Medicament for treatment and / or prevention of cancer

Abstract

This medicament characterized by containing an antibody or a fragment thereof having an immunological reactivity with a CAPRIN-1 protein together or separately in combination with a topoisomerase I inhibitor is useful as a medicament for treatment and / or prevention of cancer.

Description

Medicines for the treatment and / or prevention of cancer

[0001] The present invention relates to a pharmaceutical for treating and / or preventing cancer using an antibody against CAPRIN-1 protein or a fragment thereof and a topoisomerase I inhibitor.

[0002] Various antibody drugs targeting specific antigen proteins on cancer cells have been applied to cancer treatment as cancer therapeutic drugs with few side effects due to their cancer specificity. For example, cytopasmic-activation and proliferation-associated protein 1 (CAPRIN-1) is expressed on the cell membrane surface of many solid cancers, and antibodies against this CAPRIN-1 protein are known to be promising pharmaceuticals for the treatment and / or prevention of cancer (Patent Document 1).

[0003] In recent clinical trials, the use of multiple anticancer drugs in combination has become standard treatment to enhance the efficacy of cancer treatments. For example, for colorectal cancer, a combination of irinotecan, folinic acid, and fluorouracil is commonly used; for breast cancer, a combination of doxorubicin and cyclophosphamide, or a combination of paclitaxel, trastuzumab, and pertuzumab is commonly used; and for gastric cancer, a combination of multiple anticancer drugs, such as cisplatin and fluorouracil, is commonly used. Cancer treatments containing anti-CAPRIN-1 antibodies as active ingredients have also been shown to have excellent cancer therapeutic effects when used in combination with chemotherapeutic agents (Patent Document 2). However, cancer treatments using combinations of chemotherapeutic agents are not effective against all cancers, and while some may additively enhance therapeutic effects, few significantly synergistically enhance therapeutic effects.

[0004] One specific example of a cancer treatment method that uses multiple cancer therapeutic drugs in combination is the combination of a pyrimidine drug (e.g., gemcitabine) and carboplatin. The combination of gemcitabine and carboplatin, also known as CBDCA+GEM, has been attempted as a treatment for non-small cell lung cancer, recurrent and advanced ovarian cancer, bladder cancer, breast cancer, urothelial cancer, and the like. Ovarian cancer is prone to metastasis into the abdominal cavity, lymph nodes, liver, and lungs, and is an extremely malignant cancer, with more than 50% of cases of advanced ovarian cancer, particularly stage III and stage IV, recurring within two years after initial treatment. Combination therapy with gemcitabine and carboplatin (GC) is used for such metastatic cancers originating from primary ovarian cancer. However, in patients whose PFI (platinum-free interval) from the end of the first chemotherapy to recurrence is 6 months or more (so-called platinum-sensitive patients), the success rate of treatment after recurrence is 40% or more, whereas in patients whose PFI from the end of chemotherapy to recurrence is less than 6 months (so-called platinum-insensitive patients), the success rate of treatment after recurrence is 10% or less, resulting in an extremely poor prognosis (Non-Patent Document 2). A triple combination therapy (GC-BEV) of gemcitabine, carboplatin, and bevacizumab has been approved as an intensive therapy for patients with platinum-sensitive ovarian cancer. In a clinical trial of this triple combination, OCEANS, GC-BEV significantly extended progression-free survival (PFS) compared with GC, but there was no significant difference in median overall survival (OS) (Non-Patent Document 3).

[0005] On the other hand, for patients who are platinum-insensitive, platinum agents such as carboplatin are not permitted under the guidelines, and other treatments are selected. For example, chemotherapeutic agents such as the taxane drugs paclitaxel and docetaxel, the anthracycline drug doxorubicin and its liposomal formulation, and the topoisomerase inhibitors etoposide and topotecan have been approved. Although various administration regimens have been tested, the response rates are only 10-30%, and no satisfactory effects have been achieved (Non-Patent Documents 4-7).

[0006] In recent years, combination therapy using various chemotherapy agents plus the angiogenesis inhibitor bevacizumab has been approved for platinum-insensitive patients. In the clinical trial AURELIA, which examined the additive effect of bevacizumab on chemotherapy, PFS was significantly extended to 6.7 months with bevacizumab compared to 3.4 months with single-agent chemotherapy, but no significant difference was observed in OS, and no life-prolonging effect was achieved (Non-Patent Document 8).

[0007] WO2010 / 016526 WO2011 / 096535

[0008] J Clin Oncol, 2012, 30, 1879-1887 Crit Rev Oncol Hematol, 2007, 64, 129-138 J Clin Oncol, 2012, 30, 2039-2045 J Clin Oncol, 1998, 16, 405-410J Clin Oncol, 2001, 19, 3312-3322J Clin Oncol, 2003, 21, 2843-2848J Clin Oncol, 2008, 26, 890-896J Clin Oncol, 2014, 32, 1302-1308

[0009] An object of the present invention is to provide a pharmaceutical agent for treating and / or preventing cancers that specifically express CAPRIN-1 protein on the cell surface.

[0010] As a result of intensive research, the present inventors have found that the combined use of an antibody against CAPRIN-1 protein or a fragment thereof, which has immunological reactivity with cancer cells, and a topoisomerase I inhibitor exhibits an extremely strong antitumor effect compared to the monotherapy of either agent, that the antitumor effect is a synergistic effect that causes tumor regression, and that the effect is significantly higher than the combined effect with other topoisomerase inhibitors, and have thus completed the present invention.

[0011] Specifically, the present invention has the following features (1) to (13).

[0012] (1) A pharmaceutical for treating and / or preventing cancer, comprising a combination, together or separately, of an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and a topoisomerase I inhibitor.

[0013] (2) The pharmaceutical according to (1), wherein the topoisomerase I inhibitor is topotecan or irinotecan.

[0014] (3) The pharmaceutical according to (1) or (2), wherein the antibody or fragment is an antibody or fragment thereof that is immunologically reactive with a CAPRIN-1 protein having an amino acid sequence represented by any of the even-numbered sequence numbers among SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.

[0015] (4) The pharmaceutical according to any one of (1) to (3), wherein the antibody or fragment thereof has immunological reactivity with the extracellular domain of CAPRIN-1 protein present on the surface of cancer cells.

[0016] (5) The pharmaceutical according to any one of (1) to (4), wherein the antibody or a fragment thereof is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by any one of SEQ ID NOs: 31 to 35, 296 to 299, 308, and 309, or an amino acid sequence having 80% or more sequence identity with said amino acid sequence.

[0017] (6) The pharmaceutical according to any one of (1) to (5), wherein the antibody is a monoclonal antibody or a polyclonal antibody.

