WO2019189780A1 - 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 PDFInfo
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- 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 medicament for the treatment and / or prevention of cancer using an antibody against a CAPRIN-1 protein or a fragment thereof and imiquimod.
- a treatment method using a combination of a plurality of cancer therapeutic agents has been used as a standard treatment method.
- treatment with irinotecan, folinic acid and fluorouracil for breast cancer, treatment with combination of doxorubicin and cyclophosphamide, or for paclitaxel, trastuzumab and veltuzumab, for gastric cancer
- multiple anticancer drugs such as cisplatin and fluorouracil.
- a cancer therapeutic agent comprising an anti-CAPRIN-1 antibody as an active ingredient has also been confirmed to have an excellent cancer therapeutic effect when used in combination with a chemotherapeutic agent (Patent Document 2).
- Patent Document 2 the treatment of cancer with a combination of chemotherapeutic agents is not effective for all applied cancers, and may increase synergistically, albeit additively. There are few things that enhance the therapeutic effect.
- Imiquimod is known as an agonist of Toll-like receptor (TLR) 7 or 8.
- TLR Toll-like receptor
- the main mechanism of action of imiquimod in vivo is against the disease associated with viral infection due to the inhibition of virus growth through the promotion of IFN- ⁇ production and the damage of virus-infected cells by the activation of cellular immune response. Based on this mechanism of action, it is an application-type pharmaceutical that was originally approved as a treatment for warts and scabs, not as a treatment for cancer. Thereafter, effectiveness has been recognized for superficial diseases such as actinic keratosis and Bowen's disease.
- imiquimod has also been recognized for application to superficial basal cell carcinoma, and is applied to the treatment of superficial skin cancer (Boen's disease, melanoma, cutaneous T-cell lymphoma) (non-patented) Reference 1).
- the mechanism of action against superficial basal cell carcinoma is thought to be one of the mechanisms by strong activation of the innate immune system by monocytes and macrophages, which are one of the immune cells in the body (non- Patent Document 2).
- imiquimod is only approved for some cancers (superficial basal cell carcinoma).
- imiquimod is known to be used as a symptomatic treatment in extramammary budget disease, and Cohen et al. Reported that 7 out of 9 cases were completely successful (Non-patent Document 3).
- a method for treating cancer by combining a cancer antibody drug and an agent that activates an antigen-presenting cell containing a Toll-like receptor agonist (Patent Document 3), a targeted therapeutic agent including an antibody drug (targeted therapeutic) ) And human plasmacytoid dendritic cells, myeloid dendritic cells or immunotherapeutic agents that can activate NK cells (immunotherapeutic) in combination with cancer (Patent Document 4), Imiquimod is described as an example of an agent and an immunotherapeutic agent that activates the antigen-presenting cells.
- Non-patent Document 4 a case where the antitumor effect of imiquimod was attenuated has been reported.
- An object of the present invention is to provide a pharmaceutical composition for treating and / or preventing cancer that specifically expresses the CAPRIN-1 protein on the cell surface.
- rituximab a monoclonal antibody that specifically binds to the CD20 protein expressed on the surface of cancer cells
- rituximab a monoclonal antibody that specifically binds to the CD20 protein expressed on the surface of cancer cells
- a type of cancer antibody drug for the treatment of non-Hodgkin's lymphoma
- imiquimod when imiquimod was administered to cancer, the antitumor effect of imiquimod was reduced, but this report shows that imiquimod may be used in combination with imiquimod depending on the cancer antibody drug that targets cancer cells. This suggested to the person skilled in the art that the anti-tumor effect of the drug might be attenuated.
- a combination of an antibody against CAPRIN-1 protein having immunological reactivity with cancer cells or a fragment thereof and imiquimod is an antibody against CAPRIN-1 protein or a fragment thereof alone.
- it exhibits an extremely strong antitumor effect compared to imiquimod alone, and further enhances the antitumor effect when an antibody against CAPRIN-1 protein or a fragment thereof and imiquimod is used in combination with existing cancer antibody drugs and imiquimod.
- the present invention has the following features (1) to (14).
- a pharmaceutical for the treatment and / or prevention of cancer characterized by comprising an antibody or fragment thereof having immunological reactivity with the CAPRIN-1 protein and imiquimod together or separately in combination.
- CAPRIN in which the antibody or fragment thereof has an amino acid sequence represented by any of SEQ ID NOs: 2 to 30 or an amino acid sequence having 80% or more sequence identity with the amino acid sequence -The pharmaceutical product according to (1), which has immunological reactivity with a protein.
- the antibody or fragment thereof is an amino acid sequence represented by any of SEQ ID NOs: 31 to 35, 296 to 299, 308, 309, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.
- a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 48, 49 and 50 (CDR1, CDR2 and CDR3, respectively), and immunological reactivity with the CAPRIN-1 protein.
- Antibody or fragment (D) having heavy reactivity having heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 60, 61 and 62 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 64, 65 and 66
- a light chain variable region comprising (CDR1, CDR2 and CDR3, respectively) and having an immunological reactivity
- An antibody having a variable region and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 275, 276 and 277 (CDR1, CDR2 and CDR3, respectively) and having immunological reactivity with a CAPRIN-1 protein or Fragment (K) heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 290, 291 and 292 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 293, 294 and 295 (CDR1, CDR2 and CDR3, respectively) And a light chain variable region containing CAPRIN-1 A heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of an antibody or fragment thereof (L) SEQ ID NOs: 301, 302 and 303 having immunological reactivity with a protein and SEQ ID NOs: 305, 306 and An antibody or fragment thereof (M) SEQ ID NO: 134, 135 compris
- the antibody or fragment thereof is any of the following (a) to (ak): (A) an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 43 (b) the heavy chain variable region of SEQ ID NO: 47 An antibody or fragment thereof comprising an amino acid sequence and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 51 (c) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprising: An antibody comprising the amino acid sequence of SEQ ID NO: 59 or a fragment thereof (d) an antibody wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 67;
- the fragment (e) is an antibody or heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68 and the light chain variable region
- the cancer is basal cell cancer, budget disease, skin cancer, breast cancer, kidney cancer, pancreatic cancer, colon cancer, lung cancer, brain tumor, stomach cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, esophageal cancer, leukemia. Lymphoma, liver cancer, gallbladder cancer, sarcoma, mastocytoma, adrenocortical cancer, Ewing tumor, Hodgkin lymphoma, mesothelioma, multiple myeloma, testicular cancer, thyroid cancer or head and neck cancer, (1) to (9)
- the pharmaceutical product according to any one of
- a drug efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer comprising imiquimod as an active ingredient and an antibody or fragment thereof having immunological reactivity with CAPRIN-1 protein as an active ingredient.
- a drug efficacy enhancer for a pharmaceutical composition for the treatment and / or prevention of cancer comprising imiquimod as an active ingredient, comprising an antibody or fragment thereof immunologically reactive with the CAPRIN-1 protein as an active ingredient.
- the combined use of the antibody against CAPRI-1 protein or a fragment thereof and imiquimod according to the present invention not only exhibits a strong antitumor effect compared with the antibody against CAPRIN-1 protein alone and imiquimod alone, but also an antibody drug against existing cancer It exhibits an antitumor effect superior to the combined use of and imiquimod. Furthermore, the combined use of the antibody against CAPRI-1 protein and imiquimod according to the present invention shows a stronger antitumor effect than the combined use of an existing chemotherapeutic agent and an antibody against CAPRIN-1 protein. Therefore, the combined use of an antibody against CAPRIN-1 protein and imiquimod is effective in treating or preventing cancer.
- anti-CAPRIN-1 antibody an antibody against a CAPRIN-1 protein or a fragment thereof (hereinafter referred to as “anti-CAPRIN-1 antibody”) and imiquimod used in the present invention is a tumor against cancer-bearing animals in vivo as described later It can be evaluated by examining growth inhibition.
- “combination” or “combination” refers to administration of an anti-CAPRIN-1 antibody and imiquimod to the same living body simultaneously or as separate active ingredients at a predetermined interval.
- the interval may be simultaneous administration, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, 5 days, 7 days, 2 weeks, 3 weeks, It may be 4 weeks later.
- the anti-CAPRIN-1 antibody or imiquimod shows its activity in vivo, either one may be administered. Further, the anti-CAPRIN-1 antibody may be administered first, or imiquimod may be administered first.
- the anti-CAPRIN-1 antibody according to the present invention may be a monoclonal antibody or a polyclonal antibody, and is preferably a monoclonal antibody, and may be any kind of antibody as long as the antibody of the present invention can exhibit antitumor activity.
- the antibody may be a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, or a non-human animal antibody.
- the subject to be treated and / or prevented from cancer in the present invention is a mammal such as a human, a pet animal, livestock, a sporting animal, etc., and a preferred subject is a human.
- the anti-CAPRIN-1 antibody, imiquimod, a pharmaceutical containing them as an active ingredient, and a method for treating and / or preventing cancer according to the present invention will be described.
- CAPRIN-1 having an amino acid sequence represented by any of SEQ ID NOs: 2 to 30, which is a specific example of an antigen immunologically reactive with an anti-CAPRIN-1 antibody used in the present invention
- the amino acid sequences shown in SEQ ID NOs: 6, 8, 10, 12, and 14 are the amino acid sequences of canine CAPRIN-1 protein
- the amino acid sequences shown in SEQ ID NOs: 2 and 4 are human CAPRIN-1 protein
- the amino acid sequence shown in SEQ ID NO: 16 is the amino acid sequence of bovine CAPRIN-1 protein
- the amino acid sequence shown in SEQ ID NO: 18 is the amino acid sequence of equine CAPRIN-1 protein
- the amino acid sequence shown by 20-28 is the amino acid of mouse CAPRIN-1 protein A column
- the amino acid sequence shown in SEQ ID NO: 30 is the amino acid sequence of caprin-1 protein of chicken.
