen-binding fragment thereof to a subject without using an additional anticancer agent in combination, wherein the cancer is lung cancer, renal cancer, or gastric cancer.
  • the polynucleotide encoding the anti-human Fnl4 antibody or the antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention is a polynucleotide comprising a base sequence encoding the heavy chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, and examples thereof include a polynucleotide comprising a base sequence of base numbers 1 to 375 of SEQ ID NO: 1.
  • the polynucleotide comprising a base sequence encoding the heavy chain variable region of the anti-human Fnl4 antibody comprised in the pharmaceutical composition of the present invention is a polynucleotide comprising a base sequence encoding the heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 2, and examples thereof include a polynucleotide comprising a base sequence represented by SEQ ID NO: 1.
  • the polynucleotide comprising a base sequence encoding the light chain variable region of the anti -human Fnl4 antibody or antigen-binding fragment thereof comprised in the pharmaceutical composition of the present invention is a polynucleotide comprising a base sequence encoding the light chain variable region consisting of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4, and examples thereof include a polynucleotide comprising a base sequence of base numbers 1 to 342 of SEQ ID NO: 3.
  • the polynucleotide comprising a base sequence encoding the light chain variable region of the anti-human Fnl4 antibody comprised in the pharmaceutical composition of the present invention is a polynucleotide comprising a base sequence encoding the light chain consisting of the amino acid sequence represented by SEQ ID NO: 4, and examples thereof include a polynucleotide comprising a base sequence represented by SEQ ID NO: 3.
  • the expression vectors used to express the above-described polynucleotide are not particularly limited as long as the expression vectors can produce polypeptide, and examples thereof include plasmid vectors and viral vectors (for example, adenovirus or retrovirus).
  • plasmid vectors and viral vectors for example, adenovirus or retrovirus.
  • viral vectors for example, pEE6.4 or pEE12.4 can be used.
  • An antibody gene can also be expressed by introducing a variable region gene segment into an expression vector already having a human Ig constant region gene such as AG-yl and AG-K (for example, see WO94/20632).
  • the above-described expression vector may comprise a promoter that is operably linked to the polynucleotide encoding the anti-human Fnl4 antibody or the antigen-binding fragment thereof.
  • the promoter for expressing the polynucleotide with an animal cell can include a virus-derived promoter such as CMV, RSV, or SV40, an actin promoter, an EF (elongation factor) 1 a promoter, and a heat shock promoter.
  • the promoter for expressing the polynucleotide by bacteria can include a trp promoter, a lac promoter, a XPL promoter, and a tac promoter.
  • examples of the promoter for expressing the polynucleotide by yeast can include a GALI promoter, a GAL 10 promoter, a PH05 promoter, a PGK promoter, a GAP promoter, and an ADH promoter.
  • the expression vector used in the present invention may comprise an initiation codon and a termination codon.
  • the expression vector used in the present invention may comprise an initiation codon, a termination codon, a terminator region, and a replicable unit, and may further comprise a selection marker (for example, tetracycline resistant genes, ampicillin resistant genes, kanamycin resistant genes, neomycin resistant genes, or dihydrofolate reductase genes) which is generally used according to the purpose.
  • the transformed host cell is not particularly limited as long as the host cell is appropriate for the expression vector being used, transformed with the expression vector, and can express the antibody.
  • the transformed host cell include various cells such as natural cells or artificially established cells which are generally used in the field of the present invention (for example, animal cells (for example, CHO-K1SV cells), insect cells (for example, Sf9), bacteria (for example, Escherichia), yeast (for example, Saccharomyces or Pichia) and the like).
  • cultured cells such as CHO cells (CHO-K1 SV cells and CHO-DG44 cells), 293 cells, and NSO cells can be used.
  • a method for transforming the host cell is not particularly limited, and, for example, a calcium phosphate method or an electroporation method can be used.
  • the inventors prepared a human Fnl4-human Fc fusion protein and a mouse Fnl4-mouse Fc fusion protein for use as an antigen for acquiring an anti-Fnl4 antibody and a material to be used in a screening test.
  • the human Fnl 4-human Fc fusion protein is a fusion protein in which the C terminal of the extracellular partial sequence of a human Fnl4 sequence (1st to 79th amino acids of NCBI accession number: NP 057223.1) and the N terminal of the human Fc region (106th to 330th amino acids of NCBI accession number: P01857.1) are linked by a peptide linker (SEQ ID NO: 9).
