Medicine for treating and / or preventing cancer

Abstract

Provided is a drug for treating and / or preventing cancer. A drug for the treatment and / or prevention of cancer, which comprises an antibody having immunoreactivity with CAPRIN-1 protein or a fragment thereof together or separately in combination with an anthracycline-based drug and a platinum preparation, or an anthracycline-based drug, a platinum preparation and an angiogenesis inhibitor (however, does not comprise a pyrimidine-based drug).

Description

Technical Field

[0001] The present invention relates to a medicament for the treatment and / or prevention of cancer, which uses an antibody or a fragment thereof against CAPRIN-1 protein, and an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation and an angiogenesis inhibitor. Background Art

[0002] Various antibody drugs targeting specific antigen proteins on cancer cells are 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 surface of a variety of solid cancers, and it is known that an antibody against this CAPRIN-1 protein is promising for use as a medicament for the treatment and / or prevention of cancer (Patent Document 1).

[0003] In recent years, in clinical practice, in order to improve the effectiveness of cancer therapeutics, a treatment method that combines multiple cancer therapeutics has been used as a standard treatment method. For example, a treatment method for colorectal cancer that combines irinotecan, folinic acid, and 5-fluorouracil, a treatment method for breast cancer that combines doxorubicin and cyclophosphamide, or a treatment method that combines paclitaxel, trastuzumab, and pertuzumab, and a treatment method for gastric cancer that combines multiple anticancer agents such as cisplatin and 5-fluorouracil have become common methods. For a cancer therapeutic that uses an anti-CAPRIN-1 antibody as an active ingredient, excellent cancer treatment effects have been confirmed by combining it with chemotherapeutic agents (Patent Document 2). However, the treatment of cancer using a combination of chemotherapeutic agents is not effective for all cancers to which it is applied. In addition, although the treatment effect is sometimes increased additively, there are few cases where the treatment effect is synergistically and significantly improved.

[0004] Ovarian cancer easily metastasizes to the abdominal cavity, lymph nodes, liver, or lungs. In particular, ovarian cancer at stage III or IV is a highly malignant cancer with a recurrence rate of over 50% within 2 years after the first treatment. The gemcitabine and carboplatin combination therapy (GC) is used for metastatic cancers with such ovarian cancer as the primary site. However, for patients with a platinum-free interval (PFI) of more than 6 months from the end of the first chemotherapy (so-called platinum-sensitive patients), the response rate of the treatment after recurrence is over 40%. In contrast, for patients with a PFI of less than 6 months from the end of the first chemotherapy (so-called platinum-nonsensitive patients), the response rate of the treatment after recurrence is less than 10%, and the prognosis is extremely poor (Non-Patent Document 1). As an intensive therapy for platinum-sensitive ovarian cancer patients, the three-drug combination therapy of gemcitabine, carboplatin, and bevacizumab (GC-BEV) has been approved. However, in the clinical trial OCEANS of this three-drug combination therapy, it was found that compared with GC, GC-BEV significantly prolonged the progression-free survival (PFS), but there was no significant difference in the median overall survival (OS) (Non-Patent Document 2).

[0005] In recent years, for patients with platinum-sensitive recurrent ovarian cancer, one of the types of ovarian cancer, attempts have been made to improve the treatment effect by using chemotherapy combinations such as gemcitabine / carboplatin / bevacizumab or liposomal doxorubicin-encapsulated formulation (PLD) / carboplatin / bevacizumab (Non-Patent Document 3). Non-Patent Document 3 reported that in the gemcitabine / carboplatin / bevacizumab therapy for platinum-sensitive recurrent ovarian cancer patients, the median progression-free survival (PFS) was 11.6 months and the median overall survival (OS) was 27.8 months. On the other hand, in the liposomal doxorubicin-encapsulated formulation (PLD) / carboplatin / bevacizumab therapy, the median PFS was 13.3 months and the median OS was 31.9 months, with slightly longer PFS and OS.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: WO2010 / 016526

[0009] Patent Document 2: WO2011 / 096535

[0010] Non-Patent Documents

[0011] Non-Patent Document 1: Crit Rev Oncol Hematol, 2007, 64, 129 - 138

[0012] Non-Patent Document 2: J Clin Oncol, 2012, 30, 2039 - 2045

[0013] Non-Patent Document 3: The LANCET Oncol, 2020, 21(5), 699 - 709 Summary of the Invention

[0014] Problems to be Solved by the Invention

[0015] An object of the present invention is to provide a medicament for treating and / or preventing cancer that specifically expresses CAPRIN-1 protein on the cell surface.

[0016] Means for Solving the Problems

[0017] As a result of intensive studies by the present inventors, it was found that treatment using a combination of an antibody or a fragment thereof against CAPRIN-1 protein having immunoreactivity with cancer cells, an anthracycline agent (for example, liposomal doxorubicin hydrochloride preparation (PLD)), and a platinum preparation (for example, carboplatin), or a combination of four agents adding an angiogenesis inhibitor (for example, bevacizumab) to these three agents, exhibits a very strong anti-tumor effect compared to treatment using a combination of three agents of an anthracycline agent (for example, liposomal doxorubicin hydrochloride preparation (PLD)), a platinum preparation (for example, carboplatin), and an angiogenesis inhibitor (for example, bevacizumab), thereby completing the present invention.

[0018] Specifically, the present invention relates to the following embodiments (1) to (20).

[0019] (1) A medicament for treating and / or preventing cancer, comprising together or separately in combination: an antibody or a fragment thereof having immunoreactivity with CAPRIN-1 protein, an anthracycline agent, and a platinum preparation,

[0020] and the medicament for treating and / or preventing cancer does not contain a pyrimidine-based agent.

[0021] (2) The medicament according to (1), further comprising together or separately in combination: an angiogenesis inhibitor.

[0022] (3) The medicament according to (1) or (2), wherein the anthracycline agent is doxorubicin or a liposomal doxorubicin hydrochloride preparation (PLD).

[0023] (4) The pharmaceutical product according to any one of (1) to (3), wherein the platinum preparation is carboplatin, cisplatin, oxaliplatin, nedaplatin, and / or miriplatin.

[0024] (5) The pharmaceutical product according to any one of (2) to (4), wherein the angiogenesis inhibitor is bevacizumab.

[0025] (6) The pharmaceutical product according to any one of (1) to (5), wherein the antibody or its fragment has immunoreactivity with the CAPRIN-1 protein, and the CAPRIN-1 protein has an amino acid sequence shown by any even serial number from serial numbers 2 to 30, or an amino acid sequence having a sequence identity of 80% or more with the amino acid sequence.

[0026] (7) The pharmaceutical product according to any one of (1) to (6), wherein the antibody or its fragment has immunoreactivity with the extracellular region of the CAPRIN-1 protein present on the cancer cell surface.

[0027] (8) The pharmaceutical product according to any one of (1) to (7), wherein the antibody or its fragment has immunoreactivity with a partial polypeptide of the CAPRIN-1 protein, and the partial polypeptide of the CAPRIN-1 protein has an amino acid sequence shown by any one of serial numbers 31 to 35, 296 to 299, 308, and 309, or an amino acid sequence having a sequence identity of 80% or more with the amino acid sequence.

[0028] (9) The pharmaceutical product according to any one of (1) to (8), wherein the antibody is a monoclonal antibody or a polyclonal antibody.

[0029] (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),

[0030] (A) An antibody or its fragment that contains a heavy chain variable region and a light chain variable region and has immunoreactivity with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown by serial number 36, the complementarity-determining region CDR2 shown by serial number 37, and the complementarity-determining region CDR3 shown by serial number 38, and the light chain variable region contains the complementarity-determining region CDR1 shown by serial number 40, the complementarity-determining region CDR2 shown by serial number 41, and the complementarity-determining region CDR3 shown by serial number 42;

[0031] (B) An antibody or a fragment thereof that comprises a heavy-chain variable region and a light-chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 44, complementarity-determining region CDR2 shown in SEQ ID NO: 45, and complementarity-determining region CDR3 shown in SEQ ID NO: 46, and the light-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 48, complementarity-determining region CDR2 shown in SEQ ID NO: 49, and complementarity-determining region CDR3 shown in SEQ ID NO: 50;

[0032] (C) An antibody or a fragment thereof that comprises a heavy-chain variable region and a light-chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 52, complementarity-determining region CDR2 shown in SEQ ID NO: 53, and complementarity-determining region CDR3 shown in SEQ ID NO: 54, and the light-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 56, complementarity-determining region CDR2 shown in SEQ ID NO: 57, and complementarity-determining region CDR3 shown in SEQ ID NO: 58;

[0033] (D) An antibody or a fragment thereof that comprises a heavy-chain variable region and a light-chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 60, complementarity-determining region CDR2 shown in SEQ ID NO: 61, and complementarity-determining region CDR3 shown in SEQ ID NO: 62, and the light-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 64, complementarity-determining region CDR2 shown in SEQ ID NO: 65, and complementarity-determining region CDR3 shown in SEQ ID NO: 66;

[0034] (E) An antibody or a fragment thereof that comprises a heavy-chain variable region and a light-chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 170, complementarity-determining region CDR2 shown in SEQ ID NO: 171, and complementarity-determining region CDR3 shown in SEQ ID NO: 172, and the light-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 173, complementarity-determining region CDR2 shown in SEQ ID NO: 174, and complementarity-determining region CDR3 shown in SEQ ID NO: 175;