- the anti-CAPRIN-1 antibody used in the present invention is 80% or more, preferably 90% or more, more preferably 95% of the amino acid sequence represented by any of the even SEQ ID NOs among SEQ ID NOs: 2 to 30. It may be immunologically reactive with a variant of CAPRIN-1 protein having a sequence identity of at least%, more preferably at least 99%.
- “% sequence identity” refers to the amino acid (or base) of two sequences when they are aligned (aligned) for maximum similarity with or without gaps. The percentage (%) of the same amino acid (or base) relative to the total number.
- the anti-CAPRIN-1 antibody means an antibody or fragment thereof having immunological reactivity with the full-length CAPRIN-1 protein or a fragment thereof.
- immunological reactivity means the property that an antibody binds to a CAPRIN-1 protein or a partial polypeptide thereof in a living body.
- the anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.
- a polyclonal antibody (anti-CAPRIN-1 polyclonal antibody) having immunological reactivity with the full length of a CAPRIN-1 protein or a fragment thereof is, for example, a natural CAPRIN-1 protein, a fusion protein with GST, or a partial peptide thereof.
- Sera are obtained by immunizing mice, human antibody-producing mice, rats, rabbits, chickens and the like.
- the obtained serum can be obtained by ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column to which CAPRIN-1 protein or partial peptide is bound, or the like.
- CAPRIN-1 protein For the full length of CAPRIN-1 protein or a fragment thereof used for the above immunization, the base sequence and amino acid sequence of CAPRIN-1 and its homologue are accessed by GenBank (NCBI, USA), for example, algorithms such as BLAST and FASTA (Karlin and Altschul) , Proc. Natl. Acad. Sci. USA, 90: 5873-5877, 1993; Altschul et al., Nucleic Acids Res. 25: 3389-3402, 1997).
- GenBank NCBI, USA
- FASTA Altschul et al., Nucleic Acids Res. 25: 3389-3402, 1997.
- the method for producing the CAPRIN-1 protein can be obtained by referring to WO2014 / 012479, and cells that express the CAPRIN-1 protein can also be used.
- a monoclonal antibody having immunological reactivity with the full length of a CAPRIN-1 protein or a fragment thereof is, for example, a breast cancer cell SK-BR-3 or CAPRIN-1 protein expressing CAPRIN-1.
- Immunize the mouse by administering the full length or a fragment thereof, fuse spleen cells isolated from the mouse and myeloma cells, and select clones that produce anti-CAPRIN-1 monoclonal antibodies from the resulting fused cells (hybridomas) Can be obtained.
- the antibody produced from the selected hybridoma can be obtained by the same method as the polyclonal antibody purification method described above.
- the antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.
- Human antibody sensitizes human lymphocytes infected with EB virus with protein, protein-expressing cells or lysates thereof, and fuses the sensitized lymphocytes with myeloma cells such as human-derived U266 cells.
- Antibodies having immunological reactivity with the full-length CAPRIN-1 protein or a fragment thereof can be obtained from the cells.
- a humanized antibody is a modified antibody also referred to as a reshaped human antibody.
- Humanized antibodies are constructed by transplanting the complementarity determining regions of antibodies derived from immunized animals into the complementarity determining regions of human antibodies.
- a gene recombination technique as a general technique is a well-known technique. Specifically, for example, several DNA sequences designed to link the complementarity determining regions of mouse antibodies and rabbit antibodies with the framework regions of human antibodies so as to have a portion overlapping the terminal portion. The oligonucleotide is synthesized by the PCR method.
- the obtained DNA is obtained by ligating with the DNA encoding the constant region of a human antibody, incorporating it into an expression vector, introducing it into a host and producing it (European Patent Application Publication No. EP239400, International Publication Number). WO 96/02576).
- As the framework region of a human antibody to be ligated via the complementarity determining region a region in which the complementarity determining region forms a favorable antigen binding site is selected. If necessary, the amino acid of the framework region in the variable region of the antibody may be substituted so that the complementarity determining region of the reshaped human antibody forms an appropriate antigen binding site (Sato K. et al., Cancer Research). 1993, 53: 851-856). Moreover, you may substitute by the framework area
- Antibody is usually a hetero-rich glycoprotein containing at least two heavy chains and two light chains.
- An antibody is composed of two identical light chains and two identical heavy chains.
- the heavy chain has a heavy chain variable region at one end followed by a number of constant regions.
- the light chain has a light chain variable region at one end followed by a number of constant regions.
- a variable region refers to a specific variable region called a complementarity determining region (CDR) that confers binding specificity to the antibody.
- CDR complementarity determining region
- the portion stored relatively in the variable area is called a framework area (FR).
- the complete heavy and light chain variable regions each contain four FRs linked by three CDRs (CDR1-CDR3).
- the human heavy chain and light chain constant region and variable region sequences are available, for example, from NCBI (USA: GenBank, UniGene, etc.).
- the heavy chain constant region of human IgG1 has the registration number J00228,
- the heavy chain constant region of human IgG2 refer to the registration number J00230, the registration number V00557, X64135, X64133, etc. for the human light chain ⁇ constant region, and the registration number X64132, X64134, etc. for the human light chain ⁇ constant region. be able to.
- a chimeric antibody is an antibody produced by combining sequences derived from different animals, for example, from a heavy chain variable region and a light chain variable region of a mouse antibody, and from a constant region of a heavy chain variable region and a light chain variable region of a human antibody. Antibody or the like.
- a chimeric antibody can be prepared using a known method. For example, a DNA encoding an antibody V region and a DNA encoding a C region of a human antibody are linked, incorporated into an expression vector, and introduced into a host. It is obtained by producing.
- Non-human animal antibodies are obtained by immunizing animals with a sensitizing antigen according to a known method.
- a sensitizing antigen is obtained by intraperitoneal, intradermal or subcutaneous injection of an animal such as a mouse.
- the sensitizing antigen is injected, it is mixed with an appropriate amount of various adjuvants such as CFA (Freund's complete adjuvant) and administered to the animal a plurality of times.
- serum After immunizing the animal and confirming that the anti-CAPRIN-1 antibody is contained in the serum, serum is obtained, and as described above, ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, CAPRIN-1 protein Or an affinity column to which a partial peptide is bound.
- a monoclonal antibody from a non-human animal it can be obtained by collecting immune cells from the immunized animal and subjecting them to cell fusion with myeloma cells. Cell fusion between the immune cells and myeloma cells can be performed according to a known method (see Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).
- the antibody used in the present invention can also be obtained as a gene recombinant antibody produced by cloning a gene from a hybridoma, incorporating it into an appropriate vector, introducing it into a host, and using gene recombination technology.
- Yes Refer to Carl, AK Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom, MIMILLANPUBLISHER19).
- the anti-CAPRIN-1 antibody used in the present invention may be obtained by substituting amino acids in the variable region (for example, FR) or constant region with other amino acids.
- An amino acid substitution is a substitution of one or more, for example, less than 15, less than 10, less than 8, less than 6, less than 5, less than 4, less than 4, less than 3, or less than 2, preferably 1 to 9 amino acids.
- the antibody should have an ability to bind specifically to the antigen and binding affinity to the antigen equivalent to or higher than those of an unsubstituted antibody, and should not cause rejection when applied to humans.
- the amino acid substitution is preferably a conservative amino acid substitution, which is a substitution between amino acids having similar properties such as charge, side chain, polarity, and aromaticity.
- Amino acids with similar properties include, for example, basic amino acids (arginine, lysine, histidine), acidic amino acids (aspartic acid, glutamic acid), uncharged polar amino acids (glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine), nonpolar It can be classified into sex amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched chain amino acids (threonine, valine, isoleucine), aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine).
- basic amino acids arginine, lysine, histidine
- acidic amino acids aspartic acid, glutamic acid
- uncharged polar amino acids glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine
- the anti-CAPRIN-1 antibody used in the present invention can be expected to have a stronger antitumor effect when the binding affinity with the CAPRIN-1 protein on the surface of cancer cells is higher.
- the binding constant (affinity constant) Ka (kon / koff) is preferably at least 10 7 M ⁇ 1 , at least 10 8 M ⁇ 1 , at least 5 ⁇ 10 8 M ⁇ 1 , at least 10 9 M ⁇ 1 , at least 5 ⁇ . 10 9 M ⁇ 1 , at least 10 10 M ⁇ 1 , at least 5 ⁇ 10 10 M ⁇ 1 , at least 10 11 M ⁇ 1 , at least 5 ⁇ 10 11 M ⁇ 1 , at least 10 12 M ⁇ 1 , or at least 10 13 M ⁇ 1 is desirable.
- the anti-CAPRIN-1 antibody used in the present invention may be chemically modified.
- modified antibodies include polyethylene glycol (PEG) and antitumor compounds (for example, the anti-antibody exemplified below).
- PEG polyethylene glycol
- antitumor compounds for example, the anti-antibody exemplified below
- antibodies bound to various molecules such as tumor agents.
- the substance to be bound is not limited. In order to obtain such a modified antibody, it can be obtained by chemically modifying the obtained antibody. These methods are already established in this field.
- the anti-CAPRIN-1 antibody used in the present invention substitutes one, two, or several amino acids in the heavy chain constant region of the antibody, or binds to the heavy chain constant region.
