Medicines for the treatment and / or prevention of cancer

Abstract

The present invention addresses the problem of providing a medicament for the treatment and / or prevention of cancer.　The present invention provides a medicament for the treatment and / or prevention of cancer in cancer patients who have a past history of another cancer treatment, said medicament being characterized by containing a combination of a pyrimidine drug and cisplatin with an antibody or a fragment thereof having an immunological reactivity with a CAPRIN-1 protein, either separately or in a combined form.

Description

Technical Field

[0001] The present invention relates to a medicament for treating and / or preventing cancer, which uses an antibody against CAPRIN-1 protein or a fragment thereof, a pyrimidine-based agent, and cisplatin.

Background Art

[0002] Various antibody drugs targeting specific antigen proteins on cancer cells have been applied to cancer treatment as cancer therapeutics with few side effects due to their cancer specificity. For example, Cytoplasmic-activation and proliferation-associated protein 1 (CAPRIN-1) is expressed on the cell membrane surfaces of many solid cancers, and it is known that an antibody against this CAPRIN-1 protein is promising for use as a medicament for treating and / or preventing cancer (Patent Document 1).

[0003] In recent years, in clinical practice, in order to enhance the efficacy of cancer therapeutics, a treatment method of combining multiple cancer therapeutics has been used as a standard treatment method. For example, for colorectal cancer, a treatment method of combining irinotecan, folic acid, and fluorouracil; for breast cancer, a treatment method of combining doxorubicin and cyclophosphamide; or a treatment method of combining paclitaxel, trastuzumab, and pertuzumab; for gastric cancer, it has become common to treat with multiple anticancer agents such as cisplatin and fluorouracil. For a cancer therapeutic agent containing an anti-CAPRIN-1 antibody as an active ingredient, an excellent cancer treatment effect has also been confirmed by combining it with a chemotherapeutic agent (Patent Document 2). However, the treatment of cancer by combining chemotherapeutic agents is not effective for all cancers to which it is applied, and even if the treatment effect is enhanced additively, there are few cases where the treatment effect is significantly enhanced synergistically.

[0004] As one specific example of a cancer treatment method of combining multiple cancer therapeutics, the combination of a pyrimidine-based agent (for example, gemcitabine) and cisplatin can be mentioned.

[0005] The combination of gemcitabine and cisplatin is called the GEM+CDDP therapy and has been tried for the treatment of biliary tract cancer , urine road epithelial cancer such as bladder cancer , non-small cell lung cancer (NSCLC), cervical cancer, malignant mesothelioma, ovarian cancer, and pancreatic cancer.

[0006] For bladder cancer, the M-VAC therapy (combination of methotrexate, vinblastine, doxorubicin, and cisplatin) has been used so far, but a combination therapy of gemcitabine and cisplatin with fewer side effects is being used. For example, in muscle-invasive bladder cancer, the gemcitabine + cisplatin therapy is considered the standard treatment, but there is a report that the complete response rate in bladder cancer patients who had their bladders completely removed with the gemcitabine + cisplatin combination therapy was about 24.5% (Non-Patent Document 1).

[0007] In recent years, in addition to the conventional combination of gemcitabine and cisplatin, the efficacy of the combination therapy of nab-paclitaxel in patients with advanced biliary tract cancer was verified in a phase 2 trial (NCT02392637). The first-line standard treatment for patients with advanced biliary tract cancer is the combination therapy of gemcitabine and cisplatin, but its overall survival (OS) is less than 1 year. In the above clinical trial consisting of 78% of metastatic biliary tract cancer patients and 22% of locally advanced biliary tract cancer patients, in addition to gemcitabine and cisplatin, the combination with nab-paclitaxel resulted in a progression-free survival period (P FS ) of 11.8 months, an objective response rate (ORR) of 45%, and a median overall survival (OS) of 19.2 months, showing better treatment results than the standard gemcitabine + cisplatin combination therapy (GEM+CDDP therapy). However, at the same time, grade 3 or higher adverse events (AE) were observed in more than 50% of cases, and 16% of patients were forced to discontinue treatment due to treatment-related adverse events (T RAE ) (Non-Patent Document 2).

Prior Art Documents

Patent Documents

[0008] [Patent Document 1] WO2010 / 016526 [Patent Document 2] WO2011 / 096535 No. [Non-patent literature]

[0009] [Non-Patent Document 1] JAMA Oncol,2018,4(11),1535-1542 [Non-patent document 2] JAMA Oncol. 2019,5(6),824-830 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a pharmaceutical agent for treating and / or preventing cancers that specifically express CAPRIN-1 protein on the cell surface. [Means for solving the problem]

[0011] As mentioned above, for example, when gemcitabine and cisplatin are used in combination in patients with advanced biliary tract cancer, the overall survival (OS) is only less than one year, and even when gemcitabine, cisplatin, and nab-paclitaxel are used in combination, the improvement in overall survival (OS) is only less than two years, with no significant improvement being observed. As a result of extensive research, the present inventors have found that a combination of an antibody or a fragment thereof against the CAPRIN-1 protein, which is immunologically reactive with cancer cells, with a pyrimidine drug (e.g., gemcitabine) and cisplatin, exerts an extremely strong antitumor effect in cancer patients, particularly in cancer patients with a history of cancer treatment with pharmaceuticals other than the combination therapy, and have thus completed the present invention.

[0012] Specifically, the present invention relates to the following embodiments (1) to (17).

[0013] A pharmaceutical for the treatment and / or prevention of cancer, comprising an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin, either in combination or separately, wherein the cancer patient has a history of cancer treatment with a pharmaceutical other than a pharmaceutical comprising an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin, either in combination or separately.

[0014] (2) The pharmaceutical according to (1), wherein the cancer is a cancer in a cancer patient who has a history of cancer treatment with a pyrimidine-based drug and / or a platinum-based drug.

[0015] (3) The pharmaceutical according to (1) or (2), wherein the cancer is a cancer in a cancer patient in whom cancer treatment with a pharmaceutical other than a pharmaceutical comprising an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin, either in combination or separately, has not been effective.

[0016] (4) The pharmaceutical according to any one of (1) to (3), wherein the cancer is a cancer in a cancer patient in whom cancer treatment with a pyrimidine-based drug and / or a platinum-based drug has not been effective.

[0017] (5) The pharmaceutical according to any one of (1) to (4), wherein the pyrimidine-based drug is gemcitabine and / or a derivative of gemcitabine.

[0018] (6) The pharmaceutical according to any one of (1) to (5), wherein the antibody or the fragment thereof has immunological reactivity with a CAPRIN-1 protein having an amino acid sequence represented by any of the even sequence numbers among SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.

[0019] (7) The pharmaceutical product according to any one of (1) to (6), wherein the antibody or its fragment has immunological reactivity with the extracellular region of the CAPRIN-1 protein present on the cancer cell surface.

[0020] (8) The pharmaceutical product according to any one of (1) to (7), wherein the antibody or its fragment has immunological reactivity with a partial polypeptide of the CAPRIN-1 protein having an amino acid sequence represented by any one 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.

[0021] (9) The pharmaceutical product according to any one of (1) to (8), wherein the antibody is a monoclonal antibody or a polyclonal antibody.

[0022] (10) The pharmaceutical product according to any one of (1) to (9), wherein the antibody or its fragment is any one of the following (A) to (M). (A) An antibody or its fragment that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 36, 37, and 38 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 40, 41, and 42, and has immunological reactivity with the CAPRIN-1 protein (B) An antibody or its fragment that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 44, 45, and 46 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 48, 49, and 50, and has immunological reactivity with the CAPRIN-1 protein (C) An antibody or its fragment that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 52, 53, and 54 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 56, 57, and 58, and has immunological reactivity with the CAPRIN-1 protein (D) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 60, 61, and 62 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 64, 65, and 66, and has immunological reactivity with the CAPRIN-1 protein (E) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 170, 171, and 172 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 173, 174, and 175, and has immunological reactivity with the CAPRIN-1 protein (F) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 176, 177, and 178 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 179, 180, and 181, and has immunological reactivity with the CAPRIN-1 protein (G) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 182, 183, and 184 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 185, 186, and 187, and has immunological reactivity with the CAPRIN-1 protein (H) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 188, 189, and 190 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 191, 192, and 193, and has immunological reactivity with the CAPRIN-1 protein (I) An antibody or a fragment thereof that comprises a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 146, 147, and 148 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 149, 150, and 151, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that comprises a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 272, 273, and 274 and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 275, 276, and 277, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that comprises a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 290, 291, and 292 and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 293, 294, and 295, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that comprises a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 301, 302, and 303 and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 305, 306, and 307, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that comprises a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 134, 135, and 136 and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 137, 138, and 139, and has immunological reactivity with the CAPRIN-1 protein.