[0018] (7) The pharmaceutical according to any one of (1) to (6), wherein the antibody or fragment thereof is any one of the following (A) to (M): (A) an antibody or fragment comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 36, 37, and 38 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 40, 41, and 42 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein; (B) an antibody or fragment comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 44, 45, and 46 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 48, 49, and 50 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (C) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 52, 53, and 54 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 56, 57, and 58 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with the CAPRIN-1 protein. (D) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 60, 61, and 62 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 64, 65, and 66 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with the CAPRIN-1 protein. (E) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 170, 171, and 172 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 173, 174, and 175 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (F) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 176, 177, and 178 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 179, 180, and 181 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein.(G) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 182, 183, and 184 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 185, 186, and 187 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (H) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 188, 189, and 190 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 191, 192, and 193 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (I) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 146, 147, and 148 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 149, 150, and 151 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (J) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 272, 273, and 274 (CDR1, CDR2, and CDR3, respectively), and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 275, 276, and 277 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with CAPRIN-1 protein. (K) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 290, 291 and 292 and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 293, 294 and 295, and having immunological reactivity with the CAPRIN-1 protein. (L) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 301, 302 and 303 and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 305, 306 and 307, and having immunological reactivity with the CAPRIN-1 protein.(M) An antibody or fragment thereof comprising a heavy chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 134, 135, and 136, respectively, and a light chain variable region containing the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 137, 138, and 139, respectively, and having immunological reactivity with a CAPRIN-1 protein.

[0019] (8) The pharmaceutical according to any one of (1) to (7), wherein the antibody or fragment thereof is any one of the following (a) to (a1): (a) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 43; (b) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 51; (c) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 55 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 59; (d) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 67; (e) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 69; (f) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 71. (g) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 73; (h) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 75; (i) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 77; (j) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 79; (k) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 81; (l) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 83. (m) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85.(n) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 87; (o) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 89; (p) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 91; (q) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 93; (r) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 95; (s) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 97. (t) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 99; (u) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 101; (v) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 103; (w) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 105; (x) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 107; (y) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 109. (z) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111; (aa) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113.(ab) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 115; (ac) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 117; (ad) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 119; (ae) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 121; (af) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 123; (ag) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 125. (ah) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 127; (ai) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 129; (aj) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 131; (ak) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 133; (al) an antibody or fragment thereof, whose heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and whose light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.

[0020] (9) The pharmaceutical according to any one of (1) to (8), wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, or a single-chain antibody.

[0021] (10) The pharmaceutical agent according to any one of (1) to (9), wherein the cancer is a cancer that expresses CAPRIN-1 protein on the cell membrane surface.

[0022] (11) The pharmaceutical according to any one of (1) to (10), wherein the cancer is ovarian cancer, bile duct cancer, breast cancer, kidney cancer, pancreatic cancer, colon cancer, melanoma, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial carcinoma, colorectal cancer, esophageal cancer, gastroesophageal 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's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease, or skin cancer.

[0023] (12) A drug efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises as an active ingredient an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein, and which comprises as an active ingredient a topoisomerase I inhibitor.

[0024] (13) A drug efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises as an active ingredient a topoisomerase I inhibitor, and which comprises as an active ingredient an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein.

[0025] (14) A method for treating and / or preventing cancer, comprising administering to a subject an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and a topoisomerase I inhibitor, together or separately.

[0026] The combined use of an antibody against the CAPRIN-1 protein or a fragment thereof according to the present invention with a topoisomerase I inhibitor exhibits a stronger antitumor effect than the combined use of an antibody against the CAPRIN-1 protein alone or the topoisomerase I inhibitor topotecan alone. Furthermore, the combined use of an antibody against the CAPRIN-1 protein with a topoisomerase I inhibitor according to the present invention exhibits a stronger antitumor effect than the combined use of an antibody against the CAPRIN-1 protein with other topoisomerase inhibitors. Therefore, the combined use of an antibody against the CAPRIN-1 protein with a topoisomerase I inhibitor is effective in treating or preventing cancer.

[0027] 1 shows the antitumor effect of a combination of an anti-CAPRIN-1 antibody and topotecan on NOD-SCID mice implanted with the human cancer cell line BT474, which expresses CAPRIN-1. Reference numeral 1 shows the size of tumors in mice administered with PBS instead of the drug, reference numeral 2 shows the number of mice administered with a low dose of topotecan (3 mg / kg), reference numeral 3 shows the number of mice administered with a high dose of topotecan (10 mg / kg), reference numeral 4 shows the number of mice administered with an anti-CAPRIN-1 antibody, reference numeral 5 shows the number of mice administered with a combination of an anti-CAPRIN-1 antibody and a low dose of topotecan (3 mg / kg), and reference numeral 6 shows the antitumor effect of a combination of an anti-CAPRIN-1 antibody and etoposide on NOD-SCID mice implanted with the human cancer cell line BT474, which expresses CAPRIN-1. Reference number 7 shows the tumor size in mice administered with PBS instead of the drug, reference number 8 shows the tumor size in mice administered with low-dose etoposide (5 mg / kg), reference number 9 shows the tumor size in mice administered with high-dose etoposide (15 mg / kg), reference number 10 shows the tumor size in mice administered with anti-CAPRIN-1 antibody, reference number 11 shows the tumor size in mice administered with a combination of anti-CAPRIN-1 antibody and low-dose etoposide (5 mg / kg), and reference number 12 shows the tumor size in mice administered with a combination of anti-CAPRIN-1 antibody and high-dose etoposide (15 mg / kg).

[0028] The antitumor activity of the combined use of the antibody against the CAPRIN-1 protein or a fragment thereof (hereinafter collectively referred to as "anti-CAPRIN-1 antibody") used in the present invention and a topoisomerase I inhibitor can be evaluated by examining the inhibition of tumor growth in tumor-bearing animals in vivo, as described below.

[0029] As used herein, the terms "concomitant use" or "combination" refer to the administration of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor as independent active ingredients to the same living body simultaneously or at a predetermined interval. The interval may be simultaneous administration, or may be 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, 5 days, 7 days, 2 weeks, 3 weeks, or 4 weeks later. It is sufficient for either the anti-CAPRIN-1 antibody or the topoisomerase I inhibitor to be administered when it exhibits its activity in the living body. Alternatively, the anti-CAPRIN-1 antibody or the topoisomerase I inhibitor may be administered first.

[0030] The anti-CAPRIN-1 antibody of the present invention may be a monoclonal antibody or a polyclonal antibody, and is preferably a monoclonal antibody. The antibody of the present invention may be any type of antibody, including a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, and a non-human animal antibody, as long as it can exhibit anti-tumor activity.

[0031] Furthermore, subjects for cancer treatment and / or prevention in the present invention include mammals such as humans, pet animals, livestock, and sport animals, with humans being the preferred subject.

[0032] The anti-CAPRIN-1 antibody, topotecan, pharmaceuticals containing them as active ingredients, and methods for treating and / or preventing cancer according to the present invention will be described below.

[0033] <Anti-CAPRIN-1 Antibodies> Among CAPRIN-1 proteins having amino acid sequences represented by any of the even-numbered SEQ ID NOS: 2 to 30, which are specific examples of antigens immunologically reactive with the anti-CAPRIN-1 antibodies used in the present invention, the amino acid sequences represented by SEQ ID NOS: 6, 8, 10, 12, and 14 are the amino acid sequences of canine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOS: 2 and 4 are the amino acid sequences of human CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOS: 16 is the amino acid sequence of bovine CAPRIN-1 protein, the amino acid sequence represented by SEQ ID NOS: 18 is the amino acid sequence of equine CAPRIN-1 protein, the amino acid sequences represented by SEQ ID NOS: 20 to 28 are the amino acid sequences of mouse CAPRIN-1 protein, and the amino acid sequence represented by SEQ ID NOS: 30 is the amino acid sequence of chicken CAPRIN-1 protein.