  • the mouse Fnl4-mouse Fc fusion protein is a fusion protein in which the C terminal of the extracellular partial sequence of a mouse Fnl4 sequence (1st to 75th amino acid of NCBI accession number: AAF07882.1) and the N terminal of the mouse Fc region are linked, and specifically, a fusion protein in which genes encoding the extracellular partial sequence of the mouse Fnl 4 sequence are incorporated into the multicloning site between the hEFl-HTLV promoter region and the mIgG2B-Fc region of pFUSE-m!gG2B-Fcl (InvivoGen, pfuse-mg2bfcl) using restriction enzymes EcoRI and EcoRV and expressed.
  • Expression vectors in which genes encoding the above-described fusion proteins were incorporated into a GS vector pEE12.4 (Lonza) were prepared and introduced into CHO-K1SV cells (Lonza), respectively.
  • the human Fnl4-human Fc fusion protein and the mouse Fnl4-mouse Fc fusion protein were each purified from the culture supernatant of the CHO-K1SV cells according to a conventional method.
  • An antibody was prepared using a human monoclonal antibody developing technology "Veloclmmune” (Veloclmmune antibody technology: Regeneron Pharmaceuticals, Inc. (US Patent No. 6596541)) mouse.
  • the antibody obtained by the Veloclmmune technology is an antibody (also referred to as a chimeric antibody) having a variable region of a human antibody and a constant region of a mouse antibody.
  • Veloclmmune mice were immunized with an adjuvant for causing an immune reaction together with a human Fnl4 protein in which a human Fc region was cut and removed from the human Fnl4-human Fc fusion protein prepared in Example 1 using FabRICATOR (Sigma, 77661).
  • Lymphocytes collected from the lymph node of the immunized mouse were fused with mouse-derived myeloma cells SP2/0-Agl4 (ATCC: CRL-1581) according to a conventional method to prepare hybridomas, and the hybridomas were monocloned.
  • Hybridomas producing an antibody, which binds to human Fnl4 and suppresses the NFKB activation induced by Tweak stimulation (hereinafter, referred to as "Tweak-induced NFKB activation" in Examples below), were selected, and the antibody was purified.
  • HEK293 cells ATCC, CRL-1573
  • a luciferase reporter vector pGL4.32 Promega K.K., E8491
  • NFKB/HEK29 cells a luciferase reporter vector pGL4.32
  • NFKB/HEK293 cells were suspended in 10% fetal bovine serum-containing DMEM (Sigma, D6429) at 1.25xl0 5 cells/mL, and seeded at 80 pL/well in a clear bottom white 96-well plate (Corning Incorporated, 3610). After culture for 2 hours in a CO2 incubator set at 37°C with an atmosphere of 5% CO2, a 12-step dilution series of the purified antibody obtained in Example 2 was prepared in the above culture medium with about 3-fold common ratio from a final concentration of 1 ng/mL to 300 pg/mL, and then added at 20 pL/well.
  • luciferase expression was measured using a luciferase measurement reagent ONE-Glo Luciferase Assay System (Promega Corporation) to quantify the NFKB activation.
  • Example 4 Preparation of Fully Humanized Antibody and Murinized Antibody Genes encoding the heavy chain and the light chain of the antibody were cloned from the hybridomas producing the antibody selected in Example 3, and the sequence was determined. After the determination of the antibody sequence, genes encoding signal sequences (Wittie N et al., Protein Engineering. 1987, Vol. 1, No. 6, p.
  • human Igyl constant region genes consisting of the base sequence of base numbers 376 to 1365 of SEQ ID NO: 1 having amino acid mutations of L234A and L235A were respectively ligated to the 5' side and the 3' side of the heavy chain variable region genes, and the heavy chain genes were inserted into a GS vector pEE6.4 (Lonza).
  • genes encoding signal sequences (Wittie N et al., Protein Engineering. 1987, Vol. 1, No. 6, p.
  • GS vector pEE12.4 constant region genes (consisting of the base sequence of base numbers 343 to 660 of SEQ ID NO: 3) of a human K chain were respectively ligated to the 5' side and the 3' side of the light chain variable region genes, and the light chain genes were inserted into a GS vector pEE12.4.