- the binding force of the anti-CAPRIN-1 antibody to effector cells can be improved.
- the above may be an amino acid substitution alone or a composition with an antibody to which fucose is bound.
- Antibodies in which one, two or several amino acids in the heavy chain constant region are substituted are prepared by referring to, for example, WO2004 / 063351, WO2011 / 120135, US Pat. No. 8,388,955, WO2011 / 005481, US Pat. No. 6,737,056, WO2005 / 063351. can do.
- An anti-CAPRIN-1 polyclonal antibody, an anti-CAPRIN-1 monoclonal antibody, an antibody production method, a purification method, and a CAPRIN-1 protein or partial polypeptide production method used for immunization are described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096553, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018884, WO2013 / 018882, WO2013 / 018881, WO2013 / 018889, WO2013 / 018883, WO2013 / 018883 WO2013 / 125654, WO2013 / 125630, WO201 / 125640, it is possible to WO2013 / 147169, obtained by reference to WO2013 / 147176 and WO2015 / 020212.
- anti-CAPRIN-1 antibody in the present invention examples include the aforementioned WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018882, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and anti-CAPR -1 antibody But, as the preferred anti-caprin-1 antibody include the following.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 31 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- An antibody or fragment thereof, or a complementarity determining region of SEQ ID NOs: 140, 141, and 142 (CDR1, CDR2, and CDR3, respectively).
- a heavy chain variable region comprising: and a light chain variable region comprising the complementarity determining regions of SEQ ID NOS: 143, 144 and 145 (CDR1, CDR2 and CDR3, respectively), and immunoreactive with the CAPRIN-1 protein Antibody or fragment thereof, or SEQ ID NOs: 164, 165 and 1
- a heavy chain variable region comprising 6 complementarity determining regions (CDR1, CDR2 and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOS: 167, 168 and 169 (CDR1, CDR2 and CDR3, respectively)
- an antibody or fragment thereof having immunological reactivity with the CAPRIN-1 protein.
- the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 43, or a fragment thereof, or the heavy chain variable region comprises SEQ ID NO: 70.
- An antibody or fragment thereof, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 71, or the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78, and the light chain variable region An antibody or fragment thereof comprising the amino acid sequence of SEQ ID NO: 79.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 33 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and still more preferably 95% or more) of the amino acid sequence.
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 60, 61 and 62 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 64, 65 and 66 (CDR1, CDR2 and CDR3, respectively)
- an antibody or fragment thereof having immunological reactivity with the CAPRIN-1 protein More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 67.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 32 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and further preferably 95% or more) of the amino acid sequence.
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 52, 53 and 54 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 56, 57 and 58 (CDR1, CDR2 and CDR3, respectively)
- an antibody or fragment thereof having immunological reactivity with the CAPRIN-1 protein More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 59.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 34 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and still more preferably 95% or more) of the amino acid sequence.
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 170, 171 and 172 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 173, 174 and 175 (CDR1, CDR2 and CDR3, respectively) Or a fragment thereof, or the complementarity determining regions of SEQ ID NOS: 176, 177 and 178 (CDR1, CDR2 and CDR3, respectively).
- a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 179, 180 and 181 (CDR1, CDR2 and CDR3, respectively), and immunologically reactive with the CAPRIN-1 protein Or a fragment thereof.
- the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80
- the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81, or a fragment thereof, or the heavy chain variable region has SEQ ID NO: 82.
- An antibody or fragment thereof, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 35 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOS: 182, 183 and 184 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 185, 186 and 187 (CDR1, CDR2 and CDR3, respectively) Or a fragment thereof, or the complementarity-determining regions of SEQ ID NOs: 188, 189 and 190 (CDR1, CDR2 and CDR3, respectively).
- a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 191, 192 and 193 (CDR1, CDR2 and CDR3, respectively), and immunoreactive with the CAPRIN-1 protein Or a fragment thereof.
- the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85, or a fragment thereof, or the heavy chain variable region has SEQ ID NO: 86.
- a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 44, 45 and 46 (CDR1, CDR2 and CDR3, respectively) and a light chain comprising the complementarity determining regions of SEQ ID NOs: 48, 49 and 50 (CDR1, CDR2 and CDR3, respectively).
- An antibody or fragment thereof comprising a chain variable region and having immunological reactivity with a CAPRIN-1 protein.
- an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47
- the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51.
- CAPRIN- having the 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, and still more preferably 95% or more) of the amino acid sequence.
- the 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)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein. More preferably, the 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 the amino acid sequence represented by SEQ ID NO: 297 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- an antibody or fragment thereof having immunological reactivity with a partial polypeptide of one protein
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 272, 273 and 274 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 275, 276 and 277 (CDR1, CDR2 and CDR3, respectively)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein.
- the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 298 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and still more preferably 95% or more) of the amino acid sequence.
- the heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 290, 291 and 292 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOs: 293, 294 and 295 (CDR1, CDR2 and CDR3, respectively)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 299 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- an antibody or fragment thereof having immunological reactivity with a partial polypeptide of one protein Preferably, the heavy chain variable region including the complementarity determining regions of SEQ ID NOS: 301, 302 and 303 (CDR1, CDR2 and CDR3, respectively) and the complementarity determining regions of SEQ ID NOS: 305, 306 and 307 (CDR1, CDR2 and CDR3, respectively)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.
- CAPRIN- having the 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, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- the 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)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69.
- CAPRIN- having the amino acid sequence represented by SEQ ID NO: 309 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, more preferably 95% or more) of the amino acid sequence with the amino acid sequence
- the 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)
- An antibody or fragment thereof comprising a light chain variable region and having immunological reactivity with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69.
- anti-CAPRIN-1 antibodies are also preferably used.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 71.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 75.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 91.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 95.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 99.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133.
- an antibody or fragment thereof wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.
- the strong anti-antigenic activity in cancer-bearing organisms is obtained by combining the above-mentioned polyclonal or monoclonal antibody with imiquimod for the full length of CAPRIN-1 protein, a partial polypeptide expressed on the cell membrane surface of cancer cells. Tumor effect was confirmed.
- the imiquimod according to the present invention is a compound having a molecular weight of about 240.3 represented by CAS number 99011-02-6, and is an agonist that binds to Toll-like receptor (TLR) 7 or 8.
- TLR Toll-like receptor
- the IUPAC name of imiquimod is 4-amino-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline.
- imiquimod may be obtained by chemically synthesizing by a method known to those skilled in the art, as pharmaceuticals containing imiquimod as an active ingredient, “Beserna cream 5%” is used in Japan, and “Aldara (registered trademark) Cream, 5%” is used in Europe and America. Are marketed, and these drugs can be used as appropriate when imiquimod is used in the present invention.
- the active ingredient of the pharmaceutical agent of the present invention may contain an antitumor agent known in the literature in addition to the anti-CAPRIN-1 antibody and imiquimod as long as the effect of the pharmaceutical agent of the present invention is not inhibited.
- the known antitumor agent is not particularly limited, and specific examples include paclitaxel, doxorubicin, daunorubicin, cyclophosphamide, methotrexate, 5-fluorouracil, thiotepa, busulfan, improsulfan, piperosulfan, benzodopa (benzodopa), Carbocon, Metredopa, Uredopa, Altreamine, Triethylenemelamine, Triethylenephosphoramide, Triethylenethiophosphoramide, Trimethylolamine, Lomethyramine , Bryostatin, calistatin ( allystatin), cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleuterbin, panclastatin, sarcodictin, spongestatin, chlorambucil, chloronaphazine, cholophosphamide, estram Ifosfamide, mechloretamine, mechloretamine oxide hydrochloride,
- the combination of the anti-CAPRIN-1 antibody of the present invention and imiquimod has cytotoxic activity in vivo. Therefore, the antitumor effect of the present invention can be known by examining the cytotoxic activity against cancer.
- the cytotoxic activity can be evaluated by administering anti-CAPRIN-1 and imiquimod to a living body having cancer, measuring the size of the tumor after administration, and examining the size of the cancer over time.
- the antitumor effect of the present invention can also be evaluated by examining the survival rate. It can also be evaluated by examining the production ability of cytokines or chemokines.
- the antitumor effect of the combination of the anti-CAPRIN-1 antibody and imiquimod according to the present invention can be determined by examining cancer prevention, metastasis prevention or recurrence prevention.
- the anti-CAPRIN-1 antibody used in the present invention can be expected to have a stronger antitumor effect when the binding affinity with the CAPRIN-1 protein on the surface of cancer cells is higher.
- the binding constant (affinity constant) Ka (kon / koff) is preferably at least 10 7 M ⁇ 1 , at least 10 8 M ⁇ 1 , at least 5 ⁇ 10 8 M ⁇ 1 , at least 10 9 M ⁇ 1 , at least 5 ⁇ . 10 9 M ⁇ 1 , at least 10 10 M ⁇ 1 , at least 5 ⁇ 10 10 M ⁇ 1 , at least 10 11 M ⁇ 1 , at least 5 ⁇ 10 11 M ⁇ 1 , at least 10 12 M ⁇ 1 , or at least 10 13 M ⁇ 1 is desirable.
- the ability of the anti-CAPRIN-1 antibody used in the present invention to bind to CAPRIN-1 can be specified by using a binding assay using, for example, ELISA, Western blot, immunofluorescence, flow cytometry, etc. it can.
- Administration of the anti-CAPRIN-1 antibody and imiquimod according to the present invention into a living body of cancer has an antitumor effect enhanced as compared with the anti-CAPRIN-1 antibody alone as described above, but the enhancement rate is preferably 30. % Or more, more preferably 40% or more, still more preferably 50% or more, even more preferably 55% or more, even more preferably 60% or more, even more preferably 65% or more, and most preferably 70% or more.