[0035] (F) An antibody or a fragment thereof that comprises a heavy-chain variable region and a light-chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 176, complementarity-determining region CDR2 shown in SEQ ID NO: 177, and complementarity-determining region CDR3 shown in SEQ ID NO: 178, and the light-chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 179, complementarity-determining region CDR2 shown in SEQ ID NO: 180, and complementarity-determining region CDR3 shown in SEQ ID NO: 181;

[0036] (G) An antibody or fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 182, complementarity determining region CDR2 shown in SEQ ID NO: 183, and complementarity determining region CDR3 shown in SEQ ID NO: 184, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 185, complementarity determining region CDR2 shown in SEQ ID NO: 186, and complementarity determining region CDR3 shown in SEQ ID NO: 187;

[0037] (H) An antibody or fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 188, complementarity determining region CDR2 shown in SEQ ID NO: 189, and complementarity determining region CDR3 shown in SEQ ID NO: 190, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 191, complementarity determining region CDR2 shown in SEQ ID NO: 192, and complementarity determining region CDR3 shown in SEQ ID NO: 193;

[0038] (I) An antibody or fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 146, complementarity determining region CDR2 shown in SEQ ID NO: 147, and complementarity determining region CDR3 shown in SEQ ID NO: 148, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 149, complementarity determining region CDR2 shown in SEQ ID NO: 150, and complementarity determining region CDR3 shown in SEQ ID NO: 151;

[0039] (J) An antibody or fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 272, complementarity determining region CDR2 shown in SEQ ID NO: 273, and complementarity determining region CDR3 shown in SEQ ID NO: 274, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 275, complementarity determining region CDR2 shown in SEQ ID NO: 276, and complementarity determining region CDR3 shown in SEQ ID NO: 277;

[0040] (K) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 290, the complementarity-determining region CDR2 shown in SEQ ID NO: 291, and the complementarity-determining region CDR3 shown in SEQ ID NO: 292, and the light chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 293, the complementarity-determining region CDR2 shown in SEQ ID NO: 294, and the complementarity-determining region CDR3 shown in SEQ ID NO: 295;

[0041] (L) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 300, the complementarity-determining region CDR2 shown in SEQ ID NO: 301, and the complementarity-determining region CDR3 shown in SEQ ID NO: 302, and the light chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 304, the complementarity-determining region CDR2 shown in SEQ ID NO: 305, and the complementarity-determining region CDR3 shown in SEQ ID NO: 306;

[0042] (M) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 134, the complementarity-determining region CDR2 shown in SEQ ID NO: 135, and the complementarity-determining region CDR3 shown in SEQ ID NO: 136, and the light chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 137, the complementarity-determining region CDR2 shown in SEQ ID NO: 138, and the complementarity-determining region CDR3 shown in SEQ ID NO: 139.

[0043] (11) 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),

[0044] (a) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence shown in SEQ ID NO: 39 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 43;

[0045] (b) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence shown in SEQ ID NO: 47 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 51;

[0046] (c) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence shown in SEQ ID NO: 55 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 59;

[0047] (d) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence shown in SEQ ID NO: 63 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 67;

[0048] (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;

[0049] (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;

[0050] (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;

[0051] (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;

[0052] (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;

[0053] (j) 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;

[0054] (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;

[0055] (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;

[0056] (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;

[0057] (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;

[0058] (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;

[0059] (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;

[0060] (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;

[0061] An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 94 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 95;

[0062] (s) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 96 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 97;

[0063] (t) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 98 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 99;

[0064] (u) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 100 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 101;

[0065] (v) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 102 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 103;

[0066] (w) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 104 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 105;

[0067] (x) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 106 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 107;

[0068] (y) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 108 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 109;

[0069] (z) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 110 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 111;

[0070] (aa) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 112 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 113;

[0071] (ab) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 114 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 115;

[0072] (ac) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 116 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 117;

[0073] (ad) An antibody or a fragment thereof, wherein the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 118 and the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 119;

[0074] 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;

[0075] 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;

[0076] 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;

[0077] 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;

[0078] 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;

[0079] 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;

[0080] 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;

[0081] An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 303 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 307.

[0082] (12) The medicament 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.

[0083] (13) The medicament according to any one of (1) to (12), wherein the cancer is a cancer that expresses the CAPRIN-1 protein on the cell membrane surface.

[0084] (14) The medicament according to any one of (1) to (13), wherein the cancer is ovarian cancer, 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, esophagogastric junction cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, 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 sarcoma, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer.

[0085] (15) A potency enhancer for a medicament for the treatment and / or prevention of cancer,

[0086] wherein the medicament for the treatment and / or prevention of cancer contains an antibody or a fragment thereof that is immunoreactive with the CAPRIN-1 protein as an active ingredient,

[0087] and the potency enhancer contains an anthracycline agent and a platinum preparation as active ingredients and does not contain a pyrimidine agent as an active ingredient.

[0088] (16) The potency enhancer according to (15), further containing an angiogenesis inhibitor as an active ingredient.

[0089] (17) A potency enhancer for a medicament for the treatment and / or prevention of cancer,

[0090] wherein the medicament for the treatment and / or prevention of cancer contains an anthracycline agent and a platinum preparation as active ingredients and does not contain a pyrimidine agent as an active ingredient,

[0091] and the potency enhancer contains an antibody or a fragment thereof that is immunoreactive with the CAPRIN-1 protein as an active ingredient.

[0092] (18) The potency enhancer according to (17), wherein the medicament further contains an angiogenesis inhibitor as an active ingredient.

[0093] (19) A method for the treatment and / or prevention of cancer, wherein an antibody or a fragment thereof that is immunoreactive with the CAPRIN-1 protein, and an anthracycline agent and a platinum preparation are administered to a subject together or separately, and a pyrimidine agent is not administered to the subject.

[0094] (20) The method according to (19), further administering an angiogenesis inhibitor to the subject together or separately.

[0095] This specification incorporates the disclosure of Japanese Patent Application No. 2022-206138, which serves as the priority basis for this application.

[0096] Effects of the Invention

[0097] The combination of an antibody or a fragment thereof against the CAPRIN-1 protein, an anthracycline agent, and a platinum preparation, or the combination of an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor according to the present invention exhibits a stronger anti-tumor effect compared to the use of the antibody or a fragment thereof against the CAPRIN-1 protein alone, the combination of an anthracycline agent and a platinum preparation, or the combination of an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor. Therefore, the combination of an antibody or a fragment thereof against the CAPRIN-1 protein, an anthracycline agent, and a platinum preparation, or the combination of an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor is effective for the treatment and prevention of cancer. Detailed Description

[0098] The anti-tumor activity of the combination of an antibody or a fragment thereof against the CAPRIN-1 protein (hereinafter collectively referred to as "anti-CAPRIN-1 antibody") used in the present invention, an anthracycline agent, and a platinum preparation, or the combination of an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor is evaluated by investigating the inhibition of tumor growth in cancer-bearing animals in vivo, as described below.

[0099] The term "comprising together or separately in combination" used in this specification means that multiple agents are included in a manner that can be administered to a patient simultaneously or separately, which can be, for example, in the form of a so-called mixed preparation in which multiple agents are mixed, or in the form of a so-called kit preparation that includes multiple agents as separate preparations.

[0100] Such a kit preparation according to the present invention can be, for example, a kit preparation containing a preparation (or pharmaceutical composition) containing an anti-CAPRIN-1 antibody and a preparation (or pharmaceutical composition) of an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor. Furthermore, the kit preparation according to the present invention may contain other preparations (other known anti-tumor agents, but not pyrimidine-based agents) in addition to the anti-CAPRIN-1 antibody, an anthracycline agent, and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor.

[0101] In this specification, "combined use" or "combination" means that an anti-CAPRIN-1 antibody is administered to the same organism simultaneously or at a specified interval apart from an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor as respective independent active ingredients. The interval can be simultaneous administration, or 30 minutes later, 1 hour later, 3 hours later, 6 hours later, 12 hours later, 1 day later, 3 days later, 5 days later, 7 days later, 2 weeks later, 3 weeks later, or 4 weeks later. When the previously administered anti-CAPRIN-1 antibody, or the agent containing an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor shows its activity in the organism, either can be administered. Additionally, the anti-CAPRIN-1 antibody can be administered first, or the agent containing an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor can be administered first.

[0102] The anti-CAPRIN-1 antibody involved in the present invention can be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody. As long as the antibody of the present invention can exhibit anti-tumor activity, it can be any type of antibody, and the antibody is a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, or a non-human animal antibody.

[0103] In addition, the subjects for the treatment and / or prevention of cancer in the present invention are mammals such as humans, pets, livestock, and sports animals, and the preferred subject is a human.

[0104] Hereinafter, a drug for the treatment and / or prevention of cancer and a method for the treatment and / or prevention of cancer, which involve an anti-CAPRIN-1 antibody, an anthracycline agent, and a platinum preparation, or an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor as active ingredients (but do not include pyrimidine agents), will be described.