[0034] Furthermore, the anti-CAPRIN-1 antibody used in the present invention may be immunologically reactive with a variant of the CAPRIN-1 protein having 80% or more, preferably 90% or more, more preferably 95% or more, and even more preferably 99% or more sequence identity with the amino acid sequence represented by any of the even-numbered SEQ ID NOs: 2 to 30. As used herein, "% sequence identity" refers to the percentage (%) of identical amino acids (or bases) relative to the total number of amino acids (or bases) when the two sequences are aligned to maximize similarity, with or without introducing gaps.

[0035] In the present invention, an anti-CAPRIN-1 antibody refers to an antibody or a fragment thereof that is immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof. Here, "immunological reactivity" refers to the property of an antibody binding to the CAPRIN-1 protein or a partial polypeptide thereof in vivo.

[0036] The anti-CAPRIN-1 antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody.

[0037] Polyclonal antibodies immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof (anti-CAPRIN-1 polyclonal antibodies) can be obtained by immunizing mice, human antibody-producing mice, rats, rabbits, chickens, etc. with, for example, the natural CAPRIN-1 protein, a fusion protein with GST or the like, or a partial peptide thereof, and then obtaining serum. The obtained serum can be subjected to ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange column, affinity column to which the CAPRIN-1 protein or partial peptide is bound, or the like.

[0038] The full-length CAPRIN-1 protein or a fragment thereof used in the immunization, the nucleotide sequence and amino acid sequence of CAPRIN-1 and its homologs, 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, a method for producing the CAPRIN-1 protein can be obtained by referring to WO2014 / 012479, and cells expressing the CAPRIN-1 protein can also be used.

[0039] A monoclonal antibody immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof (anti-CAPRIN-1 monoclonal antibody) can be obtained, for example, by immunizing a mouse with SK-BR-3 breast cancer cells expressing CAPRIN-1 or the full-length CAPRIN-1 protein or a fragment thereof, fusing 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 (hybridoma). The antibody produced by the selected hybridoma can be obtained by a method similar to the method for purifying polyclonal antibodies described above.

[0040] The antibodies used in the present invention include human antibodies, humanized antibodies, chimeric antibodies, and non-human animal antibodies.

[0041] Human antibodies can be obtained by sensitizing human lymphocytes infected with EB virus with the protein, protein-expressing cells, or a lysate thereof, fusing the sensitized lymphocytes with myeloma cells such as human-derived U266 cells, and then obtaining antibodies immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof from the resulting fused cells.

[0042] A humanized antibody is a modified antibody, also known as a reshaped human antibody. Humanized antibodies are constructed by grafting the complementarity-determining regions (CDRs) of an antibody derived from an immunized animal onto the CDRs of a human antibody. Genetic recombination, a common technique for this purpose, is well known. Specifically, for example, a DNA sequence designed to link the CDRs of a mouse or rabbit antibody with the framework regions of a human antibody is synthesized by PCR from several oligonucleotides engineered to have overlapping ends. The resulting DNA is ligated to DNA encoding the constant regions of a human antibody, incorporated into an expression vector, and then introduced into a host for production (see European Patent Application Publication No. EP 239400 and International Publication No. WO 96 / 02576). The framework regions of the human antibody linked via the CDRs are selected so that the CDRs form a good antigen-binding site. If necessary, amino acids in the framework regions of the variable regions of the antibody may be substituted so that the complementarity-determining regions of the reshaped human antibody form an appropriate antigen-binding site (Sato K. et al., Cancer Research 1993, 53:851-856). Alternatively, they may be substituted with framework regions derived from various human antibodies (see WO99 / 51743).

[0043] Antibodies are typically heteromeric glycoproteins containing at least two heavy chains and two light chains. Antibodies consist of two identical light chains and two identical heavy chains. Heavy chains have a heavy chain variable region at one end, followed by several constant regions. Light chains have a light chain variable region at one end, followed by several constant regions. The variable regions exhibit specific variable regions called complementarity-determining regions (CDRs) that confer binding specificity to the antibody. Portions of the variable regions that are relatively conserved are called framework regions (FRs). Complete heavy and light chain variable regions each contain four FRs connected by three CDRs (CDR1 to CDR3).

[0044] The sequences of the constant and variable regions of human-derived heavy and light chains are available from, for example, NCBI (USA: GenBank, UniGene, etc.). For example, reference can be made to the sequences of the human IgG1 heavy chain constant region under accession number J00228, the human IgG2 heavy chain constant region under accession number J00230, the human light chain κ constant region under accession numbers V00557, X64135, X64133, etc., and the human light chain λ constant region under accession numbers X64132, X64134, etc.

[0045] A chimeric antibody is an antibody produced by combining sequences derived from different animals, such as an antibody consisting of the heavy chain variable region and light chain variable region of a mouse antibody and the heavy chain variable region and light chain variable region constant region of a human antibody. Chimeric antibodies can be produced using known methods, for example, by linking DNA encoding an antibody V region with DNA encoding a human antibody C region, incorporating the resultant into an expression vector, and introducing the vector into a host for production.

[0046] Non-human animal antibodies can be obtained by immunizing an animal with a sensitizing antigen according to known methods. A typical method is to inject the sensitizing antigen intraperitoneally, intradermally, or subcutaneously into an animal such as a mouse. When injecting the sensitizing antigen, the antigen is mixed with an appropriate amount of various adjuvants, such as Freund's complete adjuvant (CFA), and administered to the animal multiple times. After immunizing an animal and confirming that the serum contains anti-CAPRIN-1 antibodies, the serum can be obtained and purified, as described above, by ammonium sulfate precipitation, protein A, protein G, DEAE ion exchange columns, affinity columns coupled with CAPRIN-1 protein or partial peptides, or the like. Furthermore, monoclonal antibodies can be obtained from non-human animals by collecting immune cells from the immunized animal and fusing them with myeloma cells. The fusion of the immune cells with myeloma cells can be carried out according to known methods (see Kohler, G. and Milstein, C. Methods Enzymol. (1981) 73, 3-46).

[0047] The antibodies used in the present invention can also be obtained as recombinant antibodies produced by cloning an antibody gene from a hybridoma, incorporating it into a suitable vector, and introducing it into a host using genetic engineering techniques (see Carl, A.K. Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990).