[0023] The pharmaceutical product according to any one of (1) to (10), wherein the antibody or the fragment thereof is any one of the following (a) to (al). (a) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 39 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 43 (b) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 47 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 51 (c) An antibody or a 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 (d) An antibody or a 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 (e) An antibody or a 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 (f) An antibody or a 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 (g) An antibody or a 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 (h) An antibody or a 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 (i) An antibody or a 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 (j) An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79 (k) An antibody or a 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 (l) An antibody or a 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 (m) An antibody or a 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 (n) An antibody or a 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 (o) An antibody or a 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 (p) An antibody or a 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 (q) An antibody or a 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 (r) An antibody or a 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 (s) An antibody or a 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 (t) An antibody or a 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 (u) An antibody or a 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 (v) An antibody or a 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 (w) An antibody or a 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 (x) An antibody or a 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 (y) An antibody or a 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 (z) An antibody or a 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 (aa) An antibody or a 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 (ab) An antibody or a 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 (ac) An antibody or a 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 (ad) An antibody or a 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 (ae) An antibody or a 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 (af) An antibody or a 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 (ag) An antibody or a 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 (ah) An antibody or a 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 (ai) An antibody or a 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 (aj) An antibody or a 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 (ak) An antibody or a 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 (al) An antibody or a 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.

[0024] The pharmaceutical product according to any one of (1) to (11), wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody or a single-chain antibody.

[0025] The pharmaceutical product according to any one of (1) to (12), wherein the cancer is a cancer that expresses CAPRIN-1 protein on the cell membrane surface.

[0026] (14) The cancer is cholangiocarcinoma, breast cancer, kidney cancer, pancreatic cancer, colorectal cancer, melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, gastric cancer, mesothelioma, colon and rectal cancer, esophageal cancer, gastroesophageal junction part cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, ovarian cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer. The pharmaceutical product according to any one of (1) to (13).

[0027] A pharmaceutical efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which contains an antibody having immunological reactivity with CAPRIN-1 protein or a fragment thereof, with pyrimidine-based drugs and cisplatin as active ingredients, wherein the cancer patient has a history of cancer treatment with a pharmaceutical product other than cancer treatment with a pharmaceutical product containing an antibody having immunological reactivity with CAPRIN-1 protein or a fragment thereof, together or separately, in combination with pyrimidine-based drugs and cisplatin.

[0028] A potency enhancer for a pharmaceutical composition for treating and / or preventing cancer, which contains as an active ingredient an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, and a pyrimidine-based drug and cisplatin, wherein the cancer patient has a history of cancer treatment with a pharmaceutical other than a pharmaceutical containing, in combination or separately, an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin.

[0029] (17)A method for treating and / or preventing cancer, which comprises administering, to a subject, an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, and a pyrimidine-based drug and cisplatin, either together or separately, wherein the cancer patient has a history of cancer treatment with a pharmaceutical other than a pharmaceutical containing, in combination or separately, an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin.

[0030] This specification incorporates the disclosure of Japanese Patent Application No. 2020-043019, which is the basis of the priority of this application.

Advantages of the Invention

[0031] The combined use of an antibody or a fragment thereof against CAPRIN-1 protein according to the present invention and a drug containing a pyrimidine-based drug and cisplatin exhibits a stronger antitumor effect than the antibody against CAPRIN-1 protein alone and the existing chemotherapeutic agents (the combined use of a pyrimidine-based drug and a platinum preparation). Furthermore, the combined use of an antibody or a fragment thereof against CAPRIN-1 protein according to the present invention and a drug containing a pyrimidine-based drug and cisplatin shows a stronger antitumor effect than the existing anticancer agent therapy and the treatment with the antibody against CAPRIN-1 protein alone. Therefore, the combined use of an antibody or a fragment thereof against CAPRIN-1 protein, a pyrimidine-based drug, and cisplatin is effective for treating and preventing cancer.

BEST MODE FOR CARRYING OUT THE INVENTION

[0032] The antitumor activity by the combined use of an antibody against CAPRIN-1 protein or a fragment thereof (hereinafter referred to as "anti-CAPRIN-1 antibody") used in the present invention, a pyrimidine-based drug, and cisplatin can be evaluated by examining the suppression of tumor growth in cancer-bearing animals in vivo as described below.

[0033] The term "comprising together or separately in combination" used in the present specification means that a plurality of drugs are included in a form that can be administered to a patient simultaneously or separately, and such a form may be, for example, in the form of a so-called mixed preparation in which a plurality of drugs are mixed, or in the form of a so-called kit preparation in which a plurality of drugs are included as individual preparations.

[0034] Such a kit preparation according to the present invention may be, for example, a kit preparation comprising a preparation (or pharmaceutical composition) containing an anti-CAPRIN-1 antibody and a preparation (or pharmaceutical composition) containing a pyrimidine-based drug and cisplatin. Further, the kit preparation according to the present invention may contain other preparations (other known antitumor agents or other pyrimidine-based drugs) in addition to the anti-CAPRIN-1 antibody, the pyrimidine-based drug, and cisplatin.

[0035] In the present specification, "combined use" or "combination" means that the anti-CAPRIN-1 antibody, the pyrimidine-based drug, and cisplatin are administered as independent active ingredients to the same living body simultaneously or at a predetermined interval. The interval may be simultaneous administration, or after 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, 5 days, 7 days, 2 weeks, 3 weeks, or 4 weeks. Either may be administered when the drug containing the anti-CAPRIN-1 antibody or the pyrimidine-based drug and cisplatin exhibits its activity in vivo. Also, the anti-CAPRIN-1 antibody may be administered first, or the drug containing the pyrimidine-based drug and cisplatin may be administered first.

[0036] The anti-CAPRIN-1 antibody according to the present invention may be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody. As long as the antibody of the present invention can exhibit antitumor activity, it may be any type of antibody, and the antibody may be a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, or a non-human animal antibody.

[0037] In addition, the subject to be treated and / or prevented for cancer in the present invention is a mammal such as a human, a pet animal, a livestock, or a sports animal, and a preferred subject is a human.

[0038] Hereinafter, the anti-CAPRIN-1 antibody, the pyrimidine-based drug, the pharmaceutical composition containing cisplatin as an active ingredient, and the method for treating and / or preventing cancer according to the present invention will be described.

[0039] <Anti-CAPRIN-1 antibody>[[ID=ID=14]] Among the CAPRIN-1 proteins having an amino acid sequence represented by any of the even sequence numbers among SEQ ID NOs: 2 to 30, which are specific examples of antigens having immunological reactivity with the anti-CAPRIN-1 antibody used in the present invention, the amino acid sequences represented by SEQ ID NOs: 6, 8, 10, 12, and 14 are the amino acid sequences of canine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOs: 2 and 4 are the amino acid sequences of human CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOs: 16 is the amino acid sequence of bovine CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOs: 18 is the amino acid sequence of equine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOs: 20, 22, 24, 26, and 28 are the amino acid sequences of mouse CAPRIN-1 protein, and the amino acid sequence represented by SEQ ID NOs: 30 is the amino acid sequence of chicken CAPRIN-1 protein.