[0105] <Anti-CAPRIN-1 Antibody>

[0106] Among the CAPRIN-1 proteins having the amino acid sequences shown in any of the even serial numbers from 2 to 30, which are specific examples of antigens immunoreactive with the anti-CAPRIN-1 antibody used in the present invention, the amino acid sequences shown in serial numbers 6, 8, 10, 12, and 14 are the amino acid sequences of canine CAPRIN-1 protein, the amino acid sequences shown in serial numbers 2 and 4 are the amino acid sequences of human CAPRIN-1 protein, the amino acid sequence shown in serial number 16 is the amino acid sequence of bovine CAPRIN-1 protein, the amino acid sequence shown in serial number 18 is the amino acid sequence of equine CAPRIN-1 protein, the amino acid sequences shown in serial numbers 20, 22, 24, 26, and 28 are the amino acid sequences of murine CAPRIN-1 protein, and the amino acid sequence shown in serial number 30 is the amino acid sequence of chicken CAPRIN-1 protein.

[0107] In addition, the anti-CAPRIN-1 antibody used in the present invention may also be an antibody immunoreactive 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 further preferably 99% or more with respect to the amino acid sequence shown in any of the even serial numbers from 2 to 30. Here, "% sequence identity" is the percentage (%) of identical amino acids (or bases) relative to the total number of amino acids (or bases) when two sequences are aligned (arranged) in a manner that forms the maximum similarity (or identity) with or without introducing gaps.

[0108] The anti-CAPRIN-1 antibody in the present invention refers to an antibody or its fragment (antigen-binding fragment) immunoreactive with the full length or a fragment of the CAPRIN-1 protein. Here, "immunoreactivity" refers to the property of specifically binding an antibody to the CAPRIN-1 protein or a partial polypeptide thereof in a living body.

[0109] The anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.

[0110] For example, a polyclonal antibody (anti-CAPRIN-1 polyclonal antibody) immunoreactive with the full length or a fragment of the CAPRIN-1 protein can be obtained by immunizing mice, human antibody-producing mice, rats, rabbits, chickens, etc. with a natural CAPRIN-1 protein, a fusion protein with GST, etc., or a partial peptide thereof, obtaining serum, and purifying the obtained serum using, for example, ammonium sulfate precipitation, protein A, protein G, a DEAE ion exchange column, an affinity column conjugated with the CAPRIN-1 protein or a partial peptide, etc.

[0111] The base sequence and amino acid sequence of CAPRIN-1 and its homologs used in the above-mentioned immunity 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.

[0112] A monoclonal antibody (anti-CAPRIN-1 monoclonal antibody) having immunoreactivity with the full length or a fragment of the CAPRIN-1 protein can be obtained, for example, by immunizing a mouse with a breast cancer cell line SK-BR-3 expressing CAPRIN-1, the full length or a fragment of the CAPRIN-1 protein, etc., fusing the spleen cells isolated from the mouse with myeloma cells, and selecting a clone producing an anti-CAPRIN-1 monoclonal antibody from the resulting fused cells (hybridomas). The antibody produced by the selected hybridomas can be obtained by the same method as the purification method of the aforementioned polyclonal antibody.

[0113] The antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.

[0114] For human antibodies, human lymphocytes infected with Epstein-Barr virus can be sensitized with a protein, a protein-expressing cell, or its lysate, and the sensitized lymphocytes can be cell-fused with myeloma cells such as human-derived U266 cells to obtain an antibody having immunoreactivity with the full length or a fragment of the CAPRIN-1 protein.

[0115] A humanized antibody is an altered 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. A genetic recombination method as its general method is also a well-known technique. Specifically, by the PCR method, several oligonucleotides prepared in such a manner that their terminal portions have overlapping parts are used to synthesize a DNA sequence designed to connect, for example, the complementarity-determining regions of a mouse antibody or a rabbit antibody to the framework region of a human antibody. The obtained DNA is ligated to the DNA encoding the constant region of a human antibody, and then integrated into an expression vector, which is introduced into a host to produce it, thereby obtaining a humanized antibody (see European Patent Application Publication No. EP239400, WO96 / 02576). The framework region of a human antibody connected via a complementarity-determining region can be selected to be a framework region that enables the complementarity-determining region to form a good antigen-binding site. If necessary, the amino acids in the framework region of the variable region of the antibody can also be replaced so that the complementarity-determining region of the reshaped human antibody forms an appropriate antigen-binding site (Sato K. et al., Cancer Research 1993, 53: 851-856). In addition, it can also be replaced with a framework region derived from various human antibodies (see WO99 / 51743).

[0116] An antibody is generally a heteropolymeric glycoprotein containing at least two heavy chains and two light chains. An antibody is composed of two identical light chains and two identical heavy chains. The heavy chain has a heavy chain variable region at one end, and several constant regions are connected thereto. The light chain has a light chain variable region at one end, and several constant regions are connected thereto. The variable region has specific variable regions called complementarity-determining regions (CDRs), which confer binding specificity on the antibody. The relatively conserved parts in the variable region are called framework regions (FRs). The variable regions of the complete heavy and light chains each contain four FRs connected by three CDRs (CDR1 to CDR3), respectively.

[0117] In addition, the sequences of the constant and variable regions of human heavy and light chains can be obtained from, for example, NCBI (USA: GenBank, UniGene, etc.). For example, the sequence of the heavy chain constant region of human IgG1 can be referred to the sequence of accession number J00228, the sequence of the heavy chain constant region of human IgG2 can be referred to the sequence of accession number J00230, the sequence of the human light chain κ constant region can be referred to the sequences of accession numbers V00557, X64135, X64133, etc., and the sequence of the human light chain λ constant region can be referred to the sequences of accession numbers X64132, X64134, etc.

[0118] Chimeric antibodies are antibodies made by combining sequences from different animals. For example, antibodies that contain the heavy-chain variable region and the light-chain variable region of a mouse antibody, as well as the heavy-chain constant region and the light-chain constant region of a human antibody. The production of chimeric antibodies can be carried out using well-known methods. For example, it can be obtained by ligating the DNA encoding the antibody V region with the DNA encoding the human antibody C region, integrating it into an expression vector and introducing it into a host to produce it.

[0119] Non-human animal antibodies can be obtained by immunizing animals with a sensitizing antigen according to well-known methods. As a general method, it is obtained by injecting the sensitizing antigen into the abdominal cavity, intradermally or subcutaneously of animals such as mice. When injecting the sensitizing antigen, it can be appropriately mixed with various adjuvants represented by CFA (Freund's complete adjuvant) and administered to the animal multiple times. After immunizing the animal and confirming that the serum contains anti-CAPRIN-1 antibodies, the serum is obtained. As described above, non-human animal antibodies can be obtained by purification using ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column conjugated with CAPRIN-1 protein or partial peptide, etc. In addition, when obtaining monoclonal antibodies from non-human animals, it can be obtained by collecting immune cells from the immunized animal and performing cell fusion with myeloma cells. The cell fusion of the immune cells and myeloma cells can be carried out according to well-known methods (refer to Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).

[0120] The antibodies used in the present invention can also be obtained as recombinant antibodies by cloning the antibody gene from a hybridoma, integrating it into an appropriate vector, introducing it into a host, and producing it using genetic recombination techniques (refer to Carl, A. K. Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).

[0121] The anti-CAPRIN-1 antibody used in the present invention may be an antibody in which amino acids in the variable region (e.g., FR) or constant region are replaced with other amino acids. The amino acid replacement is for 1 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 replacements. The antibody after replacement should have the property of specifically binding to the antigen and a binding affinity for the antigen equal to or higher than that of the non-replaced antibody, and should not cause rejection when applied to humans. The amino acid replacement is desirably a conservative amino acid replacement, which is a replacement 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), non-polar amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched-chain amino acids (threonine, valine, isoleucine), aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine), etc.

[0122] The higher the binding affinity of the anti-CAPRIN-1 antibody used in the present invention for the CAPRIN-1 protein on the surface of cancer cells, the stronger the anti-tumor effect can be expected. The desired 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 。

[0123] The ability of the anti-CAPRIN-1 antibody to bind to CAPRIN-1 can be specified, for example, by a binding assay using methods such as ELISA, Western blotting, immunofluorescence, and flow cytometry.

[0124] The anti-CAPRIN-1 antibody used in the present invention can be chemically modified. As such an antibody conjugate, for example, antibodies conjugated with various molecules such as polyethylene glycol (PEG), anti-tumor compounds (e.g., anti-tumor agents exemplified below) can be mentioned. In the antibody conjugate of the present invention, the conjugated substance is not limited. In order to obtain such an antibody conjugate, it can be obtained by subjecting the obtained antibody to chemical modification. These methods have been established in the art.

[0125] The anti-CAPRIN-1 antibody used in the present invention can enhance 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 removing fucose that binds to N-acetylglucosamine in the N-glycoside sugar chain bound to the heavy chain constant region. The above can be a single amino acid substitution, or alternatively, a composition with an antibody conjugated with fucose.

[0126] Antibodies in which one, two or several amino acids in the heavy chain constant region have been substituted can be prepared with reference to, for example, WO2004 / 063351, WO2011 / 120135, U.S. Patent No. 8388955, WO2011 / 005481, U.S. Patent No. 6737056, WO2005 / 063351.

[0127] Antibodies in which fucose attached to N-acetylglucosamine in the N-glycoside sugar chain in the heavy chain constant region has been removed, or cells that produce such antibodies, can be prepared with reference to U.S. Patent No. 6602684, European Patent No. 1914244, U.S. Patent No. 7579170. A composition of an antibody in which fucose that binds to N-acetylglucosamine in the N-glycoside sugar chain bound to the heavy chain constant region has been removed and an antibody conjugated with fucose, or cells that produce such a composition, can be prepared with reference to, for example, U.S. Patent No. 8642292.