- the anti-tumor effect enhancement rate of anti-CAPRIN-1 antibody and imiquimod combined administration according to the present invention with respect to anti-CAPRIN-1 antibody alone was administered to each cancer-bearing mouse under the same conditions. It can be calculated by comparing the tumor volume after the seventh day.
- the medicament of the present invention is intended for the treatment and / or prevention of cancer.
- the cancer targeted by the pharmaceutical of the present invention is not particularly limited as long as it is a cancer (cell) that expresses the CAPRIN-1 protein.
- treatment refers to cancer treatment based on the antitumor effects described above. Further, “prevention” as used herein means not only prevention of cancer development but also prevention of cancer metastasis or recurrence.
- tumor and cancer refer to malignant neoplasms and are used interchangeably.
- the cancer targeted in the present invention may be any cancer as long as it expresses the CAPRIN-1 protein on the cell membrane surface.
- palpable cancers cancers present under the skin, cancers present within the skin, superficial cancers, cancers present in the dermis or cancers present in non-parenchymal organs. These cancers may be primary cancer, metastatic cancer, metastasized cancer, or recurrent cancer.
- the cancer is, for example, Bowen's disease, melanoma, squamous cell carcinoma, extramammary Paget's disease, mycosis fungoides, Sezary syndrome, cutaneous T / NK cell lymphoma, T cell having lesion only in skin Leukemia / lymphoma, cutaneous B-cell lymphoma (indolent group), cutaneous T-cell lymphoid breast cancer, complex breast cancer, malignant mixed breast tumor, intraductal papillary adenocarcinoma, lung adenocarcinoma, squamous cell carcinoma, small cell carcinoma, Large cell carcinoma, neuroglial tissue glioma, glioblastoma, neuroblastoma, ventricular ependymoma, neuronal tumor, fetal neuroectodermal tumor, schwannoma, neurofibroma, Meningiomas, chronic lymphocytic leukemia, lymphoma, gastrointestinal lymphoma,
- cancers present under the skin cancers present within the skin, superficial cancers, cancers present in the dermis, or cancers present in non-parenchymal organs.
- cancer that can be palpated, cancer that exists under the skin, cancer that exists in the skin, superficial cancer, cancer that exists in the dermis, or non-parenchymal organs by metastasis or recurrence from the above cancer Cancer is included.
- preferred subjects (patients) to be targeted are mammals, for example, mammals including primates, pet animals, domestic animals, sport animals and the like, and humans, dogs and cats are particularly preferable.
- the pharmaceutical product of the present invention can be formulated by methods known to those skilled in the art.
- it can be used parenterally in the form of a sterile solution with water or other pharmaceutically acceptable liquid, or an injection of suspension.
- a pharmacologically acceptable carrier or medium specifically, sterilized water, physiological saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, fragrance, excipient, binder, etc.
- a pharmacologically acceptable carrier or medium specifically, sterilized water, physiological saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, fragrance, excipient, binder, etc.
- the amount of active ingredient in these preparations is such that an appropriate dose within the indicated range can be obtained.
- a sterile composition for injection can be formulated in accordance with normal pharmaceutical practice using a vehicle such as distilled water for injection.
- Aqueous solutions for injection include, for example, isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol and sodium chloride.
- Suitable solubilizers such as Alcohols, specifically ethanol, polyalcohols such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM), HCO-60 may be used in combination.
- the oily liquid include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizing agent.
- buffer for example, phosphate buffer, sodium acetate buffer, a soothing agent, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, antioxidant.
- the prepared injection solution is usually filled into a suitable ampoule.
- the oily liquid include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizing agent.
- blend with buffer for example, phosphate buffer, sodium acetate buffer, a soothing agent, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, antioxidant.
- the prepared injection solution is usually filled in a suitable ampoule.
- Administration is oral or parenteral, preferably parenteral administration.
- Specific examples include injection, nasal administration, pulmonary administration, and transdermal administration.
- the injection form can be administered systemically or locally by, for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intratumoral injection, and the like.
- a so-called coating agent or external medicine is used as an example of the transdermal administration type.
- the external preparation include solid preparations, liquid preparations, spray preparations, ointments, cream preparations, and gel preparations.
- the administration method can be appropriately selected depending on the age, weight, sex, symptoms, etc. of the patient.
- the dosage of the pharmaceutical composition containing the antibody or the polynucleotide encoding the antibody can be selected, for example, in the range of 0.0001 mg to 1000 mg per kg body weight.
- the dose can be selected in the range of 0.001 to 100,000 mg / body per patient, or 1 mg to 30 mg per kg of the patient's body weight, but is not necessarily limited to these values.
- the dose and administration method vary depending on the weight, age, sex, symptoms, etc. of the patient, but can be appropriately selected by those skilled in the art.
- imiquimod has been confirmed to be effective as an anticancer agent for transdermal administration, and based on the results, imiquimod is marketed as an anticancer agent under the trade name of Aldara (registered trademark) Cream, 5%.
- the dosage form for administering to the patient is preferably a transdermal administration type, preferably a cream type preparation.
- imiquimod when imiquimod is administered to a subject, it may be administered according to the dosage and administration described in the package insert of “Aldara (registered trademark) Cream, 5%”.
- the treatment and / or prevention of cancer by the medicament for the treatment and / or prevention of cancer of the present invention includes various forms other than the administration as the aforementioned medicament.
- each active ingredient of the medicament of the present invention can be administered individually at the same time or in order.
- the second active ingredient can be administered within a time interval of up to about 3 weeks, that is, immediately after the administration of the first active ingredient to about 3 weeks.
- the surgical procedure may be performed following the surgical procedure, or the surgical procedure may be performed between the administration of the first drug and the second drug.
- the therapeutic and / or prophylactic agent for cancer of the present invention may be administered according to a plurality of administration cycles.
- a pharmaceutical composition containing both active ingredients is administered in a cycle of about 2 days to about 3 weeks. Thereafter, it can be repeated as necessary according to the judgment of the doctor in charge of the treatment cycle.
- the duration of administration of each individual drug is adjusted to cover the same period. The interval between cycles can vary from 0 to 2 months.
- the dosage of each active ingredient of the therapeutic and / or prophylactic agent for cancer of the present invention can be set in the same manner as the dosage of each active ingredient in the pharmaceutical composition.
- the medicament for the treatment and / or prevention of cancer of the present invention may be in the form of a pharmaceutical kit.
- a pharmaceutical kit is a package for using an active ingredient in the form of a separate pharmaceutical composition in a method for treating and / or preventing cancer, and the package contains instructions for administering each active ingredient. included.
- Each active ingredient of the pharmaceutical composition for treating and / or preventing cancer contained in the pharmaceutical kit is a pharmaceutical composition formulated as described above so that the active ingredients can be administered together or separately. It can be in form.
- the pharmaceutical kit includes an active ingredient in an amount sufficient for one or more doses so that each active ingredient can be administered according to the above administration method.
- the present invention further provides a method for the treatment and / or prevention of cancer, comprising administering the above-mentioned pharmaceutical of the present invention to a subject suspected of having cancer. provide.
- the antibody or fragment thereof and the antitumor agent contained in the pharmaceutical product are administered to the subject simultaneously or separately.
- Example 1 Production of Anti-CAPRIN-1 Antibody
- the anti-CAPRIN-1 antibody having immunological reactivity with the CAPRIN-1 protein used in the present invention was prepared as follows.
- polyclonal antibody 1 mg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal volume of incomplete Freund's adjuvant (IFA) solution and administered subcutaneously to rabbits 4 times every 2 weeks. It was. Thereafter, blood was collected to obtain an antiserum containing a polyclonal antibody. Further, this antiserum was purified using a protein G carrier (manufactured by GE Healthcare Bioscience) and replaced with PBS ( ⁇ ) to obtain a polyclonal antibody against CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody # 1). Obtained.
- IFA incomplete Freund's adjuvant
- the removal operation was repeated 3 times to obtain spleen cells.
- the obtained spleen cells and mouse myeloma cells SP2 / 0 (purchased from ATCC) were mixed at a ratio of 10: 1, and 200 ⁇ l of RPMI 1640 medium containing 10% FBS heated to 37 ° C. and PEG 1500 (Boehringer) PEG solution prepared by mixing 800 ⁇ l was added and allowed to stand for 5 minutes for cell fusion. After centrifuging at 1700 rpm for 5 minutes and removing the supernatant, the cells were suspended in 150 ml of RPMI 1640 medium (HAT selective medium) containing 15% FBS to which 2% equivalent of Gibco's HAT solution was added.
- RPMI 1640 medium HAT selective medium
- TMB substrate solution manufactured by Thermo
- 100 ⁇ l of TMB substrate solution manufactured by Thermo
- 100 ⁇ l of 1N sulfuric acid was added per well to stop the reaction, and absorbance values at 450 nm and 595 nm were measured using an absorptiometer.
- absorbance values at 450 nm and 595 nm were measured using an absorptiometer.
- the selected hybridomas were added to the plate at a ratio of 0.5 per well of a 96-well plate and cultured. One week later, hybridomas forming a single colony in the well were observed.
- the cells in these wells were further cultured, and hybridomas were selected using the binding affinity of the antibody produced by the cloned hybridomas to the CAPRIN-1 protein as an index.