[0048] The anti-CAPRIN-1 antibody used in the present invention may have amino acids in the variable region (e.g., FR) or constant region substituted with other amino acids. The amino acid substitutions are one or more, for example, fewer than 15, fewer than 10, 8 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer amino acids, preferably 1 to 9 amino acids. The substituted antibody should have the same or higher antigen-specific binding properties and antigen-binding affinity as the unsubstituted antibody, and should not cause rejection reactions when administered to humans. The amino acid substitutions are preferably conservative, which are substitutions between amino acids with similar properties such as charge, side chain, polarity, and aromaticity. Amino acids with similar properties can be classified into, for example, basic amino acids (arginine, lysine, histidine), acidic amino acids (aspartic acid, glutamic acid), uncharged polar amino acids (glycine, asparagine, glutamine, serine, threonine, cysteine, tyrosine), nonpolar amino acids (leucine, isoleucine, alanine, valine, proline, phenylalanine, tryptophan, methionine), branched-chain amino acids (threonine, valine, isoleucine), and aromatic amino acids (phenylalanine, tyrosine, tryptophan, histidine).

[0049] The anti-CAPRIN-1 antibody used in the present invention is expected to have a stronger antitumor effect if it has a higher binding affinity with the CAPRIN-1 protein on the surface of cancer cells. 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 10１２ M －１ , or at least 10 １３ M －１ It is desirable that:

[0050] The anti-CAPRIN-1 antibody used in the present invention may be chemically modified. Examples of such modified antibodies include antibodies conjugated to various molecules, such as polyethylene glycol (PEG) or antitumor compounds (e.g., the antitumor agents exemplified below). The conjugated substance of the modified antibody of the present invention is not limited. Such modified antibodies can be obtained by chemically modifying the antibody. These methods have already been established in the field. The binding ability of the anti-CAPRIN-1 antibody used in the present invention to effector cells can be improved by substituting one, two, or several amino acids in the heavy chain constant region of the antibody, or by removing fucose bound to N-acetylglucosamine in the N-glycoside-linked sugar chain bound to the heavy chain constant region. The above may be achieved by amino acid substitution alone, or may be a composition with an antibody to which fucose is bound.

[0051] Antibodies in which one, two, or several amino acids in the heavy chain constant region have been substituted can be produced by referring to, for example, WO2004 / 063351, WO2011 / 120135, U.S. Patent No. 8,388,955, WO2011 / 005481, U.S. Patent No. 6,737,056, and WO2005 / 063351.

[0052] An antibody from which fucose bound to N-acetylglucosamine in the N-glycoside-linked sugar chain in the heavy chain constant region has been removed, or a cell producing such an antibody, can be prepared with reference to U.S. Patent No. 6,602,684, European Patent No. 1,914,244, and U.S. Patent No. 7,579,170. An antibody from which fucose bound to N-acetylglucosamine in the N-glycoside-linked sugar chain bound to the heavy chain constant region has been removed, a composition of an antibody to which fucose has been bound, or a cell producing such an antibody can be prepared with reference to, for example, U.S. Patent No. 8,642,292.

[0053] The anti-CAPRIN-1 polyclonal antibody, anti-CAPRIN-1 monoclonal antibody, antibody production method, purification method, and method for producing the CAPRIN-1 protein or its partial polypeptide used in immunization used in the present invention are described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, and WO2011 / 09653 5, 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.

[0054] Specific examples of the anti-CAPRIN-1 antibody of the present invention include those described in WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, and WO2013 / 018891. , WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125630, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176 and WO2015 / 020212, but preferred anti-CAPRIN-1 antibodies include the following:

[0055] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4, or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and still more preferably 99% or more) sequence identity with said amino acid sequence.

[0056] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence represented by SEQ ID NO: 31 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. An antibody or fragment thereof immunologically reactive with a CAPRIN-1 protein, preferably comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 36, 37, and 38 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 40, 41, and 42 (CDR1, CDR2, and CDR3, respectively), or an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 140, 141, and 142 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 143, 144, and 145. or an antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 164, 165, and 166 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 167, 168, and 169 (CDR1, CDR2, and CDR3, respectively), and having immunological reactivity with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 43, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79.

[0057] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 33 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 60, 61, and 62 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 64, 65, and 66 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 63 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 67.

[0058] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 32 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 52, 53, and 54 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 56, 57, and 58 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59.

[0059] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence represented by SEQ ID NO: 34 or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 170, 171, and 172 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 173, 174, and 175 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein; or an antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 176, 177, and 178 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 179, 180, and 181 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 81, or an antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 82 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 83.

[0060] An antibody or fragment thereof that is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 35 or an amino acid sequence that has 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 182, 183, and 184 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 185, 186, and 187 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein; or an antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity determining regions of SEQ ID NOs: 188, 189, and 190 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity determining regions of SEQ ID NOs: 191, 192, and 193 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with the CAPRIN-1 protein. More preferably, the antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85, or an antibody or fragment thereof has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 87.

[0061] An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 44, 45, and 46, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of SEQ ID NOs: 48, 49, and 50, and having immunological reactivity with a CAPRIN-1 protein. Preferably, the antibody or fragment thereof comprises the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 51.

[0062] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 296 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 146, 147, and 148 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 149, 150, and 151 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 72 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73.

[0063] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 297 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 272, 273, and 274 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 275, 276, and 277 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 114 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 115.

[0064] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 298 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 290, 291, and 292 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 293, 294, and 295 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 120 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 121.

[0065] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 299 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 301, 302, and 303 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 305, 306, and 307 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 300 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 304.

[0066] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 308 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 134, 135, and 136 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 137, 138, and 139 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 69.

[0067] An antibody or fragment thereof immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having the amino acid sequence set forth in SEQ ID NO: 309 or an amino acid sequence having 80% or more (preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more) sequence identity with said amino acid sequence. Preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 134, 135, and 136 (CDR1, CDR2, and CDR3, respectively) and a light chain variable region comprising the complementarity-determining regions of SEQ ID NOs: 137, 138, and 139 (CDR1, CDR2, and CDR3, respectively), and is immunologically reactive with a CAPRIN-1 protein. More preferably, the antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 69.

[0068] In addition, the following anti-CAPRIN-1 antibodies are also preferably used.

[0069] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69.

[0070] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 71.

[0071] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73.

[0072] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 75.

[0073] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77.

[0074] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79.

[0075] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81.

[0076] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.

[0077] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85.

[0078] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87.

[0079] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89.

[0080] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 91.

[0081] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93.

[0082] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 95.

[0083] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97.

[0084] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:99.

[0085] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101.

[0086] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103.

[0087] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105.

[0088] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107.

[0089] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109.

[0090] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111.

[0091] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113.

[0092] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115.

[0093] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117.

[0094] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119.

[0095] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121.

[0096] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123.

[0097] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125.

[0098] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127.

[0099] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129.

[0100] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131.

[0101] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133.

[0102] An antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 300 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 304.

[0103] In the Examples described below, a strong antitumor effect was confirmed in tumor-bearing living organisms by combining the above-mentioned polyclonal or monoclonal antibodies against the full-length CAPRIN-1 protein or a polypeptide of a part of the region expressed on the cell membrane surface of cancer cells with imiquimod.