[0128] The polyclonal antibody against CAPRIN-1, monoclonal antibody against CAPRIN-1, method for producing the antibody, method for purifying the antibody, and method for producing the CAPRIN-1 protein or its partial polypeptide for immunization used in the present invention can be obtained with reference 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.

[0129] As a specific example of the anti-CAPRIN-1 antibody in the present invention, 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 can be cited. However, the following antibodies can be cited as preferred anti-CAPRIN-1 antibodies.

[0130] An antibody or its fragment having immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in 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, further preferably 95% or more, and even more preferably 99% or more) with respect to the amino acid sequence.

[0131] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in 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, and still more preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains a heavy chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 36, 37, and 38 and a light chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 40, 41, and 42 and has immunoreactivity with the CAPRIN-1 protein; or an antibody or a fragment thereof that contains a heavy chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 140, 141, and 142 and a light chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 143, 144, and 145 and has immunoreactivity with the CAPRIN-1 protein; or an antibody or a fragment thereof that contains a heavy chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 164, 165, and 166 and a light chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 167, 168, and 169 and has immunoreactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 43; or an antibody or a fragment thereof in which 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; or an antibody or a fragment thereof in which 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.

[0132] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 33 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, and still more preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains a heavy chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 60, 61, and 62 and a light chain variable region comprising complementary determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 64, 65, and 66 and has immunoreactivity with the CAPRIN-1 protein. More preferably, it is an antibody or a fragment thereof in which 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.

[0133] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 32 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, and further preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 52, 53, and 54 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 56, 57, and 58 and has immunoreactivity 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: 55 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 59.

[0134] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in 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, and further preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity with a CAPRIN-1 protein; or an antibody or a fragment thereof that contains 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 immunoreactivity 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: 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.

[0135] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in 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, and further preferably 95% or more) with respect to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity with the CAPRIN-1 protein; or an antibody or a fragment thereof that contains 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 immunoreactivity 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: 84 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 85; or an antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 86 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 87.

[0136] An antibody or a fragment thereof that contains 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 immunoreactivity with the CAPRIN-1 protein. 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: 47 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 51.

[0137] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 296 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, and further preferably 95% or more) with respect to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 has immunoreactivity 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.

[0138] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 297 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) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity 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.

[0139] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 298 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) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity 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: 120 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 121.

[0140] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 299 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) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains a heavy chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 300, 301, and 302 and a light chain variable region containing the complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 304, 305, and 306 and has immunoreactivity 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: 303 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 307.

[0141] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 308 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity 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.

[0142] An antibody or a fragment thereof that has immunoreactivity with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence shown in SEQ ID NO: 309 or an amino acid sequence having a sequence identity of 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) relative to the amino acid sequence. Preferably, it is an antibody or a fragment thereof that contains 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 immunoreactivity 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.

[0143] In addition, the following anti-CAPRIN-1 antibodies are also preferably used.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 74 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 75.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 303 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 307.

[0178] In the following examples, by combining the above-mentioned polyclonal antibody or monoclonal antibody against the full-length of the CAPRIN-1 protein or the partial polypeptide of the region expressed on the cell membrane surface of cancer cells with a pharmaceutical combination comprising an anthracycline agent and a platinum preparation, or an anthracycline agent, a platinum preparation and an angiogenesis inhibitor, a strong anti-tumor effect thereof was confirmed in a cancer-bearing organism.

[0179] <Anthracycline Agents>

[0180] Although not particularly limited, examples of anthracycline agents include doxorubicin, liposomal doxorubicin, aclarubicin, amrubicin, epirubicin, zinostatin stimalamer, daunorubicin, pirarubicin, bleomycin, peplomycin, mitomycin C, mitoxantrone, actinomycin D, idarubicin preparations and pharmaceutically acceptable salts or derivatives thereof, more preferably doxorubicin or liposomal doxorubicin hydrochloride preparation (PLD), and more preferably PLD.

[0181] <Platinum Preparations>

[0182] The so-called platinum preparation is a metal complex in which the central metal is composed of platinum and four ligands are present in the same plane. It is a medicament that forms a cis-form with an amine as one of the ligands and coordinates with the guanine base of DNA to exert an anti-tumor effect, and may contain an appropriate isotonic agent or pH adjuster or an appropriate dosage form for administration to an organism. Although not particularly limited, specific examples of platinum preparations include carboplatin, cisplatin, oxaliplatin, nedaplatin, miriplatin, and more preferably carboplatin.

[0183] <Angiogenesis Inhibitors>

[0184] An angiogenesis inhibitor is an agent that inhibits the migration and proliferation of vascular endothelial cells and hinders angiogenesis, preferably an anti-VEGF inhibitor and / or an anti-vascular endothelial growth factor receptor (VEGFR) inhibitor. Although not particularly limited, specific examples of anti-VEGF inhibitors include Bevacizumab, Ranibizumab, and Ziv-Aflibercept. In addition, specific examples of anti-vascular endothelial growth factor receptor (VEGFR) inhibitors include Ramucirumab, Axitinib, Cabozantinib, Regorafenib, Sorafenib, Sunitinib, Vandetanib, Pazopanib, and Lenvatinib mesylate, with Bevacizumab being preferred.

[0185] <Other agents>

[0186] The drug of the present invention can be further combined with antitumor agents known in the literature and the like, but it is characterized by not being combined with pyrimidine-based agents from the perspective of safety. Examples of pyrimidine-based agents include fluorouracil (5-FU) or tegafur, which is a prodrug of fluorouracil, tegafur / uracil (UFT), tegafur / gimeracil / oteracil potassium (S-1), capecitabine, carmofur, floxuridine, gemcitabine (GEM), doxifluridine, preparations of cytarabine, or their derivatives.

[0187] There is no particular limitation on the well-known anti-tumor agents that can be used in combination with the drugs of the present invention. Specific examples include paclitaxel, albumin-bound paclitaxel, cyclophosphamide, methotrexate, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, blatasin, blatasinone, camptothecin, bryostatin, callystatin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, methoxymethaneamine hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, dynemicin, clodronic acid, esperamicin, aclacinomycin, authramycin, azaserine, cactinomycin, carabicin, erythromycin, carzinophilin, chromomycin, actinomycin D, detorbicin, 6-diazo-5-oxo-L-norleucine, idarubicin, marcellomycin, mycophenolicacid), nogalamycin, olivomycins, potfiromycin, puromycin, quelamycin, rodorubicin, streptothricin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, thioguanine, thiopurine, ancitabine, azauridine, didoxuridine, floxuridine, androgens such as calusterone, drostanolone propionate, cyclotestosterone, methyltestosterone, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, glucuronolactone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, defofamine, demecolcine, diaziquone, eflornithine, elliptinium acetate, epothilone, etoglucid, lentinan, lonidamine, maytansine, ansamitocine, mitoguazone, mopidanmol, nitraerine, phenamet, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonicacid), triaziquone, roridine A, anguidine, polyurethane, vindesine, dacarbazine, mannomustine, dibromomannitol, pipobroman, gacytosine, docetaxel, 6-thioguanine, mercaptopurine, vinblastine, etoposide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, ibandronate, irinotecan, topoisomerase inhibitor, difluoromethylornithine (DMFO), retinoic acid, and pharmaceutically acceptable (known) salts or (known) derivatives thereof.

[0188] <Anti-tumor effect of the present invention>

[0189] By investigating the anti-tumor effect of the drug of the present invention on cancer in vivo or in vitro, the anti-tumor effect can be evaluated. As a specific example, it can be evaluated by administering the drug of the present invention to an organism having cancer, measuring the size of the tumor after administration, and investigating the size of the cancer over time. In addition, it can also be evaluated by the survival rate of the organism having cancer after administering the drug of the present invention. In addition, it can also be evaluated by investigating the production ability of cytokines or chemokines. In addition, further, it can also be evaluated by investigating the prevention of cancer, the prevention of metastasis, or the prevention of recurrence.

[0190] The administration of the drug of the present invention to a cancer organism enhances the anti-tumor effect as described above compared to a single anti-CAPRIN-1 antibody, and the enhancement rate is preferably 30% or more, more preferably 40% or more, further preferably 50% or more, further more preferably 55% or more, further more preferably 60% or more, further more preferably 65% or more, and most preferably 70% or more. The enhancement rate of the anti-tumor effect of the drug of the present invention relative to the administration of a single anti-CAPRIN-1 antibody can be calculated by administering an effective amount to cancer-bearing mice under the same conditions and comparing the tumor volume after the 7th day from the start of administration.

[0191] <Drug for the treatment and / or prevention of cancer>

[0192] The drug of the present invention is for the purpose of treating and / or preventing cancer. The cancer that is the target of the drug of the present invention is not particularly limited as long as it is a cancer (cell) that expresses the CAPRIN-1 protein.

[0193] As used in this specification, "treatment" refers to the treatment of cancer based on the anti-tumor effect described above. In addition, "prevention" as used in this specification refers not only to the prevention of the occurrence of cancer, but also to the prevention of metastasis or recurrence of cancer.

[0194] As used in this specification, the terms "tumor" and "cancer" refer to malignant neoplasms and are used interchangeably.