[0040] In addition, the anti-CAPRIN-1 antibody used in the present invention may have immunological reactivity with a variant of the CAPRIN-1 protein having a sequence identity of 80% or more, preferably 90% or more, more preferably 95% or more, and still more preferably 99% or more with the amino acid sequence represented by any of the even sequence numbers among SEQ ID NOs: 2 to 30. Here, the “% sequence identity” means the percentage (%) of identical amino acids (or bases) with respect to the total number of amino acids (or bases) when two sequences are aligned so as to have the maximum similarity with or without introducing gaps.

[0041] In the present invention, the anti-CAPRIN-1 antibody means an antibody or a fragment thereof (antigen-binding fragment) having immunological reactivity with the full-length of the CAPRIN-1 protein or a fragment thereof. Here, “immunological reactivity” means the property that the antibody specifically binds to the CAPRIN-1 protein or a partial polypeptide thereof in vivo.

[0042] The anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.

[0043] A polyclonal antibody having immunological reactivity with the full-length of the CAPRIN-1 protein or a fragment thereof (anti-CAPRIN-1 polyclonal antibody) can be obtained, for example, by immunizing mice, human antibody-producing mice, rats, rabbits, chickens, etc. with a natural CAPRIN-1 protein, a fusion protein with GST or the like, or a partial peptide thereof, and then obtaining serum. The obtained serum can be purified by ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column bound with the CAPRIN-1 protein or partial peptide, etc.

[0044] The nucleotide sequences and amino acid sequences of CAPRIN-1 and its homologs used in the above immunization can be obtained, for example, by accessing GenBank (NCBI, USA) and using 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). In addition, the method for producing the CAPRIN-1 protein can be obtained by referring to WO2014 / 012479, or cells expressing the CAPRIN-1 protein can also be used.

[0045] A monoclonal antibody having immunological reactivity with the full-length or a fragment of the CAPRIN-1 protein (anti-CAPRIN-1 monoclonal antibody) can be obtained, for example, by administering breast cancer cell SK-BR-3 expressing CAPRIN-1, the full-length of the CAPRIN-1 protein or its fragment, etc. to a mouse for immunization, fusing spleen cells separated from the mouse with myeloma cells, and selecting a clone that produces an anti-CAPRIN-1 monoclonal antibody from the resulting fused cells (hybridomas). The antibody produced from the selected hybridomas can be obtained by the same method as the purification method of the above-described polyclonal antibody.

[0046] The antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.

[0047] For human antibodies, human lymphocytes infected with Epstein-Barr virus are sensitized with a protein, a protein-expressing cell or its lysate, the sensitized lymphocytes are cell-fused with myeloma cells such as human-derived U266 cells, and an antibody having immunological reactivity with the full-length or a fragment of the CAPRIN-1 protein can be obtained from the resulting fused cells.

[0048] A humanized antibody is a modified antibody, also known as a reshaped human antibody. A humanized antibody is constructed by transplanting the complementarity-determining regions of an antibody derived from an immunized animal into the complementarity-determining regions of a human antibody. Genetic recombination techniques, which are well-known techniques as general methods thereof, are specifically used. For example, a DNA sequence designed to link the complementarity-determining regions of a mouse antibody or a rabbit antibody and the framework region of a human antibody is synthesized by PCR from several oligonucleotides prepared to have overlapping portions at the ends. The obtained DNA is ligated to the DNA encoding the constant region of a human antibody, incorporated into an expression vector, introduced into a host, and produced (see European Patent Application Publication No. EP239400 and International Publication No. WO96 / 02576). The framework region of a human antibody linked via the complementarity-determining regions is selected such that the complementarity-determining regions form a good antigen-binding site. If necessary, amino acids in the framework region in the variable region of the antibody may be substituted so that the complementarity-determining regions of the reshaped human antibody form an appropriate antigen-binding site (Sato K. et al., Cancer Research 1993, 53: 851-856). Also, substitution may be made with framework regions derived from various human antibodies (see WO99 / 51743).

[0049] An antibody is a heteromultimeric glycoprotein usually containing at least two heavy chains and two light chains. An antibody is composed of two identical light chains and two identical heavy chains. A heavy chain has a heavy-chain variable region at one end, followed by several constant regions. A light chain has a light-chain variable region at one end, followed by several constant regions. The variable region has specific variable regions called complementarity-determining regions (CDRs), which confer binding specificity on the antibody. The relatively conserved portions in the variable region are called framework regions (FRs). The variable regions of a complete heavy chain and a light chain each contain four FRs linked by three CDRs (CDR1 to CDR3).

[0050] Incidentally, the sequences of the constant and variable regions of human-derived heavy and light chains are available from, for example, NCBI (USA: GenBank, UniGene, etc.). For example, the heavy chain constant region of human IgG1 has the accession number J00228, the heavy chain constant region of human IgG2 has the accession number J00230, for the human kappa light chain constant region, accession numbers V00557, X64135, X64133, etc., and for the human lambda light chain constant region, accession numbers X64132, X64134, etc. can be referred to.

[0051] A chimeric antibody is an antibody produced by combining sequences from different animals. For example, the heavy chain variable region and light chain variable region of a mouse antibody and the heavy chain steady region and light chain steady region region or of a human antibody, etc. The production of chimeric antibodies can be carried out using known methods. For example, it can be obtained by ligating DNA encoding the antibody V region and DNA encoding the C region of a human antibody, integrating this into an expression vector, introducing it into a host, and producing it.

[0052] Non-human animal antibodies can be obtained by a general method of immunizing an animal with a sensitizing antigen according to known methods. As a general method, the sensitizing antigen is injected intraperitoneally, intradermally, or subcutaneously into an animal such as a mouse. When injecting the sensitizing antigen, it is mixed with various adjuvants including CFA (Freund's complete adjuvant) in an appropriate amount and administered to the animal multiple times. After immunizing the animal and confirming that the anti-CAPRIN-1 antibody is contained in the serum, the serum is obtained and purified by ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column conjugated with CAPRIN-1 protein or partial peptides, etc. to obtain non-human animal antibodies. Also, when obtaining monoclonal antibodies from non-human animals, they can be obtained by collecting immune cells from the immunized animal and subjecting them to cell fusion with myeloma cells. The cell fusion of the immune cells and myeloma cells can be carried out according to known methods (see Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).

[0053] The antibody used in the present invention can also be obtained as a recombinant antibody produced by cloning an antibody gene from a hybridoma, incorporating it into an appropriate vector, introducing this into a host, and using gene recombination technology (see Carl, A.K. Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).

[0054] The anti-CAPRIN-1 antibody used in the present invention may have amino acids in the variable region (e.g., FR) or constant region substituted with other amino acids. The amino acid substitution may be one or more, for example, less than 15, less than 10, 8 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less amino acids, preferably 1 to 9 amino acid substitutions. The substituted antibody should have the property of specifically binding to the antigen, and the binding affinity to the antigen should be equal to or higher than that of the unsubstituted antibody, and should not cause a rejection reaction when applied to humans. The amino acid substitution is preferably a conservative amino acid substitution, which is a substitution between amino acids with similar properties such as charge, side chain, polarity, aromaticity, etc. Amino acids with similar properties can be classified, for example, into 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 amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched-chain amino acids (threonine, valine, isoleucine), aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine), etc.

[0055] In the present invention, the higher the binding affinity of the anti-CAPRIN-1 antibody to the CAPRIN-1 protein on the cancer cell surface, the stronger the anti-tumor effect can be expected. 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.

[0056] The anti-CAPRIN-1 antibody used in the present invention may be chemically modified. Examples of such antibody modifications include antibodies conjugated with various molecules such as polyethylene glycol (PEG), anti-tumor compounds (e.g., anti-tumor agents exemplified below), etc. In the antibody modification of the present invention, the substance to be conjugated is not limited. Such antibody modifications 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 can improve the binding ability of the anti-CAPRIN-1 antibody to effector cells by substituting one, two, or several amino acids in the heavy chain constant region of the antibody, or by removing fucose bound to N-acetylglucosamine in the N-glycoside-linked sugar chain bound to the heavy chain constant region. The above may be amino acid substitution alone, or a composition with an antibody to which fucose is bound.