[0104] <Topoisomerase I Inhibitors> Topoisomerase I inhibitors selectively bind to type I topoisomerase complexed with DNA, stabilizing its structure, inhibiting relaxation of the DNA helix and causing DNA fragmentation, resulting in the arrest of cell division and cell death. To administer a topoisomerase I inhibitor to a living body, the topoisomerase I inhibitor may contain an appropriate isotonicity agent, pH, or dosage form. Specific examples of topoisomerase I inhibitors include topotecan (nogitecan) or irinotecan. Topoisomerase I inhibitors can be obtained by chemical synthesis using techniques known to those skilled in the art. Topoisomerase I Topoisomerase I <Topotecan> Topotecan is a semisynthetic derivative of camptothecin, a natural product extracted from the bark of the camptothecin tree. It is a type I topoisomerase inhibitor with a molecular weight of approximately 421.4, represented by CAS number 123948-87-8 (119413-54-6 for the hydrate). In this specification, the term "topotecan" includes topotecan hydrochloride and topotecan hydrochloride hydrate unless otherwise specified. The IUPAC name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride, and is also known as nogitecan hydrochloride. As pharmaceuticals containing topotecan hydrochloride as an active ingredient, "Hycamtin (registered trademark)" and "Potactasol (registered trademark)" are commercially available, and these pharmaceuticals can be used appropriately when using topotecan in the present invention.

[0105] <Irinotecan> Irinotecan according to the present invention is a type I topoisomerase inhibitor having a molecular weight of approximately 586.678 and represented by CAS number 100286-90-6 (hydrate: 136572-09-3). In this specification, the term "irinotecan" encompasses irinotecan hydrochloride and irinotecan hydrochloride hydrate unless otherwise specified. Pharmaceuticals containing irinotecan hydrochloride as an active ingredient include "Campto (registered trademark)," "Topotecin" (registered trademark), and "Onivyde (registered trademark)," and these pharmaceuticals can be used as appropriate when using irinotecan in the present invention.

[0106] <Other Antitumor Agents> The active ingredients of the pharmaceutical of the present invention may include, in addition to the anti-CAPRIN-1 antibody and any topoisomerase I inhibitor, antitumor agents known in the literature, etc., within the scope of not inhibiting the effects of the pharmaceutical of the present invention. There are no particular limitations on known antitumor agents, and specific examples include paclitaxel, doxorubicin, daunorubicin, cyclophosphamide, methotrexate, 5-fluorouracil, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenetriamine, methylparaben ... Lenthiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, bryostatin, calystatin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphadine RNAphazine), colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, phosphatidylcholine, phenesterine, phenicol, phenanthroline ... Temustine (fotemustine), lomustine, nimustine, ranimustine, calicheamicin, dynemycin, clodronate, esperamicin, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin,Dactinomycin, detorbicin, 6-diazo-5-oxo-L-norleucine, adriamycin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid acid), nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, fludarabine (f ludarabine), 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid acid), aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, epothilone, etoglucid, lentinan, lonidamine,Maytansine, ansamitocine, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid acid), triaziquone, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, oxaliplatin, These include ruboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, difluoromethylolnitine (DMFO), retinoic acid, capecitabine, and pharmaceutically acceptable (known) salts or (known) derivatives thereof.

[0107] <Anti-tumor Effect of the Present Invention> The combination of the anti-CAPRIN-1 antibody and topoisomerase I inhibitor of the present invention has cytotoxic activity in vivo. Therefore, the anti-tumor effect of the present invention can be determined by examining the cytotoxic activity against cancer. The cytotoxic activity can be evaluated by administering anti-CAPRIN-1 and a topoisomerase I inhibitor to a living body with cancer, measuring the size of the tumor after administration, and examining the size of the cancer over time. The anti-tumor effect of the present invention can also be evaluated by examining the survival rate. It can also be evaluated by examining the ability to produce cytokines or chemokines. The anti-tumor effect of the combination of the anti-CAPRIN-1 antibody and topoisomerase I inhibitor of the present invention can be determined by examining the prevention of cancer, metastasis, or recurrence.

[0108] The anti-CAPRIN-1 antibody used in the present invention is expected to have a stronger antitumor effect if it has a higher binding affinity with the CAPRIN-1 protein on the surface of cancer cells. 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 It is desirable that:

[0109] The ability of the anti-CAPRIN-1 antibody used in the present invention to bind to CAPRIN-1 can be determined by using binding assays such as ELISA, Western blotting, immunofluorescence, and flow cytometry.

[0110] As described above, administration of a combination of an anti-CAPRIN-1 antibody of the present invention and a topoisomerase I inhibitor to a living body with cancer enhances the anti-tumor effect compared to the anti-CAPRIN-1 antibody alone, and the enhancement rate is preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 55% or more, even more preferably 60% or more, even more preferably 65% ​​or more, and most preferably 70% or more. The enhancement rate of the anti-tumor effect of the combination administration of an anti-CAPRIN-1 antibody of the present invention and a topoisomerase I inhibitor compared to the administration of an anti-CAPRIN-1 antibody alone can be calculated by administering effective amounts of each to tumor-bearing mice under the same conditions and comparing the tumor volumes on or after day 7 after the start of administration.

[0111] <Drug for treating and / or preventing cancer> The drug of the present invention is intended to treat and / or prevent cancer. The cancer targeted by the drug of the present invention is not particularly limited as long as it is a cancer (cell) that expresses the CAPRIN-1 protein.

[0112] As used herein, "treatment" refers to the treatment of cancer based on the antitumor effect described above. Furthermore, as used herein, "prevention" refers not only to the prevention of cancer onset, but also to the prevention of cancer metastasis or recurrence.

[0113] As used herein, the terms "tumor" and "cancer" refer to malignant neoplasms and are used interchangeably.

[0114] The cancer that is the subject of the present invention may be any cancer in which the CAPRIN-1 protein is expressed on the cell membrane surface. Preferred are ovarian cancer, bile duct cancer, breast cancer, kidney cancer, pancreatic cancer, colon cancer, melanoma (including postoperative melanoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial cancer (including malignant pleural mesothelioma), colorectal cancer (e.g., MSI-high colorectal cancer), esophageal cancer, gastroesophageal junction cancer, hepatocellular carcinoma, glioblastoma, urothelial carcinoma, bladder cancer, uterine cancer (including cervical cancer and endometrial cancer), primary central nervous system lymphoma, primary testicular lymphoma, biliary tract cancer, brain tumor, prostate cancer, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease, or skin cancer. Furthermore, these cancers may be primary cancers, metastatic cancers, metastatic or recurrent cancers, postoperative cancers, or unresectable cancers. Note that melanoma is often used synonymously with malignant melanoma or malignant melanoma.

[0115] Other cancers that are the subject of the present invention include cancers that are resistant to known treatments. The resistant cancers may be cancers derived from patients with any treatment history, and are not particularly limited to, for example, cancers derived from patients with a history of treatment with a platinum agent or 5-FU that have become resistant, metastasized, or recurred after administration.