[0195] As the cancer targeted in the present invention, any cancer can be used as long as it expresses CAPRIN-1 protein on the cell membrane surface. Preferred are ovarian cancer, cholangiocarcinoma, breast cancer, renal cancer, pancreatic cancer, colorectal cancer, melanoma (including postoperative melanoma), lung cancer (including non-small cell lung cancer, small cell lung cancer), renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, gastric cancer, mesothelioma (including malignant pleural mesothelioma), colon / rectal cancer (e.g., colon / rectal cancer with MSI-high), esophageal cancer, esophagogastric junction cancer, hepatocellular carcinoma, glioblastoma, urothelial cancer, bladder cancer, uterine cancer (including cervical cancer, corpus 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 sarcoma, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer. In addition, these cancers can be primary cancer, metastatic cancer, metastasized cancer or recurrent cancer, postoperative cancer, or inoperable cancer. Furthermore, melanoma is often used synonymously with malignant melanoma or malignant melanoma.

[0196] In addition, as the cancer targeted in the present invention, cancers resistant to known treatment methods can be cited. The cancer with resistance can be cancer derived from patients with any treatment history, without particular limitation. For example, for cancer derived from patients with a treatment history of using 5-FU, it is a cancer resistant after administration, metastasized cancer or recurrent cancer.

[0197] The cancer more specifically includes, for example, ovarian epithelial cancer, embryonal carcinoma, sex cord-stromal tumor, primary peritoneal cancer, Bowen's disease, melanoma, squamous cell carcinoma, extramammary Paget's disease, mycosis fungoides, Sézary syndrome, cutaneous T / NK cell lymphoma, T cell leukemia / lymphoma with only skin lesions, cutaneous B cell lymphoma (indolent group), cutaneous T cell lymphoma breast cancer, complex breast cancer, malignant mixed tumor of breast, intraductal papillary adenocarcinoma of breast, adenocarcinoma of lung, squamous cell carcinoma of lung, small cell carcinoma of lung, large cell carcinoma of lung, glioma as a neuroepithelial tissue tumor, glioblastoma, neuroblastoma, ependymoma, neuronal tumor, fetal-type neuroectodermal tumor, schwannoma, neurofibroma, meningioma, chronic lymphocytic leukemia, lymphoma, lymphoma of digestive tract, lymphoma of digestive organs, small to medium cell type lymphoma, cecal cancer, ascending colon cancer, descending colon cancer, transverse colon cancer, sigmoid colon cancer, rectal cancer, stromal cell tumor, pancreatic duct cancer, invasive pancreatic duct cancer, adenocarcinoma of pancreatic cancer, acinar cell carcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous tumor of pancreas, mucinous cystadenocarcinoma, pancreatoblastoma, pancreatic head cell tumor, Frantz tumor, serous cystadenocarcinoma, solid papillary carcinoma, gastrinoma, glucagonoma, insulinoma, multiple endocrine neoplasia syndrome 1 (Wermer syndrome), non-functional islet cell tumor, somatostatinoma, VIP-producing tumor, cervical cancer, endometrial cancer, fibrosarcoma, bone and joint sarcoma, Ewing sarcoma, nephroblastoma (Wilms' tumor), hepatoblastoma, soft tissue sarcoma, acute leukemia, chronic leukemia, spinal cord tumor, soft tissue malignant tumor, teratocarcinoma tumor, head and neck cancer including hypopharyngeal cancer, mid-pharyngeal cancer, tongue cancer, upper pharyngeal cancer, oral cancer, lip cancer, sinus cancer, laryngeal cancer, pyeloureteral cancer, bladder cancer, urethral cancer, testicular tumor, malignant pleural mesothelioma, malignant bone tumor, endometrial cancer, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, neuroblastoma, nephroblastoma, retinoblastoma, central nervous system embryonal cell tumor, Ewing sarcoma family tumor), serous tumor (including serous borderline malignant tumor (SBT)), mucinous tumor, surface epithelial borderline malignant tumor, interstitial borderline malignant tumor, etc., but not limited to these. Additionally, it includes palpable cancer with the above-mentioned cancer as the primary, cancer present in the subcutaneous tissue, cancer present in the dermis, superficial cancer, cancer present in the dermis or cancer present in non-solid organs, progressive cancer. Additionally, it includes palpable cancer, cancer present in the subcutaneous tissue, cancer present in the dermis, superficial cancer, cancer present in the dermis or cancer present in non-solid organs that is primary to the above-mentioned cancer and can be palpated through metastasis or recurrence.

[0198] The cancer patients to whom the drug of the present invention is administered are not particularly limited. Specific examples include cancer patients with a history of cancer treatment using drugs other than the cancer treatment using the drug of the present invention. Such cancer patients also include patients who have been treated with chemotherapeutic agents, molecular target drugs, or hormone therapy in the past, and cancer patients who have been treated with cancer treatment in accordance with the "NCCN Clinical Practice Guidelines in Oncology", "ESMO Clinical Practice Guidelines", or "Cancer Treatment Guidelines". More preferably, they are cancer patients with a history of cancer treatment using at least one of anthracycline agents (e.g., doxorubicin, liposomal doxorubicin hydrochloride (PLD)), platinum agents (e.g., carboplatin, cisplatin, oxaliplatin, nedaplatin, miboplatin), and angiogenesis inhibitors (e.g., bevacizumab). More preferably, they are cancer patients sensitive to platinum agents.

[0199] In addition, as the cancer patients with the above-mentioned history, more preferably, they are cancer patients with cancer resistant to cancer treatment using drugs other than the cancer treatment using the drug of the present invention.

[0200] In addition, the preferred subjects (patients) to whom the present invention is applicable are mammals, such as mammals including primates, pets, domestic animals, sports animals, etc. Particularly preferably, they are humans, dogs, and cats.

[0201] The drug of the present invention can be formulated by methods well-known to those skilled in the art. The drug of the present invention can be used parenterally in the form of, for example, a sterile solution or a suspension injection in water or a pharmaceutically acceptable liquid other than water. In the drug of the present invention, for each preparation or pharmaceutical composition, its active ingredient (at least one of an anti-CAPRIN-1 antibody, an anthracycline agent, a platinum agent, and an angiogenesis inhibitor) can be appropriately combined with, for example, a pharmacologically acceptable carrier, medium, or additive, specifically, sterilized water, physiological saline, isotonic solution, buffer (buffer solution, etc.), vegetable oil, oily liquid, antioxidant, solubilizer, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, binder, etc. Preferably, it can be formulated by mixing them in a unit dosage form required for pharmaceutical implementation generally considered. The amount of the active ingredient in these preparations is an amount such that an appropriate dosage within the indicated range can be obtained.

[0202] Sterile compositions for injection can be formulated according to usual pharmaceutical practices using a vehicle such as distilled water for injection. Examples of aqueous injection solutions include, for example, physiological saline, isotonic solutions containing glucose and / or other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and can also be used in combination with suitable solubilizers such as alcohols, specifically ethanol, polyols such as propylene glycol, polyethylene glycol, and nonionic surfactants such as polysorbate 80 (TM), HCO-60. Examples of oily liquids include sesame oil and soybean oil, which can also be used in combination with benzyl benzoate and benzyl alcohol as solubilizers. In addition, it can be combined with buffers such as phosphate buffer, sodium acetate buffer, analgesics such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into appropriate ampoules.

[0203] Administration is by oral or parenteral routes, preferably parenteral administration. Specifically, examples include injection dosage forms, nasal administration dosage forms, pulmonary administration dosage forms, transdermal administration forms, etc. As an example of an injection dosage form, it can be administered systemically or locally, for example, by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intratumoral injection, etc. As an example of a transdermal administration form, for example, it is a dosage form called a liniment or an external preparation. Examples of external preparations include solid preparations, liquid preparations, sprays, ointments, creams, or gels.

[0204] In addition, an appropriate administration method can be selected according to the patient's age, weight, gender, symptoms, etc. As the administration amount of the pharmaceutical composition containing at least one of the active ingredients of the drug of the present invention, in terms of the amount of each active ingredient, for example, it can be selected in the range of 0.0001 mg to 1000 mg per 1 kg body weight per administration. Or, for example, it can be selected in the range of 0.001 to 100000 mg / individual per patient, or for example, 1 mg to 30 mg per 1 kg body weight of the patient, but is not necessarily limited to these values. The administration amount and administration method vary depending on the patient's weight, age, gender, symptoms, etc., and can be appropriately selected by those skilled in the art.

[0205] <Administration Method>

[0206] The treatment and / or prevention of cancer using the medicament of the present invention includes various forms in addition to administration as the aforementioned medicament. For example, the active ingredients of the medicament of the present invention can be administered simultaneously in parallel or sequentially one by one. As a specific example, the second, third, and fourth active ingredients can be administered within a time interval of about 3 weeks, that is, in the range from after the administration of the first active ingredient to about 3 weeks. At this time, it can be carried out after surgical treatment, or surgical treatment can be carried out between the administration of the first medicament and the second, third, and fourth medicaments. In addition, the medicament for the treatment and / or prevention of cancer of the present invention can be administered according to multiple administration cycles. For example, in the case of simultaneous administration of the active ingredients of the medicament for the treatment and / or prevention of cancer of the present invention, the pharmaceutical composition containing the active ingredient of the present invention is administered in a cycle of about 2 days to about 3 weeks. Then, according to the judgment of the doctor in charge of the cycle, the treatment cycle can be repeated as needed. Similarly, when planning a sequential prescription, the administration period of each medicament is adjusted to the same period. The interval between cycles can vary from 0 to 2 months. The administration amount of each active ingredient of the medicament for the treatment and / or prevention of cancer of the present invention can be set in the same manner as the administration amount of each active ingredient in the above pharmaceutical composition.