- 100 ⁇ l of CAPRIN-1 protein solution (1 ⁇ g / ml) was added per well of a 96-well plate and allowed to stand at 4 ° C. for 18 hours. After washing each well 3 times with PBS-T, 400 ⁇ l of 0.5% BSA solution was added per well and allowed to stand at room temperature for 3 hours. After removing the solution and washing the wells three times with 400 ⁇ l of PBS-T per well, 100 ⁇ l of each culture supernatant of the hybridoma obtained above was added per well and allowed to stand at room temperature for 2 hours.
- a monoclonal antibody reactive to the CAPRIN-1 protein it is a monoclonal antibody against CAPRIN-1 described in WO2013 / 125630, and the amino acid sequence of the heavy chain variable region represented by SEQ ID NO: 114
- An antibody comprising the amino acid sequence of the light chain variable region represented by SEQ ID NO: 115 was selected.
- the CDRs 1 to 3 of the heavy chain variable region of the selected antibody are identified, the base sequence is designed so that the framework region can express the heavy chain variable region containing the human antibody sequence, and the heavy chain constant of human IgG1 is determined. It was inserted into a mammalian expression vector into which the normal region had been inserted.
- the CDRs 1 to 3 of the light chain variable region are identified, and the nucleotide sequence is designed so that the framework region can express the light chain variable region containing the sequence of the human antibody. It was inserted into a mammalian expression vector into which the region had been inserted.
- the above two recombinant expression vectors were introduced into mammalian cells according to a conventional method to obtain a culture supernatant containing humanized monoclonal antibody # 1 (humanized antibody # 1) against CAPRIN-1.
- the obtained culture supernatant containing the humanized anti-CAPRIN-1 monoclonal antibody # 1 was purified using Hitrap Protein A Sepharose FF (manufactured by GE Healthcare) according to a conventional method, and replaced with PBS ( ⁇ ) to 0.22 ⁇ m. The one filtered with a filter (manufactured by Millipore) was prepared.
- the specific reactivity of the anti-CAPRIN-1 antibody to the CAPRIN-1 protein was confirmed by detecting the CAPRIN-1 protein on a plate using the ELISA method.
- Example 2 Antitumor effect by combined use of anti-CAPRIN-1 antibody and imiquimod
- anti-CAPRIN-1 antibody anti-CAPRIN-1 polyclonal antibody # 1 and humanized antibody # 1 prepared in Example 1 and imiquimod
- the antitumor effect in vivo of tumor-bearing mice by administration in combination with was evaluated.
- the NOD-SCID mouse transplanted subcutaneously with human-derived cancer cells expressing the CAPRIN-1 protein has the antitumor effect of the combined use of the anti-CAPRIN-1 antibody and imiquimod according to the present invention.
- 10 7 human breast cancer cells BT474 per mouse were mixed with Matrigel (SIGMA) and transplanted subcutaneously to prepare tumor-bearing mice grown to a tumor of about 60 mm 3 .
- BT474 is a cancer cell in which the CAPRIN-1 protein is expressed on the cell membrane surface, and the anti-CAPRIN-1 antibody prepared in Example 1 has been confirmed to react with a part of CAPRIN-1 on the cell membrane surface. .
- Example 1 Ten anti-CAPRIN-1 antibodies prepared in Example 1 were administered to the tail vein of the above cancer-bearing mice at a dose of 10 mg / kg once a week. To the same mouse, imiquimod started application at the same time as the first anti-CAPRIN-1 antibody administration. “Versena Cream 5%” (Mochida Pharmaceutical Co., Ltd., hereinafter referred to as “imiquimod cream”) containing imiquimod as an active ingredient is applied to the surface of the skin transplanted with cancer cells for five consecutive days, and then Administration was not performed for 2 days, and antibody administration and application of imiquimod cream were performed on the 8th day from the start of antibody administration.
- imiquimod cream “Versena Cream 5%” (Mochida Pharmaceutical Co., Ltd., hereinafter referred to as “imiquimod cream”) containing imiquimod as an active ingredient is applied to the surface of the skin transplanted with cancer cells for five consecutive days, and then Administration was not performed for 2 days, and antibody administration and application of imiqui
- the same anti-CAPRIN-1 antibody as described above was administered to cancer-bearing mice once a week in the same amount. Further, as a comparative control group, imiquimod cream was applied to another cancer-bearing mouse individual at the same administration interval on the surface of the skin transplanted with cancer cells. In addition, cancer-free mice in the untreated group were used as negative controls. After the start of administration, the size of the cancer of the tumor-bearing mouse was measured with a caliper over time, and the tumor volume was calculated according to a standard method: (length of the major axis of the cancer) ⁇ (length of the minor axis of the cancer) ) Calculated at 2 ⁇ 0.5.
- the anti-CAPRIN-1 polyclonal antibody # 1 prepared in Example 1 and the anti-CAPRIN-1 polyclonal antibody # 1 prepared in Example 1 were obtained on the 45th day after the start of administration of the anti-CAPRIN-1 polyclonal antibody # 1. It was less than 60% in the cancer-bearing mice administered with imiquimod cream. Among the tumor-bearing mice in the control group, 78% were in the group to which only anti-CAPRIN-1 polyclonal antibody # 1 was administered, and 69% were in the group to which only imiquimod cream was administered.
- the humanized antibody # 1 which is an anti-CAPRIN-1 monoclonal antibody
- the humanized antibody # 1 prepared in Example 1 and imiquimod cream
- the tumor-bearing mice to which was administered less than 33% In the tumor-bearing mice of the comparative control group, it was 65% in the group administered with humanized antibody # 1 alone. It was 69% in the group administered with imiquimod cream alone.
- Example 3 Comparison of Anti-Tumor Effect by Combined Use of Anti-CAPRIN-1 Antibody and Anticancer Agent
- the anti-CAPRIN-1 antibody prepared in Example 1 anti-CAPRIN-1 polyclonal antibody # 1 and humanized antibody # 1)
- imiquimod in combination with an antitumor effect in a cancer-bearing mouse in vivo and an antitumor effect in the case where an existing anticancer agent different from the above antibody and imiquimod was used in combination.
- the NOD-SCID mouse transplanted subcutaneously with human-derived cancer cells expressing the CAPRIN-1 protein has the antitumor effect of the combined use of the anti-CAPRIN-1 antibody and imiquimod according to the present invention.
- 10 7 human breast cancer cells BT474 per mouse were mixed with Matrigel (SIGMA) and transplanted subcutaneously to produce tumor-bearing mice grown to a tumor of about 90 mm 3 .
- BT474 is a cancer cell in which the CAPRIN-1 protein is expressed on the cell membrane surface, and the anti-CAPRIN-1 antibody prepared in Example 1 has been confirmed to react with a part of CAPRIN-1 on the cell membrane surface. .
- the combined treatment group of anti-CAPRIN-1 antibody and imiquimod was 10 mg / kg each of the anti-CAPRIN-1 antibody (humanized antibody # 1) prepared in Example 1 in the tail vein of the above cancer-bearing mice. Once a week. Further, to the same mouse, imiquimod was applied to the skin surface where cancer was present at the same time as the first anti-CAPRIN-1 antibody administration.
- “Versena Cream 5%” (Mochida Pharmaceutical Co., Ltd., hereinafter referred to as “imiquimod cream”) containing imiquimod active ingredient is applied to the surface of the skin transplanted with cancer cells for 5 consecutive days, and then 2 On the 8th day from the start of antibody administration, antibody administration and application of imiquimod cream were performed on the 8th day from the start of antibody administration.
- the anti-CAPRIN-1 antibody prepared in Example 1 was 10 mg / kg each in the tail vein of the prepared cancer-bearing mice. Once a week. Further, the same anti-CAPRIN-1 antibody was administered simultaneously to the same mice, and the anticancer drugs paclitaxel and docetaxel were intraperitoneally administered once a week at 7 mg / kg and 8 mg / kg, respectively.
- the same anti-CAPRIN-1 antibody as described above was administered to cancer-bearing mice once a week in the same amount.
- the size of the cancer of the tumor-bearing mouse was measured with a caliper over time, and the tumor volume was calculated according to a standard method: (length of the major axis of the cancer) ⁇ (length of the minor axis of the cancer) ) Calculated at 2 ⁇ 0.5.
- the anti-CAPRIN- prepared in Example 1 was obtained on the 53rd day after the start of the administration of the humanized antibody # 1, when the tumor volume of the mouse administered with the anti-CAPRIN-1 antibody alone was taken as 100%. It was less than 20% in the cancer-bearing mice administered with 1 antibody and imiquimod cream. On the other hand, when paclitaxel and docetaxel were used in combination with humanized antibody # 1, respectively, 47% or more.
- the anti-CAPRIN-1 polyclonal antibody # 1 was subjected to the same comparative evaluation as described above. As a result, on the 30th day after the start of the administration of the anti-CAPRIN-1 polyclonal antibody # 1, the anti-CAPRIN-1 polyclonal antibody When the tumor volume of mice administered only with # 1 was taken as 100%, the tumor-bearing mice administered with anti-CAPRIN-1 polyclonal antibody # 1 and imiquimod cream accounted for less than 46%. On the other hand, when paclitaxel and docetaxel were used in combination with anti-CAPRIN-1 polyclonal antibody # 1, the ratio was 65% or more.
- the antitumor effect when combined with an antibody against CAPRIN-1 and imiquimod is compared to the antitumor effect when treated with a combination of an antibody against CAPRIN-1 and imiquimod with an existing anticancer agent. It was shown to have a remarkably strong synergistic anti-tumor effect.