[0116] More specifically, the cancers include, for example, Bowen's disease, melanoma, squamous cell carcinoma, extramammary Paget's disease, mycosis fungoides, Sezary syndrome, cutaneous T / NK cell lymphoma, T-cell leukemia / lymphoma with lesions only in the skin, cutaneous B-cell lymphoma (indolent group), cutaneous T-cell lymphoma of the breast, combined breast adenocarcinoma, malignant mixed breast tumor, intraductal papillary adenocarcinoma, lung adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, neuroepithelial tissue tumors such as glioma, glioblastoma, neuroblastoma, and supraventricular Neumoma, neuronal cell tumor, embryonal neuroectodermal tumor, schwannoma, neurofibroma, meningioma, chronic lymphocytic leukemia, lymphoma, gastrointestinal lymphoma, digestive lymphoma, small to medium cell lymphoma, cecal cancer, ascending colon cancer, descending colon cancer, transverse colon cancer, sigmoid colon cancer, rectal cancer, ovarian epithelial cancer, germ cell tumor, stromal cell tumor, pancreatic ductal carcinoma, invasive pancreatic ductal carcinoma, adenocarcinoma of the pancreas, acinar cell carcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary mucinous tumor, mucinous cystadenocarcinoma, pancreatoblastoma, pancreatic head cell tumor, Fra NTs tumors, serous cystadenocarcinoma, solid papillary carcinoma, gastrinoma, glucagonoma, insulinoma, multiple endocrine neoplasia 1 (Wermer's syndrome), non-functioning islet cell tumor, somatostatinoma, VIP-producing tumor, cervical cancer, uterine cancer, fibrosarcoma, bone and joint sarcoma, Ewing's sarcoma, Wilms' tumor, hepatoblastoma, soft tissue sarcoma, acute leukemia, chronic leukemia, spinal cord tumor, soft tissue malignant tumor, teratoma group tumor, head and neck cancer including hypopharyngeal cancer, oropharynx cancer, tongue cancer, nasopharyngeal cancer, oral cancer, and lip cancer These include, but are not limited to, paranasal sinus cancer, laryngeal cancer, renal pelvis and urinary tract cancer, bladder cancer, urethral cancer, testicular tumor, malignant pleural mesothelioma, malignant bone tumor, uterine cancer (postoperative chemotherapy, chemotherapy at metastasis / recurrence), pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, retinoblastoma, central nervous system germ cell tumor, Ewing's sarcoma family tumors), serous tumors (including serous borderline tumors (SBT)), mucinous tumors, superficial epithelial borderline tumors, stromal borderline tumors, etc. Also included are palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, or cancers in non-parenchymal organs, and progressive cancers that originate from the above cancers. Furthermore, palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, or non-parenchymal organ cancers that have metastasized or recurred from the above cancers are also included.

[0117] Furthermore, preferred subjects (patients) are mammals, including, for example, primates, pet animals, livestock, sport animals, etc., with humans, dogs, and cats being particularly preferred.

[0118] The pharmaceuticals of the present invention can be formulated by methods known to those skilled in the art. The pharmaceuticals of the present invention can be administered parenterally, for example, in the form of an injection of a sterile solution or suspension in water or other pharmaceutically acceptable liquid. For each formulation or pharmaceutical composition of the present invention, the active ingredients (anti-CAPRIN-1 antibody and topoisomerase I inhibitor) may be appropriately combined with, for example, a pharmacologically acceptable carrier or vehicle, specifically, sterilized water, physiological saline, isotonic solution, buffer (buffer solution, etc.), vegetable oil, oily oil, antioxidant, solubilizer, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, binder, etc., and preferably formulated by mixing with these in a unit dosage form required for generally accepted pharmaceutical practice. The amount of the active ingredient in these formulations is such that an appropriate dose within the indicated range can be obtained.

[0119] Sterile compositions for injection can be formulated according to standard pharmaceutical practice using a vehicle such as distilled water for injection. Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride. These solutions may be used in combination with appropriate solubilizers, such as alcohols, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, and nonionic surfactants such as Polysorbate 80™ and HCO-60. Examples of oily solutions include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. Furthermore, these solutions may be combined with buffers such as phosphate buffers and sodium acetate buffers, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solutions are usually filled into appropriate ampoules.

[0120] Administration may be oral or parenteral, preferably parenteral, and specific examples include injections, nasal administration, pulmonary administration, and transdermal administration. Examples of injections include intravenous, intramuscular, intraperitoneal, subcutaneous, and intratumoral injections, which can be administered systemically or locally. Examples of transdermal administrations include topical liniments and topical agents. Topical agents include solids, liquids, sprays, ointments, creams, and gels.

[0121] Furthermore, an appropriate administration method can be selected depending on the patient's age, body weight, sex, symptoms, etc. The dosage of a pharmaceutical composition containing at least one of an anti-CAPRIN-1 antibody and a topoisomerase I inhibitor can be selected, for example, from the range of 0.0001 mg to 1,000 mg per kg of body weight per administration, in terms of the amount of each active ingredient. Alternatively, the dosage can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, or from 1 mg to 30 mg per kg of body weight, but is not necessarily limited to these numerical values. The dosage and administration method vary depending on the patient's body weight, age, sex, symptoms, etc., but can be appropriately selected by one skilled in the art.

[0122] <Administration Method> The treatment and / or prevention of cancer using the pharmaceutical compositions for treating and / or preventing cancer of the present invention includes various forms in addition to the administration of the aforementioned pharmaceutical compositions. For example, the active ingredients of the pharmaceutical compositions of the present invention can be administered simultaneously or separately in a sequential order. Specifically, the second active ingredient can be administered within a time interval of up to about three weeks, i.e., immediately after the administration of the first active ingredient and up to about three weeks after. This administration can be performed following a surgical procedure, or a surgical procedure can be performed between the administration of the first and second agents. The cancer therapeutic and / or preventive agents of the present invention can also be administered in multiple administration cycles. For example, when the active ingredients of the cancer therapeutic and / or preventive agents of the present invention are administered simultaneously, a pharmaceutical composition containing both active ingredients is administered for about two days to about three weeks as one cycle. Thereafter, the treatment cycle can be repeated as necessary, according to the judgment of the physician in charge of the treatment cycle. Similarly, when a sequential regimen is planned, the administration period of each individual drug is adjusted so that it lasts for the same period. The interval between cycles can vary from 0 to 2 months. The dosage of each active ingredient of the agent for treating and / or preventing cancer of the present invention can be set in the same manner as the dosage of each active ingredient in a pharmaceutical composition.

[0123] <Pharmaceutical Kit> The pharmaceutical product for treating and / or preventing cancer of the present invention may be in the form of a pharmaceutical kit. A pharmaceutical kit is a package for using active ingredients in the form of separate pharmaceutical compositions in a method for treating and / or preventing cancer, and the package includes instructions for administering each active ingredient. Each active ingredient of the pharmaceutical composition for treating and / or preventing cancer included in the pharmaceutical kit may be in the form of a pharmaceutical composition formulated as described above so that the active ingredients can be administered together or separately. The pharmaceutical kit also includes an amount of each active ingredient sufficient for one or more doses so that each active ingredient can be administered according to the administration method described above.

[0124] Based on the above-described specific details, the present invention further provides a method for treating and / or preventing cancer, comprising administering the pharmaceutical composition of the present invention to a subject suspected of having cancer. In this embodiment, the antibody or a fragment thereof and the antitumor agent contained in the pharmaceutical composition are administered to the subject simultaneously or separately.