[0207] <Pharmaceutical kit>

[0208] The medicament of the present invention can be in the form of a pharmaceutical kit. A pharmaceutical kit refers to a package for using active ingredients in the form of a single pharmaceutical composition in a method for treating and / or preventing cancer, and the package can include instructions for using 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. In addition, in order to be able to administer each active ingredient according to the above administration method, the pharmaceutical kit contains an amount of active ingredient sufficient for one or more dosages.

[0209] <Treatment and / or prevention method>

[0210] Based on the above specifically described content, the present invention provides the above medicament of the present invention, or a method for treating and / or preventing cancer including administering the medicament of the present invention to a subject (patient). For example, the present invention further provides a method for treating and / or preventing cancer, including administering the above medicament of the present invention and the like to a subject (patient) having cancer or suspected of having cancer. In the method of the present invention, in addition to the medicament of the present invention, other anti-tumor agents (known anti-tumor agents, etc.) (however, pyrimidine-based agents are not administered) can also be administered to the subject (patient). In addition, in its embodiments, for example, the agents that are the active ingredients of the medicament of the present invention are administered to the above subject (patient) simultaneously or separately.

[0211] In addition, the present invention provides a medicament for use in combination with other medicaments in the above-described method for treating and / or preventing cancer, which comprises one or more selected from an antibody or a fragment thereof having immunoreactivity with CAPRIN-1 protein, an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor as active ingredients (however, a pyrimidine-based agent is not included as an active ingredient). When the medicament contains a plurality of active ingredients, each ingredient may be contained together or separately.

[0212] <Pharmacodynamic enhancer>

[0213] Based on the above-described specific content, the present invention provides any pharmacodynamic enhancer of an antibody or a fragment thereof having immunoreactivity with CAPRIN-1 protein, an anthracycline agent, and a platinum preparation, which are the active ingredients of the above-described medicament of the present invention. The medicament whose efficacy is enhanced by the pharmacodynamic enhancer contains an active ingredient not contained in the pharmacodynamic enhancer, and one or both of the pharmacodynamic enhancer and the medicament do not contain a pyrimidine-based agent as an active ingredient. The pharmacodynamic enhancer and / or the medicament whose efficacy is enhanced may further contain an angiogenesis inhibitor as an active ingredient. Specifically, for example, when the pharmacodynamic enhancer contains an anti-CAPRIN-1 antibody, the medicament whose efficacy is enhanced may contain an anthracycline agent and a platinum preparation, or may contain an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor. When the pharmacodynamic enhancer contains an anthracycline agent and a platinum preparation, or contains an anthracycline agent, a platinum preparation, and an angiogenesis inhibitor, the medicament may contain an anti-CAPRIN-1 antibody.

[0214] For example, when the pharmacodynamic enhancer and / or the medicament whose efficacy is enhanced contains a plurality of active ingredients, the agent and / or the medicament may contain each ingredient together or separately. Preferably, the above-described method for treating and / or preventing cancer of the present invention can be implemented by including an effective amount of an anti-CAPRIN-1 antibody, or an anthracycline agent and a platinum preparation, in at least either the pharmacodynamic enhancer or the medicament whose efficacy is enhanced, or by using the pharmacodynamic enhancer and the medicament whose efficacy is enhanced. In this case, either the pharmacodynamic enhancer or the medicament whose efficacy is enhanced may not contain an effective amount of an active ingredient, or the same active ingredient may be contained in both.

[0215] Examples

[0216] 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.

[0217] (Example 1) Preparation of anti-CAPRIN-1 antibody

[0218] In the present invention, an anti-CAPRIN-1 antibody having immunoreactivity with CAPRIN-1 protein is used, and the antibody prepared as follows is used.

[0219] (Polyclonal antibody)

[0220] 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 amount of MPL+TDM adjuvant (manufactured by Sigma), and the mixture was administered subcutaneously to rabbits every two weeks for a total of 4 times. Then, blood was collected to obtain antiserum containing polyclonal antibodies. Further, the antiserum was purified using a Protein G support (manufactured by GE Healthcare Biosciences), and replaced with PBS(-) to obtain a polyclonal antibody against CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody #1).

[0221] (Monoclonal antibody)

[0222] 100 μg of human recombinant CAPRIN-1 protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal amount of MPL+TDM adjuvant (manufactured by Sigma), and this was used as the antigen solution for each mouse. After administering the antigen solution intraperitoneally to 6-week-old Balb / c mice (manufactured by Japan SLC), it was further administered 3 times and 24 times at 1-week intervals to complete the immunization. Each spleen removed 3 days after the last immunization was ground by clamping with 2 sterilized glass slides, and the operation of washing with PBS(-) (manufactured by Nissui), centrifuging at 1500 rpm for 10 minutes, and removing the supernatant was repeated 3 times to obtain spleen cells. The obtained spleen cells were mixed with mouse myeloma cells SP2 / 0 (purchased from ATCC) at a ratio of 10:1, and 200 μL of RPMI1640 medium containing 10% FBS warmed to 37°C and 800 μL of PEG1500 (manufactured by Boehringer) were mixed to prepare a PEG solution, and the mixture was allowed to stand for 5 minutes to perform cell fusion. Centrifuged at 1700 rpm for 5 minutes to remove the supernatant, and then the cells were suspended in 150 ml of RPMI1640 medium containing 15% FBS with 2% equivalent of HAT solution (Gibco) (HAT selection medium) and inoculated into 15 plates at 100 μl per well of a 96-well plate (manufactured by Nunc). Cultured under the conditions of 7 days, 37°C, and 5% CO2 to obtain hybridomas formed by the fusion of spleen cells and myeloma cells. The hybridomas were screened using the binding affinity of the antibodies produced by the prepared hybridomas to the CAPRIN-1 protein as an index. 100 μL of 1 μg / ml CAPRIN-1 protein solution was added to each well of a 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well 3 times with PBS-T, 400 μL of 0.5% bovine serum albumin (BSA) solution (manufactured by Sigma) was added to each well and allowed to stand at room temperature for 3 hours. The solution was removed, and after washing each well 3 times with 400 μL of PBS-T, 100 μL of each culture supernatant of the above-obtained hybridomas was added to each well and allowed to stand at room temperature for 2 hours. After washing each well 3 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 to each well and allowed to stand at room temperature for 1 hour. After washing the wells 3 times with PBS-T, 100 μl of TMB substrate solution (manufactured by Thermo) was added to each well and allowed to stand for 15 - 30 minutes to perform a color development reaction. After color development, 100 μl of 1N sulfuric acid was added to each well to stop the reaction, and the absorbance values at 450 nm and 595 nm were measured using a spectrophotometer. As a result, multiple hybridomas producing antibodies with high absorbance values were screened out. The screened hybridomas were added to the plate at 0.5 per well of a 96-well plate for culture. One week later, hybridomas forming single colonies were observed in the wells.The cells in these wells were further cultured, and hybridomas were screened using the binding affinity of the antibody produced by the cloned hybridoma to the CAPRIN-1 protein as an index. 1 μg / ml of the CAPRIN-1 protein solution was added at 100 μL per well in a 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well 3 times with PBS-T, 400 μL of 0.5% BSA solution was added to each well and allowed to stand at room temperature for 3 hours. The solution was removed, and after washing each well 3 times with 400 μL of PBS-T, 100 μL of each culture supernatant of the above-obtained hybridomas was added to each well and allowed to stand at room temperature for 2 hours. After washing each well 3 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 to each well and allowed to stand at room temperature for 1 hour. After washing the wells 3 times with PBS-T, 100 μL of TMB substrate solution (manufactured by Thermo) was added to each well and allowed to stand for 15 to 30 minutes to perform a color development reaction. After color development, 100 μL of 1N sulfuric acid was added to each well to stop the reaction, and the absorbance values at 450 nm and 595 nm were measured using a spectrophotometer. As a result, multiple mouse monoclonal antibodies reactive to the CAPRIN-1 protein were obtained.

[0223] Furthermore, the reactivity to human cancer cells, which are cells that have been confirmed to express the CAPRIN-1 protein on the cell membrane surface, was confirmed by flow cytometry. A mouse IgG control antibody that does not show reactivity with the cancer cells was used as a negative control. As a result of the confirmation, several monoclonal antibodies with stronger fluorescence intensity compared to the mouse IgG control antibody and strongly reactive to the cell membrane surface of the above cancer cells expressing CAPRIN-1 on the cell membrane surface were obtained for the cancer cells. Among them, as a monoclonal antibody reactive to the CAPRIN-1 protein, the antibody containing the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 114 and the amino acid sequence of the light chain variable region shown in SEQ ID NO: 115, which is the monoclonal antibody against CAPRIN-1 described in WO2013 / 125630, was screened out.