[0057] Antibodies with one, two, or several amino acids substituted in the heavy chain constant region can be prepared by referring to, for example, WO2004 / 063351, WO2011 / 120135, US Patent 8388955, WO2011 / 005481, US Patent 6737056, WO2005 / 063351.

[0058] Antibodies or their producing cells in which fucose added to N-acetylglucosamine in the N-glycosidic linked sugar chain in the heavy chain constant region is removed can be prepared by referring to US Patent No. 6602684, European Patent 1914244, US Patent 7579170. A composition of an antibody in which fucose bound to N-acetylglucosamine in the N-glycosidic linked sugar chain binding to the heavy chain constant region is removed and an antibody in which fucose is bound or their producing cells can be prepared by referring to, for example, US Patent No. 8642292.

[0059] The anti-CAPRIN-1 polyclonal antibody, anti-CAPRIN-1 monoclonal antibody, method for producing an antibody, purification method, and method for producing the CAPRIN-1 protein or its partial polypeptide used in the present invention can be obtained by referring to WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212.

[0060] Specific examples of the anti-CAPRIN-1 antibody in the present invention include the anti-CAPRIN-1 antibodies described in the aforementioned WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212. Preferred anti-CAPRIN-1 antibodies include the following.

[0061] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more, and even more preferably 99% or more) with the amino acid sequence.

[0062] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 31 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) with the amino acid sequence. Preferably, it includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 36, 37, and 38 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 40, 41, and 42, and is an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein, or includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 140, 141, and 142 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 143, 144, and 145, and is an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein, or includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 164, 165, and 166 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR : 167, 168, and 169, respectively), and is an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 39 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 43, or an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 70 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 71, or an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 78 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 79.

[0063] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it is an antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions of SEQ ID NOs: 60, 61, and 62 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity-determining regions of SEQ ID NOs: 64, 65, and 66 (CDR1, CDR2, and CDR3, respectively), and has immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 63 and the light chain variable region includes the amino acid sequence of SEQ ID NO: 67.

[0064] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it is an antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions of SEQ ID NOs: 52, 53, and 54 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity-determining regions of SEQ ID NOs: 56, 57, and 58 (CDR1, CDR2, and CDR3, respectively), and has immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 55 and the light chain variable region includes the amino acid sequence of SEQ ID NO: 59.

[0065] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 34 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) with the amino acid sequence. Preferably, it includes a heavy chain variable region containing the complementarity-determining regions of SEQ ID NOs: 170, 171, and 172 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity-determining regions of SEQ ID NOs: 173, 174, and 175 (CDR1, CDR2, and CDR3, respectively), and has immunological reactivity with a CAPRIN-1 protein, or an antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions of SEQ ID NOs: 176, 177, and 178 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region containing the complementarity-determining regions of SEQ ID NOs: 179, 180, and 181 (CDR1, CDR2, and CDR3, respectively), and has immunological reactivity with a CAPRIN-1 protein. More preferably, an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 80 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 81, or an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 82 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 83.

[0066] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 35 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, still more preferably 95% or more) with the amino acid sequence. Preferably, it is an antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 182, 183, and 184 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 185, 186, and 187 and has immunological reactivity with the CAPRIN-1 protein, or an antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 188, 189, and 190 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 191, 192, and 193 and has immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 84 and the light chain variable region includes the amino acid sequence of SEQ ID NO: 85, or an antibody or a fragment thereof in which the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 86 and the light chain variable region includes the amino acid sequence of SEQ ID NO: 87.

[0067] An antibody or a fragment thereof that includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 44, 45, and 46 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 48, 49, and 50 and has immunological reactivity with the CAPRIN-1 protein. Preferably, it is an antibody or a fragment thereof in which the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 47 and the light chain variable region includes the amino acid sequence of SEQ ID NO: 51.

[0068] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of the CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 146, 147, and 148 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 149, 150, and 151, and is an antibody or a fragment thereof that has immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 72 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 73.

[0069] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of the CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it includes a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 272, 273, and 274 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 275, 276, and 277, and is an antibody or a fragment thereof that has immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 114 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 115.

[0070] An antibody or a fragment thereof having immunological reactivity with a partial polypeptide of the CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it comprises a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 290, 291, and 292 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 293, 294, and 295, and is an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 120 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 121.

[0071] An antibody or a fragment thereof having immunological reactivity with a partial polypeptide of the CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it comprises a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 301, 302, and 303 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 305, 306, and 307, and is an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 300 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 304.

[0072] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it comprises a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 134, 135, and 136 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 137, 138, and 139, and is an antibody or a fragment thereof that has immunological reactivity with a CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 68 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 69.

[0073] An antibody or a fragment thereof that has immunological reactivity with a partial polypeptide of a CAPRIN-1 protein 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, still more preferably 95% or more) sequence identity with the amino acid sequence. Preferably, it comprises a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 134, 135, and 136 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 137, 138, and 139, and is an antibody or a fragment thereof that has immunological reactivity with a CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 68 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 69.

[0074] Also, the following anti-CAPRIN-1 antibodies are preferably used.

[0075] An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 68 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 69.

[0076] An antibody or a 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.

[0077] An antibody or a 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.

[0078] An antibody or a 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.

[0079] An antibody or a 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.

[0080] An antibody or a 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.

[0081] An antibody or a 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.

[0082] An antibody or a 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.

[0083] An antibody or a 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.

[0084] An antibody or a 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.

[0085] An antibody or a 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.

[0086] An antibody or a 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.

[0087] An antibody or a 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.

[0088] An antibody or a 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.

[0089] An antibody or a 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.

[0090] An antibody or a 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.

[0091] An antibody or a 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.

[0092] An antibody or a 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.

[0093] An antibody or a 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.

[0094] An antibody or a 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.

[0095] An antibody or a 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.

[0096] An antibody or a 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.

[0097] An antibody or a 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.

[0098] An antibody or a 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.

[0099] An antibody or a 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.

[0100] An antibody or a 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.

[0101] An antibody or a 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.

[0102] An antibody or a 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.

[0103] An antibody or a 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.

[0104] An antibody or a 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.

[0105] An antibody or a 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.

[0106] An antibody or a 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.

[0107] An antibody or a 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.

[0108] An antibody or a 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.

[0109] In the following examples, by combining the above polyclonal antibody or monoclonal antibody against the full-length CAPRIN-1 protein or a polypeptide of a part of the region expressed on the cell membrane surface of cancer cells with a drug containing a pyrimidine-based drug and cisplatin, its strong antitumor effect was confirmed in a cancer-bearing living body.

[0110] <Pyrimidine-based drug> Examples of the pyrimidine-based drug include fluorouracil (5-FU) and tegafur (FT), which is a prodrug of fluorouracil. , drug Xifluridine, cytarabine preparations, or derivatives thereof may be mentioned, and preferably gemcitabine and / or derivatives of gemcitabine.

[0111] <Cisplatin> Cisplatin has the chemical name cis-diamminedichloro-platinum(II). Here, cisplatin, for administration to a living body, may include a suitable isotonic agent or pH modulator or may include a suitable dosage form.

[0112] <Other drugs> The drug containing the anti-CAPRIN-1 antibody, the pyrimidine-based drug, and cisplatin as an active ingredient of the pharmaceutical composition of the present invention may be used in combination with an antitumor agent known in the literature or the like. There is no particular limitation on the known antitumor agent, but specific examples include paclitaxel, nab-paclitaxel, doxorubicin, daunorubicin, cyclophosphamide, methotrexate, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carbocone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, platencin, platencinone, camptothecin, bryostatin, callystatin, cryptophycin 1, cryptophycin 8, dolastatin, zuocamycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine (chlo rnaphazine), cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, dynemicin, clodronate, esperamicin, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, calminomycin, carzinophilin, chromomycin, dactinomycin, detorbicin, 6-diazo-5-oxo-L-norleucine, adriamycin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolicacid), nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, didoxyruridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene , data defofamine, demecolcine, diaziquone, e fluoride nicin (e flornithine), elliptinium acetate, epothilone, etoglucid, lentinan, lonidamine, maytansine, ansamitocine, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, roridine A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, d cell Taxol 、6 -thioguanine, mercaptopurine, oxaliplatin, vinblastine, etoposide , vitamin vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, topoisomerase inhibitor, difluoromethylornithine (DMFO), retinoic acid, and pharmaceutically acceptable (known) salts or (known) derivatives thereof are included.