[0125] The present invention will be specifically described below based on examples, but the scope of the present invention is not limited to these specific examples.

[0126] Example 1: Preparation of anti-CAPRIN-1 antibody The anti-CAPRIN-1 antibody used in the present invention, which has immunological reactivity with the CAPRIN-1 protein, was prepared as follows.

[0127] (Polyclonal antibody) 1 mg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal volume of incomplete Freund's adjuvant (IFA) solution, and this mixture was subcutaneously administered to rabbits four times every two weeks. Blood was then collected to obtain antiserum containing polyclonal antibodies. This antiserum was further purified using a protein G carrier (manufactured by GE Healthcare Biosciences) and substituted with PBS(-) to obtain a polyclonal antibody against the CAPRIN-1 protein (anti-CAPRIN-1 polyclonal antibody #1).

[0128] (Monoclonal antibody) 100 μg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO2010 / 016526 was mixed with an equal amount of MPL + TDM adjuvant (Sigma), and this was used as the antigen solution per mouse. The antigen solution was administered intraperitoneally to 6-week-old Balb / c mice (Japan SLC), followed by three and 24 additional weekly administrations to complete the immunization. Three days after the final immunization, each spleen was removed, sandwiched between two sterilized glass slides, and crushed. The spleen was washed with PBS(-) (Nissui), centrifuged at 1500 rpm for 10 minutes, and the supernatant was removed. This procedure was repeated three times to obtain spleen cells. The resulting spleen cells were mixed with mouse myeloma cells SP2 / 0 (purchased from ATCC) at a ratio of 10:1, and a PEG solution prepared by mixing 200 μl of RPMI 1640 medium containing 10% FBS and 800 μl of PEG 1500 (Boehringer) preheated to 37°C was added and allowed to stand for 5 minutes to allow cell fusion. After centrifugation at 1700 rpm for 5 minutes and removal of the supernatant, the cells were suspended in 150 ml of RPMI 1640 medium containing 15% FBS (HAT selection medium) supplemented with 2% equivalent of Gibco's HAT solution, and seeded onto 15 96-well plates (Nunc) at 100 μl per well. The mixture was incubated at 37°C and 5% CO for 7 days. ２By culturing the cells under these conditions, hybridomas were obtained in which spleen cells and myeloma cells were fused. Hybridomas were selected based on the binding affinity of the antibodies produced by the hybridomas to the CAPRIN-1 protein. 100 μl of a 1 μg / ml CAPRIN-1 protein solution was added per well of a 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% bovine serum albumin (BSA) solution (Sigma) was added per well and allowed to stand at room temperature for 3 hours. The solution was removed, and the wells were washed three times with 400 μl of PBS-T per well. Then, 100 μl of each culture supernatant of the hybridomas obtained above was added per well and allowed to stand at room temperature for 2 hours. After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (Invitrogen) diluted 5000-fold with PBS was added per well and allowed to stand at room temperature for 1 hour. After washing the wells three times with PBS-T, 100 μl of TMB substrate solution (Thermo) was added per well and allowed to stand for 15-30 minutes to allow the color reaction to develop. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance values ​​at 450 nm and 595 nm were measured using an absorption spectrometer. Several hybridomas producing antibodies with high absorbance values ​​were selected. The selected hybridomas were added to a 96-well plate at 0.5 cells per well and cultured. After one week, hybridomas forming single colonies were observed in the wells. The cells in these wells were further cultured, and hybridomas were selected based on the binding affinity of the antibodies produced by the cloned hybridomas to the CAPRIN-1 protein. 100 μl of 1 μg / ml CAPRIN-1 protein solution was added per well of a 96-well plate and allowed to stand at 4°C for 18 hours. After washing each well three times with PBS-T, 400 μl of 0.5% BSA solution was added per well and allowed to stand at room temperature for 3 hours. The solution was removed, and the wells were washed three times with 400 μl of PBS-T per well. 100 μl of each culture supernatant of the hybridomas obtained above was added per well and allowed to stand at room temperature for 2 hours.After washing each well three times with PBS-T, 100 μl of HRP-labeled anti-mouse IgG (H+L) antibody (Invitrogen) diluted 5000-fold with PBS was added per well and allowed to stand at room temperature for 1 hour. After washing the wells three times with PBS-T, 100 μl of TMB substrate solution (Thermo) was added per well and allowed to stand for 15-30 minutes to allow the color reaction to occur. After color development, 100 μl of 1 N sulfuric acid was added per well to stop the reaction, and the absorbance values ​​at 450 nm and 595 nm were measured using an absorbance meter. As a result, several mouse monoclonal antibodies showing reactivity with CAPRIN-1 protein were obtained.

[0129] Furthermore, flow cytometry was used to confirm reactivity with human cancer cells in which CAPRIN-1 protein has been confirmed to be expressed on the cell membrane surface. A mouse IgG control antibody that does not show reactivity with the cancer cells was used as a negative control. As a result of this confirmation, several monoclonal antibodies were obtained that had stronger fluorescence intensity with the cancer cells than the mouse IgG control antibody and strongly reacted with the cell membrane surface of the cancer cells in which CAPRIN-1 is expressed on the cell membrane surface. From these, a monoclonal antibody reactive with CAPRIN-1 protein was selected, which is a monoclonal antibody against CAPRIN-1 described in WO2013 / 125630 and comprises the amino acid sequence of the heavy chain variable region represented by SEQ ID NO: 114 of (ab) and the amino acid sequence of the light chain variable region represented by SEQ ID NO: 115.

[0130] CDRs 1 to 3 of the heavy chain variable region of the selected antibody were identified, and a nucleotide sequence was designed to enable expression of a heavy chain variable region whose framework regions comprise the sequence of a human antibody, and this was inserted into a mammalian expression vector into which the heavy chain constant region of human IgG1 had been inserted. Similarly, CDRs 1 to 3 of the light chain variable region were identified, and a nucleotide sequence was designed to enable expression of a light chain variable region whose framework regions comprise the sequence of a human antibody, and this was inserted into a mammalian expression vector into which the light chain constant region of human IgG1 had been inserted. The above two recombinant expression vectors were introduced into mammalian cells according to standard methods to obtain a culture supernatant containing humanized monoclonal antibody #1 against CAPRIN-1 (humanized antibody #1).

[0131] The resulting culture supernatant containing humanized anti-CAPRIN-1 monoclonal antibody #1 was purified using Hitrap Protein A Sepharose FF (GE Healthcare) according to standard methods, and then the medium was replaced with PBS(-) and filtered through a 0.22 μm filter (Millipore) to prepare a sample.

[0132] The specific reactivity of the anti-CAPRIN-1 antibody to the CAPRIN-1 protein was confirmed by immobilizing the CAPRIN-1 protein on a plate and detecting it using the ELISA method.

[0133] Furthermore, by examining the reactivity of the above-mentioned anti-CAPRIN-1 antibody with cancer cells whose cell membranes had not been permeabilized by flow cytometry, it was confirmed that a portion of CAPRIN-1 was expressed on the cell membrane surface of cancer cells, as shown in the Examples below.