[0224] The CDR1-3 of the heavy chain variable region of the specifically selected antibody were designed such that the base sequence became the heavy chain variable region with a human antibody sequence as the framework region, and this was inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 had already been inserted. Similarly, the CDR1-3 of the light chain variable region were designed such that the base sequence became the light chain variable region with a human antibody sequence as the framework region, and this was inserted into a mammalian expression vector into which the light chain constant region of human IgG1 had already been inserted. The above two recombinant expression vectors were introduced into mammalian cells by a conventional method, and a culture supernatant containing the humanized monoclonal antibody #1 against CAPRIN-1 (humanized antibody #1) was obtained.

[0225] The obtained culture supernatant containing the humanized anti-CAPRIN-1 monoclonal antibody #1 was purified by 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) to prepare it.

[0226] The specific reactivity of the above anti-CAPRIN-1 antibody with the CAPRIN-1 protein was confirmed by immobilizing the CAPRIN-1 protein on a plate and detecting it by ELISA.

[0227] In addition, the reactivity with cancer cells that had not undergone cell membrane permeabilization treatment was investigated using the above anti-CAPRIN-1 antibody by flow cytometry, and as shown in the following examples, it was confirmed that a part of CAPRIN-1 was expressed on the cell membrane surface of cancer cells.

[0228] It was confirmed by flow cytometry that for any cancer cells of human breast cancer cells (BT-474), colorectal 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) and mouse breast cancer cells (4T1) in which the expression of the gene of CAPRIN-1 was confirmed, the fluorescence intensity of the humanized antibody #1 was stronger than that of the human IgG control antibody and rabbit IgG antibody that did not show reactivity to cancer cells as negative controls, and it was confirmed that it strongly reacted with the cell membrane surface of the above cancer cells expressing CAPRIN-1.

[0229] Similarly, for each anti-CAPRIN-1 antibody of (a) to (aa) and (ac) to (al) 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, it was also confirmed that they strongly reacted with the above cancer cell membrane surface.

[0230] (Example 2) Antitumor effect produced by the combination of anti-CAPRIN-1 antibody and doxorubicin hydrochloride liposomal preparation (PLD) / carboplatin (CBDCA) therapy in a human cancer cell-bearing mouse model

[0231] The antitumor effect in the body of a cancer-bearing mouse produced by the combination of the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 and doxorubicin hydrochloride liposomal preparation (PLD) / carboplatin (CBDCA) therapy was evaluated.

[0232] Specifically, using NOD-SCID mice subcutaneously transplanted with human-derived cancer cells expressing the CAPRIN-1 protein, the anti-tumor effect produced by the combination of the anti-CAPRIN-1 antibody of the present invention and the doxorubicin hydrochloride liposomal preparation (PLD) / carboplatin (CBDCA) therapy was studied. For each mouse, 2×10 7 human breast cancer cells BT-474 were mixed with Matrigel (Corning) and transplanted subcutaneously to grow the tumor to about 100-200 mm 3 , thereby producing cancer-bearing mice. BT-474 expresses the CAPRIN-1 protein on the cell membrane surface and is a cancer cell that confirmed the reaction of the anti-CAPRIN-1 antibody prepared in Example 1 with a part of CAPRIN-1 located on the cell membrane surface. The anti-CAPRIN-1 antibody prepared in Example 1 was administered to the tail vein of each of the 5 above-mentioned cancer-bearing mice at 10 mg / kg, once a week for a total of 4 times. Simultaneously with the administration of the anti-CAPRIN-1 antibody, the doxorubicin hydrochloride liposomal preparation (PLD) was administered intravenously at 1 mg / kg, and carboplatin (CBDCA) was administered intraperitoneally at 15 mg / kg. The doxorubicin hydrochloride liposomal preparation (PLD) and carboplatin (CBDCA) were each administered once a week for a total of 4 times (anti-CAPRIN-1 antibody / PLD / CBDCA combination administration group).

[0233] As a comparative control group, the same anti-CAPRIN-1 antibody as above was administered to the cancer-bearing mice once a week in an equal amount (anti-CAPRIN-1 antibody administration group). Furthermore, as a comparative control group, to other cancer-bearing mouse individuals, only the doxorubicin hydrochloride liposomal preparation (PLD) / carboplatin (CBDCA) was administered at the same administration interval (PLD / CBDCA combination administration group). Furthermore, cancer-bearing mice in a specified carrier administration group were used as negative controls. After the start of administration, the size of the cancer in the cancer-bearing mice was measured over time using vernier calipers, and the tumor volume was calculated for each individual by the formula: (length of the major axis of the cancer)×(length of the minor axis of the cancer) 2 ×0.5, and the average value of the administration group was calculated.

[0234] The evaluation results showed that about 1 week after the end of the drug administration (the 45th day after cancer-bearing), when the tumor volume of the negative control was 100%, the tumor volumes of the anti-CAPRIN-1 antibody administration group and the PLD / CBDCA combination administration group as comparative control groups were both 45% or more. In contrast, the tumor volume of the anti-CAPRIN-1 antibody / PLD / CBDCA combination administration group was 25% or less, showing a significant anti-tumor effect compared with the PLD / CBDCA combination administration group.

[0235] Similarly, for each of the anti-CAPRIN-1 antibodies of (a)-(aa) and (ac)-(al) 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, it was also confirmed that the combination with the PLD / CBDCA therapy had a significantly stronger antitumor effect compared to the individual anti-CAPRIN-1 antibody and the PLD / CBDCA therapy.

[0236] The results of this evaluation showed that the combination of an anti-CAPRIN-1 antibody with a liposomal doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) therapy had a significantly stronger antitumor effect compared to the individual anti-CAPRIN-1 antibody and the liposomal doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) therapy.

[0237] (Example 3) Antitumor effect produced by the combination of an anti-CAPRIN-1 antibody with a liposomal doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) / bevacizumab (hereinafter referred to as BVZ) therapy in a human cancer cell-bearing mouse model

[0238] The antitumor effect in the body of a cancer-bearing mouse produced by the combination of the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 with a liposomal doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy was evaluated.

[0239] Specifically, using NOD-SCID mice subcutaneously transplanted with human-derived cancer cells expressing the CAPRIN-1 protein, the antitumor effect produced by the combination of the anti-CAPRIN-1 antibody of the present invention with the PLD / CBDCA / BVZ therapy was studied. For each mouse, 2×10 7 human breast cancer cells BT-474 were mixed with Matrigel (Corning) and transplanted subcutaneously, and allowed to grow until the tumor reached approximately 100-200 mm3 , thus making cancer-bearing mice. BT-474 expresses the CAPRIN-1 protein on the cell membrane surface, and it is the cancer cells that confirmed the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a part of CAPRIN-1 located on the cell membrane surface. To each of the tail veins of 5 above-mentioned cancer-bearing mice, the anti-CAPRIN-1 antibody prepared in Example 1 was administered at 10 mg / kg, once a week for a total of 4 times. To the same mice, simultaneously with the administration of the anti-CAPRIN-1 antibody, PLD was administered intravenously at 1 mg / kg, CBDCA was administered intraperitoneally at 15 mg / kg, and BVZ was administered intraperitoneally at 1.25 mg / kg. PLD, CBDCA, and BVZ were each administered once a week for a total of 4 times (the combined administration group of anti-CAPRIN-1 antibody / PLD / CBDCA / BVZ).

[0240] As a comparative control group, the same anti-CAPRIN-1 antibody as above was administered to the cancer-bearing mice once a week in an equal amount (the anti-CAPRIN-1 antibody administration group). Furthermore, as a comparative control group, to other individual cancer-bearing mice, only PLD / CBDCA / BVZ was administered at the same administration interval (the combined administration group of PLD / CBDCA / BVZ). Furthermore, the cancer-bearing mice in the group administered with a specified carrier were used as a negative control. After the start of the administration, the size of the cancer in the cancer-bearing mice was measured over time using a vernier caliper, and the tumor volume was calculated for each individual according to the conventional method by the formula: (the length of the major axis of the cancer) × (the length of the minor axis of the cancer) 2 × 0.5, and the average value of the administration group was calculated.

[0241] The result of the evaluation was that about 1 week after the end of the drug administration (the 45th day after cancer-bearing), when the tumor volume of the negative control was 100%, the tumor volumes of the anti-CAPRIN-1 antibody administration group and the combined administration group of PLD / CBDCA / BVZ as the comparative control groups were both 45% or more. In contrast, the tumor volume of the combined administration group of anti-CAPRIN-1 antibody / PLD / CBDCA / BVZ was 15% or less, showing a significant anti-tumor effect compared with the combined administration group of PLD / CBDCA / BVZ.

[0242] Similarly, for each of the anti-CAPRIN-1 antibodies of (a) to (aa) and (ac) to (al) 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, the combination with the PLD / CBDCA / BVZ therapy was also confirmed to have a significantly stronger anti-tumor effect than the anti-CAPRIN-1 antibody alone and the PLD / CBDCA / BVZ therapy.

[0243] The results of this evaluation showed that the combination of the anti-CAPRIN-1 antibody with the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy had a significantly stronger anti-tumor effect than the anti-CAPRIN-1 antibody alone and the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy.

[0244] In addition, in the evaluation results of Example 2 and Example 3, the anti-tumor effect of the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy was at the same level as that of the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) therapy, and no significant enhancement of the anti-tumor effect due to the combination of bevacizumab (BVZ) was observed. On the other hand, the anti-tumor effect produced by the combination of the anti-CAPRIN-1 antibody with the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy was more excellent than the anti-tumor effect of the combination of the anti-CAPRIN-1 antibody with the liposomal doxorubicin hydrochloride preparation (PLD) / carboplatin (CBDCA) therapy, and an enhancement of the anti-tumor effect due to the combination of bevacizumab (BVZ) was observed.