[0113] <The antitumor effect of the present invention> The combination of the anti-CAPRIN-1 antibody, pyrimidine-based drug, and cisplatin of the present invention 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 a drug containing an anti-CAPRIN-1 antibody, a pyrimidine-based drug, and cisplatin to a living body having cancer, measuring the size of the tumor after administration, and examining the size of the cancer over time. In addition, the antitumor effect of the present invention can also be evaluated by examining the survival rate. It can also be evaluated by examining the ability to produce cytokines or chemokines. The antitumor effect by the combination of the anti-CAPRIN-1 antibody, pyrimidine-based drug, and drug containing cisplatin in the present invention can be further known by examining cancer prevention, metastasis prevention, or recurrence prevention.

[0114] The higher the binding affinity of the anti-CAPRIN-1 antibody used in the present invention for the CAPRIN-1 protein on the cancer cell surface, the stronger the expected antitumor effect. 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.

[0115] The ability of the anti-CAPRIN-1 antibody used in the present invention to bind to CAPRIN-1 can be determined, for example, by using a binding assay such as ELISA, Western blotting, immunofluorescence, and flow cytometry.

[0116] Administration of the combination of the anti-CAPRIN-1 antibody in the present invention, a pyrimidine-based drug, and a drug containing cisplatin into a cancer-bearing organism enhances the antitumor effect as compared to the anti-CAPRIN-1 antibody alone as described above. 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 enhancement rate of the antitumor effect of the combined administration of the anti-CAPRIN-1 antibody in the present invention, a pyrimidine-based drug, and a drug containing cisplatin against the administration of the anti-CAPRIN-1 antibody alone can be calculated by administering the effective amounts to cancer-bearing mice under the same conditions and comparing the tumor volumes after the 7th day from the start of administration.

[0117] <Pharmaceutical for the treatment and / or prevention of cancer> The pharmaceutical of the present invention is for the purpose of treating and / or preventing 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.

[0118] As used herein, "treatment" means the treatment of cancer based on the aforementioned antitumor effect. Also, as used herein, "prevention" means not only the prevention of the occurrence of cancer but also the prevention of cancer metastasis or recurrence.

[0119] As used herein, the terms "tumor" and "cancer" mean malignant neoplasms and are used interchangeably.

[0120] In the present invention, a cancer patient with a history of cancer treatment with pharmaceuticals other than cancer treatment with a pharmaceutical comprising an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, a pyrimidine-based agent, and cisplatin, either together or separately, may be any cancer patient who has received cancer treatment with pharmaceuticals other than those combinations, including patients who have been treated with chemotherapeutic agents, molecular target drugs, or hormonal therapy in the past. For example, it may be a cancer patient who has received cancer treatment in accordance with the "NCCN Clinical Practice Guidelines in Oncology", the "ESMO Clinical Practi ce Guidelines", or the "Cancer Treatment Guidelines". Preferably, it is a cancer patient with a history of cancer treatment with a pyrimidine-based agent and / or a platinum preparation (specific examples include cisplatin, carboplatin, oxaliplatin, nedaplatin).

[0121] Also, as the patient, preferably, it is a cancer patient in whom cancer treatment with pharmaceuticals other than cancer treatment with a pharmaceutical comprising an anti-CAPRIN-1 antibody, a pyrimidine-based agent, and a platinum preparation, either together or separately, has not been effective, and more preferably, it is a cancer patient in whom cancer treatment with a pyrimidine-based agent and / or a platinum preparation has not been effective.

[0122] Also, as the patient, preferably, it is a cancer patient having a cancer resistant to cancer treatment with pharmaceuticals other than cancer treatment with a pharmaceutical comprising an anti-CAPRIN-1 antibody, a pyrimidine-based agent, and a platinum preparation, either together or separately, and more preferably, it is a cancer patient having a cancer resistant to cancer treatment with a pyrimidine-based agent and / or a platinum preparation. Here, "cancer treatment has not been effective" and "resistant to cancer treatment" are used synonymously.

[0123] In the present invention, the cancer targeted may be any cancer as long as it expresses the CAPRIN-1 protein on the cell membrane surface. Preferably, cholangiocarcinoma, breast cancer, renal cancer, pancreatic cancer, colorectal cancer, melanoma (including postoperative melanoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, gastric cancer, mesothelioma (including malignant pleural mesothelioma), colorectal cancer (e.g., colorectal cancer with MSI-high), esophageal cancer, gastroesophageal junction part cancer, hepatocellular carcinoma, glioblastoma, urothelial cancer, ovarian cancer, bladder cancer, uterine cancer (including cervical cancer and endometrial cancer), primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mastocytoma, adrenocortical carcinoma, Ewing tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget disease or skin cancer. Further, these cancers may be primary cancer, metastatic cancer, metastasized cancer or recurrent cancer, postoperative cancer, or inoperable cancer. Note that melanoma is often used synonymously with malignant melanoma.

[0124] In addition, examples of the cancer targeted in the present invention include platinum / taxane-resistant recurrent ovarian cancer.

[0125] In addition, examples of the cancer targeted in the present invention include cancers resistant to known treatment methods. The cancer with resistance is not particularly limited as long as it is derived from a patient with any treatment history. For example, it is a cancer derived from a patient with a treatment history with 5-FU, and after administration, it is a cancer with resistance, metastasized cancer or recurrent cancer.

[0126] More specifically, the cancer is, for example, Bowen's disease, squamous cell carcinoma, extramammary Paget's disease, fungating polyposis, Sezary syndrome, cutaneous T / NK cell lymphoma, T cell leukemia / lymphoma with lesions only in the skin, cutaneous B cell lymphoma (indolent group), cutaneous T cell lymphoma of the breast, complex breast cancer, malignant mixed tumor of the breast, intraductal papillary adenocarcinoma of the breast, adenocarcinoma of the lung, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, glioma, glioblastoma, neuroblastoma, ependymoma, neuronal tumor, fetal-type neuroectodermal tumor, schwannoma, neurofibroma, meningioma, chronic lymphocytic leukemia, lymphoma, gastrointestinal lymphoma, digestive organ lymphoma, small to medium cell lymphoma, cecal cancer, ascending colon cancer, descending colon cancer, transverse colon cancer, sigmoid colon cancer, rectal cancer, ovarian epithelial cancer, germ cell tumor, stromal cell tumor, pancreatic duct cancer, invasive pancreatic duct cancer, adenocarcinoma of the pancreas, acinar cell cancer, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous tumor of the pancreas, mucinous cystadenocarcinoma, pancreatoblastoma, pancreatic head cell tumor, Frant z tumor, serous cystadenocarcinoma, solid papillary carcinoma, gastrinoma, glucagonoma, insulinoma, multiple endocrine neoplasia type 1 (Wermer syndrome), non-functional islet cell tumor, somatostatinoma, VIP-producing tumor, cervical cancer, endometrial cancer, fibrosarcoma, bone and joint sarcoma, Ewing's sarcoma, Wilms tumor, hepatoblastoma, soft tissue sarcoma, acute leukemia, chronic leukemia, spinal cord tumor, soft tissue malignant tumor, teratoma group tumor, head and neck cancer includes hypopharyngeal cancer, mid-pharyngeal cancer, tongue cancer, nasopharyngeal cancer, oral cancer, lip cancer, paranasal sinus cancer, laryngeal cancer, renal pelvic ureteral cancer, bladder cancer, urethral cancer, etc., but is not limited thereto. Also included are palpable cancers, cancers existing subcutaneously, cancers existing intradermally, superficial cancers, cancers existing in the dermis, or cancers existing in non-parenchymal organs, and progressive cancers that originate from the above cancers. Also included are palpable cancers, cancers existing subcutaneously, cancers existing intradermally, superficial cancers, cancers existing in the dermis, or cancers existing in non-parenchymal organs that occur due to metastasis or recurrence of the above cancers.