Abstract
Description
(A)配列番号36、37及び38の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号40、41及び42の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(B)配列番号44、45及び46の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号48、49及び50の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(C)配列番号52、53及び54の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号56、57及び58の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(D)配列番号60、61及び62の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号64、65及び66の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(E)配列番号170、171及び172の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号173、174及び175の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(F)配列番号176、177及び178の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号179、180及び181の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(G)配列番号182、183及び184の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号185、186及び187の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(H)配列番号188、189及び190の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号191、192及び193の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(I)配列番号146、147及び148の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号149、150及び151の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(J)配列番号272、273及び274の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号275、276及び277の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(K)配列番号290、291及び292の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号293、294及び295の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(L)配列番号301、302及び303の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号305、306及び307の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(M)配列番号134、135及び136の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号137、138及び139の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント。
(a)重鎖可変領域が配列番号39のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号43のアミノ酸配列を含んでなる抗体又はそのフラグメント
(b)重鎖可変領域が配列番号47のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号51のアミノ酸配列を含んでなる抗体又はそのフラグメント
(c)重鎖可変領域が配列番号55のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号59のアミノ酸配列を含んでなる抗体又はそのフラグメント
(d)重鎖可変領域が配列番号63のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号67のアミノ酸配列を含んでなる抗体又はそのフラグメント
(e)重鎖可変領域が配列番号68のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号69のアミノ酸配列を含んでなる抗体又はそのフラグメント
(f)重鎖可変領域が配列番号70のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号71のアミノ酸配列を含んでなる抗体又はそのフラグメント
(g)重鎖可変領域が配列番号72のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号73のアミノ酸配列を含んでなる抗体又はそのフラグメント
(h)重鎖可変領域が配列番号74のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号75のアミノ酸配列を含んでなる抗体又はそのフラグメント
(i)重鎖可変領域が配列番号76のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号77のアミノ酸配列を含んでなる抗体又はそのフラグメント
(j)重鎖可変領域が配列番号78のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号79のアミノ酸配列を含んでなる抗体又はそのフラグメント
(k)重鎖可変領域が配列番号80のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号81のアミノ酸配列を含んでなる抗体又はそのフラグメント
(l)重鎖可変領域が配列番号82のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号83のアミノ酸配列を含んでなる抗体又はそのフラグメント
(m)重鎖可変領域が配列番号84のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号85のアミノ酸配列を含んでなる抗体又はそのフラグメント
(n)重鎖可変領域が配列番号86のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号87のアミノ酸配列を含んでなる抗体又はそのフラグメント
(o)重鎖可変領域が配列番号88のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号89のアミノ酸配列を含んでなる抗体又はそのフラグメント
(p)重鎖可変領域が配列番号90のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号91のアミノ酸配列を含んでなる抗体又はそのフラグメント
(q)重鎖可変領域が配列番号92のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号93のアミノ酸配列を含んでなる抗体又はそのフラグメント
(r)重鎖可変領域が配列番号94のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号95のアミノ酸配列を含んでなる抗体又はそのフラグメント
(s)重鎖可変領域が配列番号96のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号97のアミノ酸配列を含んでなる抗体又はそのフラグメント
(t)重鎖可変領域が配列番号98のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号99のアミノ酸配列を含んでなる抗体又はそのフラグメント
(u)重鎖可変領域が配列番号100のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号101のアミノ酸配列を含んでなる抗体又はそのフラグメント
(v)重鎖可変領域が配列番号102のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号103のアミノ酸配列を含んでなる抗体又はそのフラグメント
(w)重鎖可変領域が配列番号104のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号105のアミノ酸配列を含んでなる抗体又はそのフラグメント
(x)重鎖可変領域が配列番号106のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号107のアミノ酸配列を含んでなる抗体又はそのフラグメント
(y)重鎖可変領域が配列番号108のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号109のアミノ酸配列を含んでなる抗体又はそのフラグメント
(z)重鎖可変領域が配列番号110のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号111のアミノ酸配列を含んでなる抗体又はそのフラグメント
(aa)重鎖可変領域が配列番号112のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号113のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ab)重鎖可変領域が配列番号114のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号115のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ac)重鎖可変領域が配列番号116のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号117のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ad)重鎖可変領域が配列番号118のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号119のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ae)重鎖可変領域が配列番号120のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号121のアミノ酸配列を含んでなる抗体又はそのフラグメント
(af)重鎖可変領域が配列番号122のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号123のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ag)重鎖可変領域が配列番号124のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号125のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ah)重鎖可変領域が配列番号126のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号127のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ai)重鎖可変領域が配列番号128のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号129のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ai)重鎖可変領域が配列番号130のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号131のアミノ酸配列を含んでなる抗体又はそのフラグメント
(aj)重鎖可変領域が配列番号132のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号133のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ak)重鎖可変領域が配列番号300のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号304のアミノ酸配列を含んでなる抗体又はそのフラグメント。
本発明で用いられる抗CAPRIN-1抗体と免疫学的反応性を有する抗原の具体例である、配列番号2~30のうち偶数の配列番号のいずれかで表されるアミノ酸配列を有するCAPRIN-1タンパク質のうち、配列番号6、8、10、12及び14で示されるアミノ酸配列はイヌのCAPRIN-1タンパク質のアミノ酸配列であり、配列番号2及び4で示されるアミノ酸配列はヒトのCAPRIN-1タンパク質のアミノ酸配列であり、配列番号16で示されるアミノ酸配列はウシのCAPRIN-1タンパク質のアミノ酸配列であり、配列番号18で示されるアミノ酸配列はウマのCAPRIN-1タンパク質のアミノ酸配列であり、配列番号20~28で示されるアミノ酸配列はマウスのCAPRIN-1タンパク質のアミノ酸配列であり、配列番号30で示されるアミノ酸配列はニワトリのCAPRIN-1タンパク質のアミノ酸配列である。
本発明に係るイミキモドは、CASナンバー99011-02-6で表される分子量約240.3の化合物であり、Toll様受容体(TLR)7あるいは8に結合するアゴニストである。イミキモドのIUPAC名は4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolineであり、別な記述として、R837、S-26308、1-(2-METHYLPROPYL)-1H-IMIDAZO[4,5-C]QUINOLIN-4-AMINE;4-amino- 1-isobutyl-1h-imidazo[4,5-c]quinoline、1-isoButyl-1H-Inudazole[4.5-c]quinoline-4-amine;1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amineで表される。