  • GS vectors were subjected to restriction enzyme fragmentation with Notl-HF and PvuI-HF, and ligated using DNA Ligation Kit ⁇ Mighty Mix> (Takara Bio Inc., 6023) to form a GS vector in which both the heavy chain genes and the light chain genes were inserted.
  • the antibody was purified according to a conventional method from the culture supernatant of CHOK1SV cells obtained by transfecting the vector, and thus a fully humanized antibody of 4-1 was acquired and named 4-lh.
  • the base sequence of the heavy chain of 4-lh prepared is represented by SEQ ID NO: 1, the amino acid sequence encoded thereby is represented by SEQ ID NO: 2, the base sequence of the light chain is represented by SEQ ID NO: 3, and the amino acid sequence encoded thereby is represented by SEQ ID NO: 4.
  • the variable region of the heavy chain represented by SEQ ID NO: 2 consists of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 2, and the variable region of the light chain represented by SEQ ID NO: 4 consists of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 4.
  • CDR1, CDR2, and CDR3 of the heavy chain variable region of 4-lh consist of the amino acid sequences of amino acid numbers 31 to 35, 50 to 65, and 98 to 114 of SEQ ID NO: 2, respectively.
  • CDR1, CDR2, and CDR3 of the light chain variable region of 4-lh consist of the amino acid sequences of amino acid numbers 24 to 40, 56 to 62, and 95 to 103 of SEQ ID NO: 4, respectively.
  • a murinized antibody of 4-lh (hereinafter, referred to as “4-lm” or “surrogate antibody”) was prepared to reduce the immunogenic risk in the evaluation of the anti-human Fnl4 antibody by a mouse in vivo test.
  • a base sequence encoding the variable region of 4-lm was prepared by partially substituting the framework region (FR) of the light chain and the heavy chain of 4-lh with FR of other mouse antibodies.
  • 4-lm was obtained using the same method as the vector formation, antibody expression, and purification for 4-lh described above.
  • genes encoding mouse Igy2a constant region genes consisting of the base sequence of base numbers 376 to 1365 of SEQ ID NO: 5 having a D265A amino acid mutation are used, and for the constant region of the light chain, constant region genes (consisting of the base sequence of base numbers 343 to 660 of SEQ ID NO: 7) of a mouse K chain were used.
  • the base sequence of the heavy chain of 4-lm prepared is represented by SEQ ID NO: 5, the amino acid sequence encoded thereby is represented by SEQ ID NO: 6, the base sequence of the light chain is represented by SEQ ID NO: 7, and the amino acid sequence encoded thereby is represented by SEQ ID NO: 8.
  • the variable region of the heavy chain represented by SEQ ID NO: 6 consists of the amino acid sequence of amino acid numbers 1 to 125 of SEQ ID NO: 6, and the variable region of the light chain represented by SEQ ID NO: 8 consists of the amino acid sequence of amino acid numbers 1 to 114 of SEQ ID NO: 8.
  • CDR1, CDR2, and CDR3 of the heavy chain variable region of 4- Im consist of the amino acid sequences of amino acid numbers 31 to 35, 50 to 65, and 98 to 114 of SEQ ID NO: 6, respectively.
  • CDR1, CDR2, and CDR3 of the light chain variable region of 4- Im consist of the amino acid sequences of amino acid numbers 24 to 40, 56 to 62, and 95 to 103 of SEQ ID NO: 8, respectively.
  • Example 5 Amino Acid Modification Analysis of Fully Humanized Antibody 4-lh purified was subjected to amino acid modification analysis, and as a result, most of the purified antibodies had pyroglutamylation at the N terminal of the heavy chain and deletion of lysine at the C terminal.
  • Example 6 Human and Mouse Fnl4 Binding ELISA of Fully Humanized Antibody and Murinized Antibody
  • Binding activities of 4-lh and 4- Im acquired in Example 4 to a Fn 14 protein were evaluated.
  • the human Fnl4-human Fc fusion protein and the mouse Fnl4-mouse Fc fusion protein acquired in Example 1 were prepared with phosphate buffered saline (PBS) at 1 pg/mL, and added to a MaxiSorp 384-well transparent plate (Nunc, 464718) at 15 L/well. Incubation was performed overnight at 4°C for immobilization. On the next day, the solid phase liquid was removed, and washing was performed with a 0.05% Tween-20-containing Tris-buffered saline (TBS-T).