[0127] Also, the preferred subject (patient) to be targeted is a mammal, for example, a mammal including primates, pet animals, domestic animals, sport animals, etc., and particularly humans, dogs, and cats are preferred.

[0128] The pharmaceutical of the present invention can be formulated by methods known to those skilled in the art. The pharmaceutical of the present invention can be used parenterally, for example, in the form of a sterile solution in water or other pharmaceutically acceptable liquids, or an injection in the form of a suspension. In the pharmaceutical of the present invention, for each formulation or pharmaceutical composition, its active ingredient (at least one of an anti-CAPRIN-1 antibody, a pyrimidine-based drug, and cisplatin) is, for example, a pharmacologically acceptable carrier, medium, or additive, specifically, sterile water, physiological saline, isotonic solution, buffer (buffer solution, etc.), vegetable oil, oily liquid , antioxidant, solubilizing agent, emulsifier, suspending agent, surfactant, stabilizer, fragrance, excipient, binder, etc. may be appropriately combined, and preferably, they may be formulated by mixing them in a unit dosage form required for generally recognized pharmaceutical practice. The amount of the active ingredient in these formulations is such that an appropriate dosage within the indicated range can be obtained.

[0129] A sterile composition for injection can be formulated according to normal pharmaceutical practice using a vehicle such as distilled water for injection. Examples of the aqueous solution for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and appropriate solubilizing agents, such as alcohol, specifically ethanol, polyalcohols, such as propylene glycol, polyethylene glycol, and nonionic surfactants, such as polysorbate 80 (TM), HCO-60, may be used in combination. Examples of the oily liquid include sesame oil and soybean oil, and benzyl benzoate and benzyl alcohol may be used in combination as solubilizing agents. Also, it may be formulated with a buffer, such as phosphate buffer, sodium acetate buffer, a pain reliever, such as procaine hydrochloride, a stabilizer, such as benzyl alcohol, phenol, and an antioxidant. The prepared injection solution is usually filled into appropriate ampoules.

[0130] Administration can be oral or parenteral, preferably parenteral administration, specifically including injection dosage forms, nasal administration dosage forms, pulmonary administration dosage forms, transdermal administration forms, etc. As examples of injection dosage forms, for example, it can be administered systemically or locally by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intratumoral injection, etc. As an example of a transdermal administration form, for example, it is what is called an application agent or topical medicine. Examples of topical medicines include solid agents, liquid agents, spray agents, ointments, creams, or gel agents.

[0131] Also, the administration method can be appropriately selected according to the patient's age, weight, gender, symptoms, etc. The dosage of the pharmaceutical composition containing at least one of the anti-CAPRIN-1 antibody, pyrimidine-based drug, and cisplatin can be selected within the range of 0.0001 mg to 1000 mg per kg of body weight per administration, for example, in terms of the amount of each active ingredient. Alternatively, for example, it can be selected within the range of 0.001 to 100000 mg / body per patient, or, for example, the dosage of each active ingredient can be selected from 1 mg to 30 mg per kg of the patient's body weight, but these numerical values are not necessarily limiting. The dosage and administration method vary depending on the patient's weight, age, gender, symptoms, etc., but those skilled in the art can appropriately select them.

[0132] <Administration Method> The treatment and / or prevention of cancer by the pharmaceutical for the treatment and / or prevention of cancer of the present invention includes various forms in addition to administration as the aforementioned pharmaceutical. For example, each active ingredient of the pharmaceutical of the present invention can be administered simultaneously, in parallel, or individually according to an order. As a specific example, within a time interval of up to about 3 weeks, that is, the second active ingredient can be administered from immediately after the administration of the first active ingredient to up to about 3 weeks. At that time, it may be carried out following a surgical procedure, or a surgical procedure may be carried out between the administration of the first agent and the second agent. Further, the pharmaceutical for the treatment and / or prevention of cancer of the present invention may be administered according to a plurality of administration cycles. For example, when simultaneous administration of each active ingredient of the pharmaceutical for the treatment and / or prevention of cancer of the present invention is carried out, a pharmaceutical composition containing the active ingredient of the present invention (the anti-CAPRIN-1 antibody, pyrimidine-based agent, and cisplatin of the present invention) is administered with 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. Similarly, when planning a prescription according to an order, adjust so that the administration period of each individual agent covers the same period. The interval between cycles can be changed from 0 to 2 months. The dosage of each active ingredient of the pharmaceutical for the treatment and / or prevention of cancer of the present invention can be set in the same manner as the dosage of each active ingredient in the above pharmaceutical composition.

[0133] <Pharmaceutical Kit> The pharmaceutical 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 active ingredients in the form of separate pharmaceutical compositions (formulations) in a method for treating and / or preventing cancer, and the package may include instructions for administering each active ingredient. Each active ingredient of the above pharmaceutical composition for the treatment and / or prevention of cancer contained in the pharmaceutical kit can be in the form of a pharmaceutical composition formulated as described above so that each active ingredient can be administered together or separately. Further, the pharmaceutical kit contains an amount of the active ingredient sufficient for one or more doses so that each active ingredient can be administered according to the above administration method.

[0134] <Treatment and / or Prevention Method> Based on the content specifically described above, the present invention provides a method for the treatment and / or prevention of cancer, which includes administering to a subject (patient) the above-mentioned pharmaceutical of the present invention, or the anti-CAPRIN-1 antibody of the present invention, together with a pyrimidine-based agent and cisplatin. For example, the present invention further provides a method for the treatment and / or prevention of cancer, which includes administering the above-mentioned pharmaceutical of the present invention, etc. to a subject (patient) having cancer or suspected of having cancer. In the method of the present invention, in addition to the anti-CAPRIN-1 antibody of the present invention, a pyrimidine-based agent and cisplatin, other anti-tumor agents (such as known anti-tumor agents) may be administered to the subject (patient). Also, in that embodiment, for example, the anti-CAPRIN-1 antibody or its fragment contained in the above-mentioned pharmaceutical, a pyrimidine-based agent, cisplatin, and optionally an anti-tumor agent can be administered to the above-mentioned subject (patient) simultaneously or separately.

Examples

[0135] Hereinafter, the present invention will be specifically described based on examples, but the scope of the present invention is not limited by these specific examples.

[0136] (Example 1) Preparation of anti-CAPRIN-1 antibody As the anti-CAPRIN-1 antibody having immunological reactivity with the CAPRIN-1 protein used in the present invention, the one prepared as follows was used.

[0137] (Polyclonal antibody) 1 mg of human CAPRIN-1 recombinant protein (SEQ ID NO: 2) prepared according to Example 3 of WO2010 / 016526 was mixed with an equal volume of incomplete Freund's adjuvant (IFA) solution, and this was administered subcutaneously to rabbits 4 times every 2 weeks. Then 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 Biosciences), replaced with PBS(-), to obtain a polyclonal antibody against the CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody #1).