本発明の医薬品の有効成分としては、本発明の医薬品としての効果を阻害しない範囲において前記抗CAPRIN-1抗体及びイミキモドの他に、文献等で公知の抗腫瘍剤を含んでいてもよい。公知の抗腫瘍剤としては特に制限はないが、具体例としては、パクリタキセル、ドキソルビシン、ダウノルビシン、シクロフォスファミド、メトトレキサート、5-フルオロウラシル、チオテパ、ブスルファン、インプロスルファン、ピポスルファン、ベンゾドーパ(benzodopa)、カルボコン、メツレドーパ(meturedopa)、ウレドーパ(uredopa)、アルトレートアミン(altretamine)、トリエチレンメラミン、トリエチレンホスホラミド、トリエチレンチオホスホラミド(triethilenethiophosphoramide)、トリメチローロメラミン(trimethylolomelamine)、ブラタシン、ブラタシノン、カンプトセシン、ブリオスタチン、カリスタチン(callystatin)、クリプトフィシン1、クリプトフィシン8、ドラスタチン、ズオカルマイシン、エレウテロビン、パンクラチスタチン、サルコジクチン(sarcodictyin)、スポンジスタチン、クロランブシル、クロロナファジン(chloRNAphazine)、コロホスファミド(cholophosphamide)、エストラムスチン、イホスファミド、メクロレタミン、メクロレタミンオキシドヒドロクロリド、メルファラン、ノベンビチン(novembichin)、フェネステリン(phenesterine)、プレドニムスチン(prednimustine)、トロフォスファミド(trofosfamide)、ウラシルマスタード、カルムスチン、クロロゾトシン(chlorozotocin)、フォテムスチン(fotemustine)、ロムスチン、ニムスチン、ラニムスチン、カリケアマイシン(calicheamicin)、ダイネマイシン、クロドロネート、エスペラマイシン、アクラシノマイシン、アクチノマイシン、オースラマイシン(authramycin)、アザセリン、ブレオマイシン、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン、カルジノフィリン(carzinophilin)、クロモマイシン、ダクチノマイシン、デトルビシン(detorbicin)、6-ジアゾ-5-オキソ-L-ノルロイシン、アドリアマイシン(adriamycin)、エピルビシン、エソルビシン、イダルビシン、マーセロマイシン(marcellomycin)、マイトマイシンC、マイコフェノール酸(mycophenolic acid)、ノガラマイシン(nogalamycin)、オリボマイシン(olivomycins)、ペプロマイシン、ポトフィロマイシン(potfiromycin)、ピューロマイシン、ケラマイシン(quelamycin)、ロドルビシン(rodorubicin)、ストレプトニグリン、ストレプトゾシン、ツベルシジン(tubercidin)、ウベニメクス、ジノスタチン(zinostatin)、ゾルビシン(zorubicin)、デノプテリン(denopterin)、プテロプテリン(pteropterin)、トリメトレキセート(trimetrexate)、フルダラビン(fludarabine)、6-メルカプトプリン、チアミプリン、チオグアニン、アンシタビン、アザシチジン(azacitidine)、6-アザウリジン(azauridine)、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン(enocitabine)、フロキシウリジン(floxuridine);アンドロゲン類、例えばカルステロン(calusterone)、プロピオン酸ドロモスタノロン、エピチオスタノール、メピチオスタン、テストラクトン(testolactone)、アミノグルテチミド、ミトタン、トリロスタン、フロリン酸(frolinic acid)、アセグラトン、アルドホスファミドグリコシド、アミノレブリン酸、エニルウラシル、アムサクリン(amsacrine)、ベストラブシル(bestrabucil)、ビサントレン(bisantrene)、エダトラキセート(edatraxate)、デフォファミン(defofamine)、デメコルシン(demecolcine)、ジアジコン(diaziquone)、エルフォルニチン (elfornithine)、酢酸エリプチニウム(elliptinium)、エポチロン(epothilone)、エトグルシド(etoglucid)、レンチナン、ロニダミン(lonidamine)、メイタンシン(maytansine)、アンサミトシン(ansamitocine)、ミトグアゾン(mitoguazone)、ミトキサントロン、モピダンモール(mopidanmol)、ニトラエリン(nitraerine)、ペントスタチン、フェナメット(phenamet)、ピラルビシン、ロソキサントロン(losoxantrone)、ポドフィリン酸(podophyllinic acid)、2-エチルヒドラジド、プロカルバジン、ラゾキサン(razoxane)、リゾキシン、シゾフィラン、スピロゲルマニウム(spirogermanium)、テニュアゾン酸(tenuazonic acid)、トリアジコン(triaziquone)、ロリジン(roridine)A、アングイジン(anguidine)、ウレタン、ビンデシン、ダカーバジン、マンノムスチン(mannomustine)、ミトブロニトール、ミトラクトール(mitolactol)、ピポブロマン(pipobroman)、ガシトシン(gacytosine)、ドキセタキセル、クロランブシル、ゲムシタビン(gemcitabine)、6-チオグアニン、メルカプトプリン、シスプラチン、オキサリプラチン、カルボプラチン、ビンブラスチン、エトポシド、イホスファミド、マイトキサントロン、ビンクリスチン、ビノレルビン、ノバントロン(novantrone)、テニポシド、エダトレキセート(edatrexate)、ダウノマイシン、アミノプテリン、キセローダ(xeloda)、イバンドロナート(ibandronate)、イリノテカン、トポイソメラーゼインヒビター、ジフルオロメチロールニチン(DMFO)、レチノイン酸、カペシタビン(capecitabine)、並びにそれらの薬学的に許容可能な(公知の)塩又は(公知の)誘導体を包含する。
本発明の抗CAPRIN-1抗体とイミキモドとの組合せは、インビボで細胞障害活性を有する。よって本発明の抗腫瘍効果は、癌に対する細胞障害活性を調べることによって知ることが可能である。細胞障害活性は、癌を有する生体へ抗CAPRIN-1とイミキモドを投与し、投与後の腫瘍の大きさを計測して、癌の大きさを経時的に調べる事によって評価できる。また、本発明の抗腫瘍効果は、生存率を調べることによっても評価できる。また、サイトカインあるいはケモカインの産生能を調べる事によっても評価できる。本発明にある抗CAPRIN-1抗体とイミキモドとの組み合わせによる抗腫瘍効果は、さらに癌の予防、転移の予防あるいは再発の予防を調べることによって知ることができる。
本発明の医薬品は癌の治療及び/又は予防を目的とする。本発明の医薬品が標的とする癌は、CAPRIN-1タンパク質を発現する癌(細胞)であれば特に限定されない。
本発明の癌の治療及び/又は予防のための医薬品による癌の治療及び/又は予防は、前述の医薬品として投与することの他に様々な形式を含む。例えば、本発明の医薬品の各有効成分は、同時に、又は順序に従って個別に投与することができる。具体例として、約3週間までの時間間隔内で、すなわち1番目の有効成分を投与した直後から約3週間までに2番目の有効成分を投与することができる。その際、外科的処置に引き続いて実施しても、1番目の薬剤と2番目の薬剤の投与間に外科的処置を実施してもよい。また、本発明の癌の治療及び/又は予防剤を、複数の投与サイクルに従って投与してもよい。例えば、本発明の癌の治療及び/又は予防剤の各有効成分の同時投与を実施した場合、両方の有効成分を含む医薬組成物を約2日から約3週間を1サイクルとして投与する。その後は該治療サイクルを担当する医師の判断に従って、必要に応じて繰り返すことも可能である。同様に順序に従った処方を計画する場合、それぞれの個々の薬剤の投与期間が同じ期間に及ぶように調節する。サイクル間の間隔は0~2ヶ月まで変えることができる。本発明の癌の治療及び/又は予防剤の各有効成分の投与量は、医薬組成物での各有効成分の投与量と同様に設定することができる。
本発明の癌の治療及び/又は予防用の医薬品は、製薬キットの形態であってもよい。製薬キットとは、癌を治療及び/又は予防する方法において、有効成分を別個の医薬組成物の形態で使用するためのパッケージであり、該パッケージには各有効成分を投与するための指示書が含まれる。製薬キットに含まれる癌の治療及び/又は予防用の上記医薬組成物の各有効成分は、各有効成分を一緒に又は別々に投与できるようにそれぞれが上記の通り製剤化された医薬組成物の形態でありうる。また、製薬キットには、各有効成分を上記投与方法に従って投与できるよう、1つ又は複数回の用量に十分な量の有効成分が含まれる。
本発明に用いるCAPRIN-1タンパク質と免疫学的反応性を有する抗CAPRIN-1抗体は以下の様に作製したものを用いた。
WO2010/016526の実施例3に従って作製したヒトCAPRIN-1組換えタンパク質1mgを等容量の不完全フロイントアジュバント(IFA)溶液と混合し、これを2週間毎に4回、ウサギの皮下に投与を行った。その後血液を採取し、ポリクローナル抗体を含む抗血清を得た。さらにこの抗血清をプロテインG担体(GEヘルスケアバイオサイエンス社製)を用いて精製し、PBS(-)に置換して、CAPRIN-1タンパク質に対するポリクローナル抗体(抗CAPRIN-1ポリクローナル抗体#1)を得た。
WO2010/016526の実施例3に従って作製したヒトCAPRIN-1組換えタンパク質100μgを等量のMPL+TDMアジュバント(シグマ社製)と混合し、これをマウス1匹当たりの抗原溶液とした。抗原溶液を6週齢のBalb/cマウス(日本SLC社製)の腹腔内に投与後、1週間毎にさらに3回及び24回投与を行い免疫を完了した。最後の免疫から3日後に摘出したそれぞれの脾臓を滅菌した2枚のスライドガラスに挟んで擦り潰し、PBS(-)(日水社製)を用いて洗浄し1500rpmで10分間遠心して上清を除去する操作を3回繰り返して脾臓細胞を得た。得られた脾臓細胞とマウスミエローマ細胞SP2/0(ATCCから購入)とを10:1の比率にて混和し、そこに37℃に加温した10%FBSを含むRPMI1640培地200μlとPEG1500(ベーリンガー社製)800μlを混和して調製したPEG溶液を加えて5分間静置して細胞融合を行った。1700rpmで5分間遠心し、上清を除去後、Gibco社製のHAT溶液を2%当量加えた15%FBSを含むRPMI1640培地(HAT選択培地)150mlで細胞を懸濁し、96穴プレート(ヌンク社製)の1ウェル当たり100μlずつ、プレート15枚に播種した。7日間、37℃、5%CO2の条件で培養することで、脾臓細胞とミエローマ細胞が融合したハイブリドーマを得た。作製したハイブリドーマが産生する抗体のCAPRIN-1タンパク質に対する結合親和性を指標にハイブリドーマを選抜した。CAPRIN-1タンパク質溶液1μg/mlを96穴プレート1ウェル当たりに100μl添加し、4℃にて18時間静置した。各ウェルをPBS-Tで3回洗浄後、0.5% Bovine Serum Albumin(BSA)溶液(シグマ社製)を1ウェル当たり400μl添加して室温にて3時間静置した。溶液を除いて、1ウェル当たり400μlのPBS-Tでウェルを3回洗浄後、上記で得られたハイブリドーマの各培養上清を1ウェル当たり100μl添加し、室温にて2時間静置した。PBS-Tで各ウェルを3回洗浄した後、PBSで5000倍に希釈したHRP標識抗マウスIgG(H+L)抗体(インビトロジェン社製)を1ウェル当たり100μl添加して室温にて1時間静置した。PBS-Tでウェルを3回洗浄した後、TMB基質溶液(Thermo社製)を1ウェル当たり100μl添加して15~30分間静置して発色反応を行った。発色後、1規定硫酸を1ウェル当たり100μl添加して反応を停止させ吸光度計を用いて450nmと595nmの吸光度値を測定した。その結果、吸光度値が高かった抗体を産生するハイブリドーマを複数個選抜した。選抜したハイブリドーマを96穴プレート1ウェル当たりに0.5個となるようにプレートに添加し培養した。1週間後、ウェル中に単一のコロニーを形成しているハイブリドーマが観察された。それらウェルの細胞をさらに培養して、クローニングされたハイブリドーマが産生する抗体のCAPRIN-1タンパク質に対する結合親和性を指標にハイブリドーマを選抜した。CAPRIN-1タンパク質溶液1μg/mlを96穴プレート1ウェル当たりに100μl添加し、4℃にて18時間静置した。各ウェルをPBS-Tで3回洗浄後、0.5%BSA溶液を1ウェル当たり400μl添加して室温にて3時間静置した。溶液を除いて、1ウェル当たり400μlのPBS-Tでウェルを3回洗浄後、上記で得られたハイブリドーマの各培養上清を1ウェル当たり100μl添加し、室温にて2時間静置した。PBS-Tで各ウェルを3回洗浄後、PBSで5000倍に希釈したHRP標識抗マウスIgG(H+L)抗体(インビトロジェン社製)を1ウェル当たり100μl添加して室温にて1時間静置した。PBS-Tでウェルを3回洗浄した後、TMB基質溶液(Thermo社製)を1ウェル当たり100μl添加して15~30分間静置して発色反応を行った。発色後、1規定硫酸を1ウェル当たり100μl添加して反応を停止させ吸光度計を用いて450nmと595nmの吸光度値を測定した。その結果、CAPRIN-1タンパク質に反応性を示すマウスモノクローナル抗体を複数個得た。
次に、実施例1にて作製した抗CAPRIN-1抗体(抗CAPRIN-1ポリクローナル抗体#1ならびにヒト化抗体#1)とイミキモドとの組み合わせた投与による担癌マウス生体内における抗腫瘍効果を評価した。
次に、実施例1にて作製した抗CAPRIN-1抗体(抗CAPRIN-1ポリクローナル抗体#1およびヒト化抗体#1)とイミキモドとの組み合わせた投与による担癌マウス生体内における抗腫瘍効果と、上記抗体とイミキモドとは異なる既存の抗癌剤を併用した場合の抗腫瘍効果を比較評価した。
Claims (14)
- CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメントと、イミキモドとを、一緒に又は別々に組み合わせて含むことを特徴とする、癌の治療及び/又は予防のための医薬品。
- 前記抗体又はフラグメントが、配列番号2~30のうち偶数の配列番号のいずれかで表されるアミノ酸配列又は、該アミノ酸配列と80%以上の配列同一性を有するアミノ酸配列を有するCAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメントである、請求項1に記載の医薬品。
- 前記抗体又はそのフラグメントが、癌細胞表面上に存在するCAPRIN-1タンパク質の細胞外領域と免疫学的反応性を有する、請求項1又は2に記載の医薬品。
- 前記抗体又はそのフラグメントが、配列番号31~35、296~299、308、309のいずれかで表されるアミノ酸配列、あるいは該アミノ酸配列と80%以上の配列同一性を有するアミノ酸配列を有するCAPRIN-1タンパク質の部分ポリペプチドと免疫学的反応性を有する、請求項1~3のいずれか1項に記載の医薬品。
- 前記抗体がモノクローナル抗体又はポリクローナル抗体である、請求項1~4のいずれか1項に記載の医薬品。
- 前記抗体又はそのフラグメントが以下の(A)~(M)のいずれかである、請求項1~5のいずれか1項に記載の医薬品。