  • PBS phosphate buffered saline
  • PBS containing 20% Blocking One (Nacalai tesque, Inc., 03953-95) was added thereto at 50 pL/well. The resultant was left at room temperature for 1 hour, and then washed with TBS-T.
  • a dilution series of 4-lh or 4-1 m acquired in Example 4 was prepared by dilution in 12 steps with a 4-fold common ratio from a maximum concentration of 30 pg/mL using TBS-T containing 5% Blocking One (hereinafter, referred to as a diluent), and added at 20 pL/well. After incubation for 1 hour at room temperature, washing was performed with TBS-T.
  • a horseradish peroxidase-labeled anti-human K light chain antibody (SouthemBiotech, 2060-05) as a secondary antibody diluted 5000 times with a diluent was added at 20 .L/well for detection of 4-lh, and a horseradish peroxidase-labeled anti-mouse K light chain antibody (SouthemBiotech, 1050-05) as a secondary antibody diluted 4000 times with a diluent was added at 20 pL/well for detection of 4-lm. After incubation for 1 hour at room temperature, washing was performed with TBS-T.
  • a TMB Microwell Peroxidase Substrate (Kirkegaard & Perry Laboratories, Inc., 50-76-03) was added, and the resultant was left for 3 minutes in the evaluation of 4-lh, or left for 5 minutes in the evaluation of 4-lm. Then, the reaction was stopped by adding a 2M sulfuric acid, and the absorbance at 450 nm was measured with SpectraMax Paradigm (Molecular Devices, LLC). The test was performed in duplicate, and EC50 values were calculated by 4-parameter logistic curve fitting.
  • Example 7 Comparison of Drug Efficacy Between 4-lh Surrogate Antibody (4-lm) and Commercially Available Anti-Fnl4 Antibody in Mouse B16-F10 Tumor-Bearing Model The antitumor effect of the surrogate antibody of 4-lh (4-lm) acquired in Example
  • mice 4 and that of a commercially available mouse anti-mouse/human Fnl4 antibody were compared by using a mouse tumor-bearing model with the mouse-derived melanoma cell line B 16-F 10 transplanted thereinto.
  • B 16-F 10 (ATCC, CRL-6475) was cultured in DMEM containing 10% fetal bovine serum and 50 units/mL penicillin-50 pg/mL streptomycin.
  • mice (Charles River Laboratories Japan, Inc.) at a volume of 0.5 x 10 5 cells/100 .L (day 0).
  • the tumor diameter was measured with time, and the tumor volume (mm 3 ) was calculated by calculation expression: Long axis (mm) x Short axis (mm) x Short axis (mm)/2.
  • the configuration and the date of administration are as follows for each group.
  • Control Group anti-Keyhole Limpet Hemocyanin (KLH) antibody (KLH_173Al_maO, prepared by Astellas Pharma Inc.); 0.3 mg/kg intraperitoneal administration; administration on day 4, day 7, day 11, day 14
  • ITEM-4 Group ITEM-4 (manufactured by BioLegend, Inc., Part No. 900003587, Lot No. B335282); 0.3 mg/kg intraperitoneal administration; administration on day 4, day 7, day 11, day 14
  • Example 8 Drug Efficacy of 4-lh Surrogate Antibody (4-lm) in Mouse CT26.WT Tumor-Bearing Model
  • the surrogate antibody of 4-lh (4-lm) acquired in Example 4 was compared by using a mouse tumor-bearing model with the mouse-derived colorectal cancer cell line CT26.WT transplanted thereinto.
  • the tumor diameter was measured with time, and the tumor volume (mm 3 ) was calculated by calculation expression: Long axis (mm) x Short axis (mm) x Short axis (mm)/2.
  • the configuration and the date of administration are as follows for each group.
  • Control Group anti-Keyhole Limpet Hemocyanin (KLH) antibody (KLH 173 Al maO, prepared by Astellas Pharma Inc.); 0.3 mg/kg intraperitoneal administration; administration on day 4, day 8, day 11
  • KLH Keyhole Limpet Hemocyanin
  • the pharmaceutical composition of the present invention is very useful with regard to the capability of preventing or treating various cancers in which human Fnl4 is involved in pathogenesis without using an additional anticancer agent in combination.