[0138] (Monoclonal antibody) 100 μg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal amount of MPL+TDM adjuvant (Sigma), and this was used as the antigen solution per mouse. The antigen solution was administered intraperitoneally to 6-week-old Balb / c mice (Japan SLC), followed by three and 24 additional weekly administrations to complete the immunization. Three days after the final immunization, each spleen was removed and crushed between two sterilized glass slides. The spleen was washed with PBS(-) (Nissui), centrifuged at 1500 rpm for 10 minutes, and the supernatant was removed. This procedure was repeated three times to obtain spleen cells. The resulting spleen cells were mixed with mouse myeloma cells SP2 / 0 (purchased from ATCC) at a 10:1 ratio. A PEG solution (200 μl of RPMI 1640 medium containing 10% FBS and 800 μl of PEG 1500 (Boehringer) preheated to 37°C) was added and allowed to stand for 5 minutes to allow cell fusion. After centrifugation at 1700 rpm for 5 minutes and removal of the supernatant, the cells were suspended in 150 ml of RPMI 1640 medium containing 15% FBS and 2% equivalent of Gibco HAT solution (HAT selection medium). The cells were seeded onto 15 96-well plates (Nunc) at 100 μl per well. The mixture was cultured for 7 days at 37°C in 5% CO2 to obtain hybridomas representing fusion of spleen cells and myeloma cells. Hybridomas were selected based on the binding affinity of the antibodies produced by the hybridomas to the CAPRIN-1 protein. 100 μl of 1 μg / ml CAPRIN-1 protein solution was added per well of a 96-well plate and incubated at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% bovine serum albumin (BSA) solution (Sigma) was added per well and incubated at room temperature for 3 hours. After removing the solution and washing each well three times with 400 μl of PBS-T, 100 μl of each hybridoma culture supernatant was added per well and incubated at room temperature for 2 hours. After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (Invitrogen) diluted 5000-fold with PBS was added per well and incubated at room temperature for 1 hour.After washing the wells three times with PBS-T, 100 μl of TMB substrate solution (manufactured by Thermo) was added per well and allowed to stand for 15 - 30 minutes to perform a color reaction. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance values at 450 nm and 595 nm were measured using an absorbance meter. As a result, multiple hybridomas producing antibodies with high absorbance values were selected. The selected hybridomas were added to the plate at 0.5 per well of a 96-well plate and cultured. After one week, hybridomas forming single colonies in the wells were observed. The cells in those wells were further cultured, and hybridomas were selected using the binding affinity of the antibodies produced by the cloned hybridomas to the CAPRIN-1 protein as an index. 100 μl of 1 μg / ml CAPRIN-1 protein solution was added per well of a 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% BSA solution was added per well and allowed to stand at room temperature for 3 hours. After removing the solution, the wells were washed three times with 400 μl of PBS-T per well, then 100 μl of each culture supernatant of the hybridomas obtained above was added per well and allowed to stand at room temperature for 2 hours. After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (manufactured by Invitrogen) diluted 5000-fold with PBS was added per well and allowed to stand at room temperature for 1 hour. After washing the wells three times with PBS-T, 100 μl of TMB substrate solution (manufactured by Thermo) was added per well and allowed to stand for 15 - 30 minutes to perform a color reaction. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance values at 450 nm and 595 nm were measured using an absorbance meter. As a result, multiple mouse monoclonal antibodies reactive to the CAPRIN-1 protein were obtained.

[0139] Furthermore, the reactivity with human cancer cells in which the expression of CAPRIN-1 protein on the cell membrane surface has been confirmed by flow cytometry was confirmed. As a negative control, a mouse IgG control antibody that does not show reactivity to the cancer cells was used. As a result of the confirmation, several monoclonal antibodies that strongly react with the cell membrane surface of the above cancer cells in which CAPRIN-1 is expressed on the cell membrane surface with stronger fluorescence intensity than the mouse IgG control antibody against the cancer cells were obtained. Among them, as a monoclonal antibody showing reactivity to CAPRIN-1 protein, a monoclonal antibody against CAPRIN-1 described in WO2013 / 125630, which contains the amino acid sequence of the heavy chain variable region represented by SEQ ID NO: 114 and the amino acid sequence of the light chain variable region represented by SEQ ID NO: 115, was selected.

[0140] The CDR1-3 of the heavy chain variable region of the selected antibody were identified, and the base sequence was designed so that the heavy chain variable region containing the sequence of the human antibody in the framework region could be expressed, and this was inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 was inserted. Similarly, the CDR1-3 of the light chain variable region were identified, and the base sequence was designed so that the light chain variable region containing the sequence of the human antibody in the framework region could be expressed, and this was inserted into a mammalian expression vector into which the light chain constant region of human IgG1 was inserted. The above two recombinant expression vectors were introduced into mammalian cells according to a conventional method to obtain a culture supernatant containing a humanized monoclonal antibody #1 (humanized antibody #1) against CAPRIN-1.

[0141] The culture supernatant containing the obtained humanized anti-CAPRIN-1 monoclonal antibody #1 was purified according to a conventional method using Hitrap Protein A Sepharose FF (manufactured by GE Healthcare), replaced with PBS(-), and filtered through a 0.22 μm filter (manufactured by Millipore).

[0142] The specific reactivity of the anti-CAPRIN-1 antibody to CAPRIN-1 protein was confirmed by solid-phasing the CAPRIN-1 protein on a plate and detecting it using the ELISA method.

[0143] Note that by using the anti-CAPRIN-1 antibody and examining the reactivity with cancer cells that have not been subjected to cell membrane permeabilization by flow cytometry, as shown in the following examples, it was confirmed that a part of CAPRIN-1 is expressed on the cell membrane surface of cancer cells.

[0144] With respect to any of the cancer cells, namely breast cancer cells (BT-474), colon cancer cells (HT-29), lung cancer cells (QG56, H1650), gastric cancer cells (NCI-N87), uterine cancer cells (HEC-1-A), prostate cancer cells (22Rv1), pancreatic cancer cells (Panc10.5), liver cancer cells (Hep3B), ovarian cancer cells (SKOV3), renal cancer cells (Caki-2), brain tumor cells (U-87MG), bladder cancer cells (T24), esophageal cancer cells (OE33), leukemia cells (OCI-AML5), lymphoma cells (Ramos), gallbladder cancer cells (TGBC14TKB), fibrosarcoma cells (HT-1080), melanoma cells (G-361), mouse renal cancer cells (Renca) in which the expression of the CAPRIN-1 gene has been confirmed, and mouse breast cancer cells (4T1), the humanized antibody #1 showed stronger fluorescence intensity compared to the human IgG control antibody and the rabbit IgG antibody that did not show reactivity with cancer cells as the negative control, and it was confirmed that it strongly reacts with the cell membrane surface of the above cancer cells expressing CAPRIN-1.

[0145] Similarly, it was also confirmed that the anti-CAPRIN-1 antibodies described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212 also strongly react with the surface of the above cancer cell membranes.

[0146] (Example 2) Anti-tumor effect by combined use of anti-CAPRIN-1 antibody, gemcitabine, and cisplatin in a human cancer cell-bearing mouse model The anti-tumor effect in vivo in cancer-bearing mice by the combined administration of the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1, gemcitabine, and cisplatin was evaluated.

[0147] Specifically, using NOD-SCID mice subcutaneously transplanted with human-derived cancer cells expressing the CAPRIN-1 protein, the anti-tumor effect by the combined use of the anti-CAPRIN-1 antibody, gemcitabine, and cisplatin according to the present invention was examined. 2×10 7 human breast cancer cells BT474 per mouse were mixed with Matrigel (SIGMA) and transplanted subcutaneously, and cancer-bearing mice were prepared until the tumor grew to about 200 mm 3 . BT474 is a cancer cell in which the CAPRIN-1 protein is expressed on the cell membrane surface, and it was confirmed that the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a part of CAPRIN-1 on the cell membrane surface. The anti-CAPRIN-1 antibody prepared in Example 1 was administered to the tail veins of the above cancer-bearing mice at 10 mg / kg once a week, 5 mice at a time. To the same mice, gemcitabine (5 mg / kg) and cisplatin (2 mg / kg) were administered once a week simultaneously with the administration of the anti-CAPRIN-1 antibody.

[0148] As a comparison control group, the same anti-CAPRIN-1 antibody as above was administered to cancer-bearing mice at the same amount once a week. Further, as a comparison control group, gemcitabine (5 mg / kg) and cisplatin (2 mg / kg) were administered to another individual cancer-bearing mouse at the same administration interval. Further, cancer-bearing mice in the untreated group were used as a negative control. After the start of administration, the size of the cancer in the cancer-bearing mice was measured over time using calipers, and the tumor volume was calculated according to a standard method using the formula: (length of the major axis of the cancer) × (length of the minor axis of the cancer)2 × 0.5.