(A)配列番号36、37及び38の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号40、41及び42の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(B)配列番号44、45及び46の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号48、49及び50の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(C)配列番号52、53及び54の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号56、57及び58の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(D)配列番号60、61及び62の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号64、65及び66の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はフラグメント
(E)配列番号170、171及び172の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号173、174及び175の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(F)配列番号176、177及び178の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号179、180及び181の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(G)配列番号182、183及び184の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号185、186及び187の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(H)配列番号188、189及び190の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号191、192及び193の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(I)配列番号146、147及び148の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号149、150及び151の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(J)配列番号272、273及び274の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号275、276及び277の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(K)配列番号290、291及び292の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号293、294及び295の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(L)配列番号301、302及び303の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号305、306及び307の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント
(M)配列番号134、135及び136の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む重鎖可変領域と配列番号137、138及び139の相補性決定領域(それぞれCDR1、CDR2及びCDR3)を含む軽鎖可変領域とを含み、かつ、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメント - 前記抗体又はそのフラグメントが以下の(a)~(ak)のいずれかである、請求項1~6のいずれか1項に記載の医薬品。
(a)重鎖可変領域が配列番号39のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号43のアミノ酸配列を含んでなる抗体又はそのフラグメント
(b)重鎖可変領域が配列番号47のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号51のアミノ酸配列を含んでなる抗体又はそのフラグメント
(c)重鎖可変領域が配列番号55のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号59のアミノ酸配列を含んでなる抗体又はそのフラグメント
(d)重鎖可変領域が配列番号63のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号67のアミノ酸配列を含んでなる抗体又はそのフラグメント
(e)重鎖可変領域が配列番号68のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号69のアミノ酸配列を含んでなる抗体又はそのフラグメント
(f)重鎖可変領域が配列番号70のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号71のアミノ酸配列を含んでなる抗体又はそのフラグメント
(g)重鎖可変領域が配列番号72のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号73のアミノ酸配列を含んでなる抗体又はそのフラグメント
(h)重鎖可変領域が配列番号74のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号75のアミノ酸配列を含んでなる抗体又はそのフラグメント
(i)重鎖可変領域が配列番号76のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号77のアミノ酸配列を含んでなる抗体又はそのフラグメント
(j)重鎖可変領域が配列番号78のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号79のアミノ酸配列を含んでなる抗体又はそのフラグメント
(k)重鎖可変領域が配列番号80のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号81のアミノ酸配列を含んでなる抗体又はそのフラグメント
(l)重鎖可変領域が配列番号82のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号83のアミノ酸配列を含んでなる抗体又はそのフラグメント
(m)重鎖可変領域が配列番号84のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号85のアミノ酸配列を含んでなる抗体又はそのフラグメント
(n)重鎖可変領域が配列番号86のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号87のアミノ酸配列を含んでなる抗体又はそのフラグメント
(o)重鎖可変領域が配列番号88のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号89のアミノ酸配列を含んでなる抗体又はそのフラグメント
(p)重鎖可変領域が配列番号90のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号91のアミノ酸配列を含んでなる抗体又はそのフラグメント
(q)重鎖可変領域が配列番号92のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号93のアミノ酸配列を含んでなる抗体又はそのフラグメント
(r)重鎖可変領域が配列番号94のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号95のアミノ酸配列を含んでなる抗体又はそのフラグメント
(s)重鎖可変領域が配列番号96のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号97のアミノ酸配列を含んでなる抗体又はそのフラグメント
(t)重鎖可変領域が配列番号98のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号99のアミノ酸配列を含んでなる抗体又はそのフラグメント
(u)重鎖可変領域が配列番号100のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号101のアミノ酸配列を含んでなる抗体又はそのフラグメント
(v)重鎖可変領域が配列番号102のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号103のアミノ酸配列を含んでなる抗体又はそのフラグメント
(w)重鎖可変領域が配列番号104のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号105のアミノ酸配列を含んでなる抗体又はそのフラグメント
(x)重鎖可変領域が配列番号106のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号107のアミノ酸配列を含んでなる抗体又はそのフラグメント
(y)重鎖可変領域が配列番号108のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号109のアミノ酸配列を含んでなる抗体又はそのフラグメント
(z)重鎖可変領域が配列番号110のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号111のアミノ酸配列を含んでなる抗体又はそのフラグメント
(aa)重鎖可変領域が配列番号112のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号113のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ab)重鎖可変領域が配列番号114のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号115のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ac)重鎖可変領域が配列番号116のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号117のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ad)重鎖可変領域が配列番号118のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号119のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ae)重鎖可変領域が配列番号120のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号121のアミノ酸配列を含んでなる抗体又はそのフラグメント
(af)重鎖可変領域が配列番号122のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号123のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ag)重鎖可変領域が配列番号124のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号125のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ah)重鎖可変領域が配列番号126のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号127のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ai)重鎖可変領域が配列番号128のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号129のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ai)重鎖可変領域が配列番号130のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号131のアミノ酸配列を含んでなる抗体又はそのフラグメント
(aj)重鎖可変領域が配列番号132のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号133のアミノ酸配列を含んでなる抗体又はそのフラグメント
(ak)重鎖可変領域が配列番号300のアミノ酸配列を含み、かつ、軽鎖可変領域が配列番号304のアミノ酸配列を含んでなる抗体又はそのフラグメント - 前記抗体が、ヒト抗体、ヒト化抗体、キメラ抗体又は単鎖抗体である、請求項1~7のいずれか1項に記載の医薬品。
- 前記癌がCAPRIN-1タンパク質を細胞膜表面に発現する癌である、請求項1~8のいずれか1項に記載の医薬品。
- 前記癌が、基底細胞癌、バジェット病、皮膚癌、乳癌、腎癌、膵臓癌、大腸癌、肺癌、脳腫瘍、胃癌、子宮癌、卵巣癌、前立腺癌、膀胱癌、食道癌、白血病、リンパ腫、肝臓癌、胆嚢癌、肉腫、肥満細胞腫、副腎皮質癌、ユーイング腫瘍、ホジキンリンパ腫、中皮腫、多発性骨髄腫、睾丸癌、甲状腺癌又は頭頸部癌である、請求項1~9のいずれか1項に記載の医薬品。
- 前記イミキモドの剤形が経皮投与型製剤である、請求項1~10のいずれか1項に記載の医薬品。
- イミキモドを有効成分とする、CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメントを有効成分とする癌の治療及び/又は予防用医薬組成物の薬効増強剤。
- CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメントを有効成分とする、イミキモドを有効成分とする癌の治療及び/又は予防用医薬組成物の薬効増強剤。
- CAPRIN-1タンパク質と免疫学的反応性を有する抗体又はそのフラグメントと、イミキモドとを、一緒に又は別々に、被験者に投与することを特徴とする、癌の治療及び/又は予防のための方法。
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CN201980023561.4A CN111936164A (zh) | 2018-03-30 | 2019-03-29 | 癌的治疗和/或预防用药物组合物 |
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CA3095719A1 (en) | 2019-10-03 |
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