[0245] As described above, the enhancement of the anti-tumor effect produced by the combination of an anti-CAPRIN-1 antibody with a liposomal formulation of doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) therapy, or the enhancement of the anti-tumor effect produced by the combination of an anti-CAPRIN-1 antibody with a liposomal formulation of doxorubicin hydrochloride (PLD) / carboplatin (CBDCA) / bevacizumab (BVZ) therapy is

[0246] an unexpected synergistic effect.

[0247] All journals, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety into this specification.

Claims

1. A medicament for the treatment and / or prevention of cancer, comprising together or separately in combination: an antibody or a fragment thereof that is immunoreactive with the CAPRIN-1 protein, an anthracycline agent, and a platinum preparation. Moreover, the medicament for the treatment and / or prevention of cancer does not contain a pyrimidine agent.

2. The medicament according to claim 1, further comprising together or separately in combination: an angiogenesis inhibitor.

3. The medicament according to claim 1 or 2, wherein the anthracycline agent is doxorubicin or a liposomal formulation of doxorubicin hydrochloride (PLD).

4. The medicament according to any one of claims 1 to 3, wherein the platinum preparation is carboplatin, cisplatin, oxaliplatin, nedaplatin, and / or miloplatin.

5. The medicament according to any one of claims 2 to 4, wherein the angiogenesis inhibitor is bevacizumab.

6. The medicament according to any one of claims 1 to 5, wherein the antibody or a fragment thereof is immunoreactive with the CAPRIN-1 protein, and the CAPRIN-1 protein has an amino acid sequence shown by any even serial number from serial number 2 to 30, or an amino acid sequence having a sequence identity of 80% or more with the amino acid sequence.

7. The medicament according to any one of claims 1 to 6, wherein the antibody or a fragment thereof is immunoreactive with the extracellular region of the CAPRIN-1 protein present on the surface of cancer cells.

8. The medicament according to any one of claims 1 to 7, wherein the antibody or a fragment thereof is immunoreactive with a partial polypeptide of the CAPRIN-1 protein, and the partial polypeptide of the CAPRIN-1 protein has an amino acid sequence shown by any one of serial numbers 31 to 35, 296 to 299, 308, 309, or an amino acid sequence having a sequence identity of 80% or more with the amino acid sequence.

9. The medicament according to any one of claims 1 to 8, wherein the antibody is a monoclonal antibody or a polyclonal antibody.

10. The medicament according to any one of claims 1 to 9, wherein the antibody or a fragment thereof is any one of the following (A) to (M). (A) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains a complementarity-determining region CDR1 shown by serial number 36, a complementarity-determining region CDR2 shown by serial number 37, and a complementarity-determining region CDR3 shown by serial number 38, and the light chain variable region contains a complementarity-determining region CDR1 shown by serial number 40, a complementarity-determining region CDR2 shown by serial number 41, and a complementarity-determining region CDR3 shown by serial number 42. (B) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 44, complementarity-determining region CDR2 shown in SEQ ID NO: 45, and complementarity-determining region CDR3 shown in SEQ ID NO: 46, and the light chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 48, complementarity-determining region CDR2 shown in SEQ ID NO: 49, and complementarity-determining region CDR3 shown in SEQ ID NO: 50; (C) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 52, complementarity-determining region CDR2 shown in SEQ ID NO: 53, and complementarity-determining region CDR3 shown in SEQ ID NO: 54, and the light chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 56, complementarity-determining region CDR2 shown in SEQ ID NO: 57, and complementarity-determining region CDR3 shown in SEQ ID NO: 58; (D) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 60, complementarity-determining region CDR2 shown in SEQ ID NO: 61, and complementarity-determining region CDR3 shown in SEQ ID NO: 62, and the light chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 64, complementarity-determining region CDR2 shown in SEQ ID NO: 65, and complementarity-determining region CDR3 shown in SEQ ID NO: 66; (E) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 170, complementarity-determining region CDR2 shown in SEQ ID NO: 171, and complementarity-determining region CDR3 shown in SEQ ID NO: 172, and the light chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 173, complementarity-determining region CDR2 shown in SEQ ID NO: 174, and complementarity-determining region CDR3 shown in SEQ ID NO: 175; (F) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 176, complementarity-determining region CDR2 shown in SEQ ID NO: 177, and complementarity-determining region CDR3 shown in SEQ ID NO: 178, and the light chain variable region comprises complementarity-determining region CDR1 shown in SEQ ID NO: 179, complementarity-determining region CDR2 shown in SEQ ID NO: 180, and complementarity-determining region CDR3 shown in SEQ ID NO: 181; (G) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 182, complementarity determining region CDR2 shown in SEQ ID NO: 183, and complementarity determining region CDR3 shown in SEQ ID NO: 184, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 185, complementarity determining region CDR2 shown in SEQ ID NO: 186, and complementarity determining region CDR3 shown in SEQ ID NO: 187; (H) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 188, complementarity determining region CDR2 shown in SEQ ID NO: 189, and complementarity determining region CDR3 shown in SEQ ID NO: 190, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 191, complementarity determining region CDR2 shown in SEQ ID NO: 192, and complementarity determining region CDR3 shown in SEQ ID NO: 193; (I) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 146, complementarity determining region CDR2 shown in SEQ ID NO: 147, and complementarity determining region CDR3 shown in SEQ ID NO: 148, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 149, complementarity determining region CDR2 shown in SEQ ID NO: 150, and complementarity determining region CDR3 shown in SEQ ID NO: 151; (J) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 272, complementarity determining region CDR2 shown in SEQ ID NO: 273, and complementarity determining region CDR3 shown in SEQ ID NO: 274, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 275, complementarity determining region CDR2 shown in SEQ ID NO: 276, and complementarity determining region CDR3 shown in SEQ ID NO: 277; (K) An antibody or a fragment thereof that comprises a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 290, complementarity determining region CDR2 shown in SEQ ID NO: 291, and complementarity determining region CDR3 shown in SEQ ID NO: 292, and the light chain variable region comprises complementarity determining region CDR1 shown in SEQ ID NO: 293, complementarity determining region CDR2 shown in SEQ ID NO: 294, and complementarity determining region CDR3 shown in SEQ ID NO: 295; (L) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 300, the complementarity-determining region CDR2 shown in SEQ ID NO: 301, and the complementarity-determining region CDR3 shown in SEQ ID NO: 302, and the light chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 304, the complementarity-determining region CDR2 shown in SEQ ID NO: 305, and the complementarity-determining region CDR3 shown in SEQ ID NO: 306; (M) An antibody or a fragment thereof that contains a heavy chain variable region and a light chain variable region and is immunoreactive with the CAPRIN-1 protein, wherein the heavy chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 134, the complementarity-determining region CDR2 shown in SEQ ID NO: 135, and the complementarity-determining region CDR3 shown in SEQ ID NO: 136, and the light chain variable region contains the complementarity-determining region CDR1 shown in SEQ ID NO: 137, the complementarity-determining region CDR2 shown in SEQ ID NO: 138, and the complementarity-determining region CDR3 shown in SEQ ID NO:

139.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the antibody or its fragment is any one of the following (a) to (al), (a) 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; (b) An antibody or a fragment thereof in which 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 in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 55 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 59; (d) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 63 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 67; (e) 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; (f) 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; (g) 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; (h) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 74 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 75; (i) An antibody or a fragment thereof in which the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 76 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 77; (j) 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; (k) 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; (l) 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. (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; 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; 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; 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; 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; 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; 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; An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 303 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

307.

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

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

14. The medicament according to any one of claims 1 to 13, wherein the cancer is ovarian cancer, 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 / rectal cancer, esophageal cancer, esophagogastric junction cancer, hepatocellular carcinoma, glioblastoma, urothelial cancer, bladder cancer, uterine cancer, primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing sarcoma, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer.

15. A potency enhancer for a medicament for the treatment and / or prevention of cancer, wherein the medicament for the treatment and / or prevention of cancer contains, as an active ingredient, an antibody or a fragment thereof that has immunoreactivity with the CAPRIN-1 protein, and the potency enhancer contains an anthracycline agent and a platinum preparation as active ingredients and does not contain a pyrimidine agent as an active ingredient.

16. The potency enhancer according to claim 15, further containing an angiogenesis inhibitor as an active ingredient.

17. A potency enhancer for a medicament for the treatment and / or prevention of cancer, wherein the medicament for the treatment and / or prevention of cancer contains an anthracycline agent and a platinum preparation as active ingredients and does not contain a pyrimidine agent as an active ingredient, and the potency enhancer contains, as an active ingredient, an antibody or a fragment thereof that has immunoreactivity with the CAPRIN-1 protein.

18. The pharmacodynamic enhancer according to claim 17, wherein the medicament further comprises an angiogenesis inhibitor as an active ingredient.

19. A method for the treatment and / or prevention of cancer, wherein, An antibody or a fragment thereof having immunoreactivity with the CAPRIN-1 protein, and an anthracycline agent and a platinum preparation are administered to a subject together or separately, and a pyrimidine agent is not administered to the subject.

20. The method according to claim 19, further comprising administering an angiogenesis inhibitor to the subject together or separately.