[0149] As a result of the evaluation, on the 46th day after cancer induction, when the tumor volume of the negative control was set to 100%, the tumor volume of the anti-CAPRIN-1 humanized antibody #1 administration group prepared in Example 1, which was the comparison illuminate group, was 30%, and in the group administered with a combination of gemcitabine and cisplatin, it was 32%. On the other hand, in the group administered with a combination of the humanized antibody #1 prepared in Example 1 and gemcitabine and cisplatin, it was 15%, and the tumor volume had shrunk compared to that at the start of administration.

[0150] As a result of this evaluation, it was shown that administration of a combination of an anti-CAPRIN-1 antibody, gemcitabine, and cisplatin has a significantly stronger anti-tumor effect compared to the case where the anti-CAPRIN-1 antibody is administered alone and the case where gemcitabine and cisplatin are used in combination. Similarly, the same anti-tumor effect was obtained with the anti-CAPRIN-1 antibodies described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212.

[0151] (Example 3) Anti-tumor effect by combined use of anti-CAPRIN-1 antibody, gemcitabine and cisplatin Existing past history (reduction mammo pl For a stage 4 cholangiocarcinoma patient with an existing past history (reduction mammoplasty, analgesic therapy with acetaminophen and oxycodone, a strong opioid analgesic), in addition to the standard combined therapy of gemcitabine and cisplatin, "TRK-950" (an anti-CAPRIN-1 antibody under clinical trial as an anti-cancer drug) at a dose of 10 mg / kg was administered in combination. As a result of evaluating the tumor size of the patient's metastases by CT examination, the total tumor size was reduced by approximately 37% approximately 40 days after the start of administration, and the total tumor size was reduced by approximately 44% approximately 80 days after the start of administration, and a drug effect of partial response was obtained. Thus, it was shown that the treatment of combining anti-CAPRIN-1 antibody, gemcitabine and cisplatin for cancer patients exhibits extremely strong drug effects.

[0152] All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

A pharmaceutical for the treatment and / or prevention of cancer, comprising an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells, gemcitabine, and cisplatin, either in combination or separately, wherein the cancer patient has a history of cancer treatment with pharmaceuticals other than a pharmaceutical comprising an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells, a pyrimidine-based agent, and cisplatin, either in combination or separately.

2. The pharmaceutical according to claim 1, wherein the cancer is a cancer in a cancer patient who has a history of cancer treatment with a pyrimidine-based agent and / or a platinum-based agent.

3. The pharmaceutical according to claim 1 or 2, wherein the cancer is a cancer in a cancer patient in whom cancer treatment with pharmaceuticals other than a pharmaceutical comprising an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells, a pyrimidine-based agent, and cisplatin, either in combination or separately, has not been effective.

4. The pharmaceutical according to any one of claims 1 to 3, wherein the cancer is a cancer in a cancer patient in whom cancer treatment with a pyrimidine-based agent and / or a platinum-based agent has not been effective.

5. The pharmaceutical according to any one of claims 1 to 4, wherein the antibody or the antigen-binding fragment thereof has an amino acid sequence represented by any of the even sequence numbers among SEQ ID NOs: 2 to 30, or an amino acid sequence having 90% or more sequence identity with the amino acid sequence, and has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells.

6. The pharmaceutical according to any one of claims 1 to 5, wherein the antibody or the antigen-binding fragment thereof has immunological reactivity with the extracellular region of the CAPRIN-1 protein present on the surface of cancer cells.

7. The pharmaceutical according to any one of claims 1 to 6, wherein the antibody or the antigen-binding fragment thereof has 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 90% or more sequence identity with the amino acid sequence, and has immunological reactivity with a partial polypeptide of the CAPRIN-1 protein present on the surface of cancer cells.

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the antibody is a monoclonal antibody or a polyclonal antibody.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the antibody or its antigen-binding fragment is any one of the following (A) to (M). (A) An antibody or its antigen-binding fragment that includes a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 36, 37, and 38 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 40, 41, and 42, and has immunological reactivity with the CAPRIN-1 protein (B) An antibody or its antigen-binding fragment that includes a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 44, 45, and 46 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 48, 49, and 50, and has immunological reactivity with the CAPRIN-1 protein (C) An antibody or its antigen-binding fragment that includes a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 52, 53, and 54 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 56, 57, and 58, and has immunological reactivity with the CAPRIN-1 protein (D) An antibody or its antigen-binding fragment that includes a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 60, 61, and 62 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 64, 65, and 66, and has immunological reactivity with the CAPRIN-1 protein (E) An antibody or its antigen-binding fragment that includes a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 170, 171, and 172 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 173, 174, and 175, and has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 176, 177, and 178 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 179, 180, and 181, and that has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 182, 183, and 184 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 185, 186, and 187, and that has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 188, 189, and 190 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 191, 192, and 193, and that has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 146, 147, and 148 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 149, 150, and 151, and that has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 272, 273, and 274 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 275, 276, and 277, and that has immunological reactivity with the CAPRIN-1 protein An antibody or an antigen-binding fragment thereof that comprises a heavy-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 290, 291, and 292 and a light-chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 293, 294, and 295, and that has immunological reactivity with the CAPRIN-1 protein A heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 301, 302, and 303, and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 305, 306, and 307, and an antibody or an antigen-binding fragment thereof having immunological reactivity with the CAPRIN-1 protein A heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 134, 135, and 136, and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 137, 138, and 139, and an antibody or an antigen-binding fragment thereof having immunological reactivity with the CAPRIN-1 protein. [

10. ] The pharmaceutical product according to any one of claims 1 to 9, wherein the antibody or the antigen-binding fragment thereof is any one of the following (a) to (al). (a) An antibody or an antigen-binding 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) An antibody or an antigen-binding fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51 (c) An antibody or an antigen-binding 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 (d) An antibody or an antigen-binding 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 (e) An antibody or an antigen-binding 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 (f) An antibody or an antigen-binding 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 (g) An antibody or an antigen-binding 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 (h) An antibody or an antigen-binding 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 (i) An antibody or an antigen-binding 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 (j) An antibody or an antigen-binding 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 (k) An antibody or an antigen-binding 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 (l) An antibody or an antigen-binding 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 (m) An antibody or an antigen-binding 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 (n) An antibody or an antigen-binding 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 (o) An antibody or an antigen-binding 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 (p) An antibody or an antigen-binding 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 (q) An antibody or an antigen-binding 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 (r) An antibody or an antigen-binding 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 (s) An antibody or an antigen-binding 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 (t) An antibody or an antigen-binding 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 (u) An antibody or an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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 an antigen-binding 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

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody or a single-chain antibody

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the cancer is a cancer that expresses the CAPRIN-1 protein on the cell membrane surface

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the cancer is cholangiocarcinoma, breast cancer, renal cancer, pancreatic cancer, colorectal cancer, melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, gastric cancer, mesothelioma, colon / rectal cancer, esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial cancer, ovarian cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer

14. A pharmaceutical efficacy enhancer for a pharmaceutical composition for the treatment and / or prevention of cancer, which comprises gemcitabine and cisplatin as active ingredients and an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the cancer cell surface, wherein the cancer patient has a history of cancer treatment with a pharmaceutical product other than a pharmaceutical product that comprises, in combination or separately, an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the cancer cell surface, a pyrimidine-based agent and cisplatin A potency enhancer for a pharmaceutical composition for treating and / or preventing cancer, which contains gemcitabine and cisplatin as active ingredients and an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells as an active ingredient, wherein the cancer patient has a history of cancer treatment with pharmaceuticals other than cancer treatment with a pharmaceutical that contains, in combination or separately, an antibody or an antigen-binding fragment thereof that has immunological reactivity with the CAPRIN-1 protein present on the surface of cancer cells, a pyrimidine-based agent, and cisplatin.