  • the base sequences represented by SEQ ID NOS: 1, 3, 5, and 7 of the sequence list are respectively the base sequences of the heavy chain and the light chain of the anti -human Fnl4 antibody
  • the amino acid sequences represented by SEQ ID NOS: 2, 4, 6, and 8 are respectively the amino acid sequences of the heavy chain and the light chain encoded by SEQ ID NOS: 1, 3, 5, and 7.
  • the amino acid sequence represented by SEQ ID NO: 9 is the peptide linker sequence linking a human Fnl4 protein and a human Fc region protein.

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Abstract

L'invention concerne une composition pharmaceutique comprenant un anticorps Fnl4 anti-humain ou un fragment de liaison à l'antigène de celui-ci qui se lie à un Fnl4 humain pour inhiber une action par l'intermédiaire du Fnl4 humain pour prévenir ou traiter le cancer, la composition pharmaceutique ne devant pas être utilisée en combinaison avec un agent anticancéreux supplémentaire. Les inventeurs ont découvert que l'utilisation d'une composition pharmaceutique comprenant un anticorps Fnl4 anti-humain ou un fragment de liaison à l'antigène de celui-ci, comprenant : une région variable de chaîne lourde comprenant CDR1 consistant en la séquence d'acides aminés des numéros d'acides aminés 31 à 35 de SEQ ID No : 2, CDR2 consistant en la séquence d'acides aminés des numéros d'acides aminés 50 à 65 de SEQ ID No : 2 et CDR3 comprenant la séquence d'acides aminés des numéros d'acides aminés 98 à 114 de SEQ ID No : 2; et une région variable de chaîne légère comprenant CDR1 consistant en la séquence d'acides aminés des numéros d'acides aminés 24 à 40 de SEQ ID No : 4, CDR2 consistant en la séquence d'acides aminés des numéros d'acides aminés 56 à 62 de SEQ ID No : 4 et CDR3 comprenant la séquence d'acides aminés des numéros d'acides aminés 95 à 103 de SEQ ID No : 4, permet la prévention ou le traitement du cancer sans utiliser d'agent anticancéreux supplémentaire en association, achevant ainsi la présente invention.
PCT/JP2021/038847 2021-10-14 2021-10-14 Composition pharmaceutique comprenant un anticorps fnl4 anti-humain ou un fragment de liaison à l'antigène de celui-ci pour la prévention ou le traitement du cancer WO2023062848A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026099A1 (fr) * 2011-08-23 2013-02-28 Transbio Ltd Protéines de liaison à fn14 et leurs utilisations
WO2020090892A1 (fr) * 2018-10-31 2020-05-07 アステラス製薬株式会社 Anticorps anti-fn14 humain
WO2021214905A1 (fr) * 2020-04-22 2021-10-28 アステラス製薬株式会社 Composition pharmaceutique et procédé de prévention ou de traitement du cancer par utilisation conjointe d'un anticorps anti-fn14 humain et d'un inhibiteur de point de contrôle immunitaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026099A1 (fr) * 2011-08-23 2013-02-28 Transbio Ltd Protéines de liaison à fn14 et leurs utilisations
WO2020090892A1 (fr) * 2018-10-31 2020-05-07 アステラス製薬株式会社 Anticorps anti-fn14 humain
WO2021214905A1 (fr) * 2020-04-22 2021-10-28 アステラス製薬株式会社 Composition pharmaceutique et procédé de prévention ou de traitement du cancer par utilisation conjointe d'un anticorps anti-fn14 humain et d'un inhibiteur de point de contrôle immunitaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YORIKI RYO, AKASHI SATORU, SHO MASAYUKI, NOMI TAKEO, YAMATO ICHIRO, HOTTA KIYOHIKO, TAKAYAMA TOMOYOSHI, MATSUMOTO SOHEI, WAKATSUKI: "Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer", EXPERIMENTAL AND THERAPEUTIC MEDICINE, SPANDIDOS PUBLICATIONS, GR, vol. 2, no. 1, 1 January 2011 (2011-01-01), GR , pages 103 - 108, XP093057325, ISSN: 1792-0981, DOI: 10.3892/etm.2010.181 *

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