[0134] Human cancer cells in which CAPRIN-1 gene expression has been confirmed by flow cytometry include breast cancer cells (BT-474), colon cancer cells (HT-29), lung cancer cells (QG56, H1650), gastric cancer cells (NCI-N87), uterine cancer cells (HEC-1-A), prostate cancer cells (22Rv1), pancreatic cancer cells (Panc10.5), liver cancer cells (Hep3B), ovarian cancer cells (SKOV3), renal cancer cells (Caki-2), brain cancer cells (U-87MG), bladder cancer cells (T24), esophageal cancer cells (OE33), and leukemia cells (OCI-AML5). It was confirmed that humanized antibody #1 had stronger fluorescence intensity against any of the following cancer cells: 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 expression of the CAPRIN-1 gene has been confirmed, compared to the negative control human IgG control antibody and rabbit IgG antibody, which show no reactivity against cancer cells, and that it strongly reacts with the cell membrane surface of the above cancer cells in which CAPRIN-1 is expressed.

[0135] Similarly, WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, WO2013 / 018889 It was also confirmed that the anti-CAPRIN-1 antibodies (a) to (aa) and (ac) to (al) described in WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212 also strongly react with the above-mentioned cancer cell membrane surface.

[0136] (Example 2) Antitumor effect of combined use of anti-CAPRIN-1 antibody and topotecan The antitumor effect of combined use of the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 and topotecan in vivo in tumor-bearing mice was evaluated.

[0137] Specifically, the antitumor effect of the combined use of the anti-CAPRIN-1 antibody of the present invention and topotecan was examined using NOD-SCID mice subcutaneously transplanted with human-derived cancer cells expressing the CAPRIN-1 protein. ７ Human breast cancer cells BT474 were mixed with Matrigel (SIGMA) and implanted subcutaneously, and the tumor grew to approximately 154-155 mm. ３ Tumor-bearing mice were generated by growing the tumor until the tumor size reached 100 μg / kg. BT474 is a cancer cell line in which CAPRIN-1 protein is expressed on the cell membrane surface, and it has been confirmed that the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a portion of CAPRIN-1 present on the cell membrane surface. Eight tumor-bearing mice were administered the anti-CAPRIN-1 antibody prepared in Example 1 at 10 mg / kg once a week for a total of four doses into the tail veins of each of the tumor-bearing mice. The same mice were administered a low dose (3 mg / kg) or a high dose (10 mg / kg) of topotecan once every four days for a total of four doses.

[0138] As a comparative control group, the same amount of anti-CAPRIN-1 antibody as above was administered to tumor-bearing mice once a week. Furthermore, as a comparative control group, a low dose (3 mg / kg) or a high dose (10 mg / kg) of topotecan was administered to other tumor-bearing mice at the same administration intervals. Furthermore, tumor-bearing mice in the untreated group served as a negative control. After the start of administration, the size of the tumor in the tumor-bearing mice was measured over time using a vernier caliper, and tumor volume was calculated according to the standard method using the formula: (length of the longest axis of the tumor) x (length of the shortest axis of the tumor). ２ × 0.5 for each individual, and the average value for the administration group was calculated.

[0139] As a result of the evaluation, approximately 2 weeks after the end of drug administration (56 days after tumor bearing), when the tumor volume of the negative control was taken as 100%, the tumor volume of the comparison group administered with anti-CAPRIN-1 humanized antibody #1 prepared in Example 1 was 38%, the group administered with low-dose topotecan was 33%, and the group administered with high-dose topotecan was 16%, indicating that the tumor volumes had increased from the start of administration. On the other hand, the tumor volume of the group administered with a combination of humanized antibody #1 prepared in Example 1 and low-dose topotecan was 6%, and the tumor volume of the group administered with a combination of humanized antibody #1 prepared in Example 1 and high-dose topotecan was 0% (tumors regressed in all individuals), indicating that the tumor volumes had decreased from the start of administration.

[0140] Similarly, 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, WO20 It has also been confirmed that the anti-CAPRIN-1 antibodies (a) to (aa) and (ac) to (al) described in WO 2013 / 125654, WO 2013 / 125640, WO 2013 / 147169, WO 2013 / 147176, and WO 2015 / 020212, when administered in combination with topotecan, have a significantly stronger antitumor effect than when the anti-CAPRIN-1 antibody is administered alone or when topotecan is administered alone.

[0141] The results of this evaluation showed that administration of an anti-CAPRIN-1 antibody in combination with topotecan had a significantly stronger antitumor effect than administration of an anti-CAPRIN-1 antibody alone or administration of topotecan alone.

[0142] (Comparative Example 1) Antitumor effect of combined use of anti-CAPRIN-1 antibody and other topoisomerase inhibitors Next, the antitumor effect in vivo in tumor-bearing mice of combined use of the anti-CAPRIN-1 antibody prepared in Example 1 (anti-CAPRIN-1 humanized antibody #1) and etoposide, a topoisomerase inhibitor (topoisomerase II inhibitor) different from topotecan, was evaluated.

[0143] Specifically, the antitumor effect of a combination of anti-CAPRIN-1 antibody and etoposide was examined using NOD-SCID mice subcutaneously transplanted with human-derived cancer cells expressing the CAPRIN-1 protein. ７ Human breast cancer cells BT474 were mixed with Matrigel (SIGMA) and implanted subcutaneously, and the tumor grew to approximately 190-192 mm. ３Tumor-bearing mice were generated by growing the tumor until the tumor size reached 100 μg / kg. BT474 is a cancer cell line in which CAPRIN-1 protein is expressed on the cell membrane surface, and it has been confirmed that the anti-CAPRIN-1 antibody prepared in Example 1 reacts with a portion of CAPRIN-1 present on the cell membrane surface. Eight tumor-bearing mice were administered the anti-CAPRIN-1 antibody prepared in Example 1 at 10 mg / kg once a week for a total of four doses via the tail vein. A low dose (5 mg / kg) or a high dose (15 mg / kg) of etoposide was administered to the same mice once every four days for a total of four doses.

[0144] As a comparative control group, the same amount of anti-CAPRIN-1 antibody as above was administered to tumor-bearing mice once a week. Furthermore, as a comparative control group, a low dose (5 mg / kg) or a high dose (15 mg / kg) of etoposide was administered to other tumor-bearing mice at the same administration intervals. Furthermore, tumor-bearing mice in the untreated group served as a negative control. After the start of administration, the size of the tumor in the tumor-bearing mice was measured over time using a vernier caliper, and tumor volume was calculated according to the standard method using the formula: (length of the longest axis of the tumor) x (length of the shortest axis of the tumor). ２ × 0.5 for each individual, and the average value for the administration group was calculated.

[0145] As a result of the evaluation, approximately 2 weeks after the end of drug administration (55 days after cancer bearing), when the tumor volume of the negative control was taken as 100%, the tumor volume of the comparison group, the anti-CAPRIN-1 humanized antibody #1 prepared in Example 1 administration group, was 35%, the low-dose etoposide administration group was 92%, the high-dose etoposide administration group was 79%, the group administered a combination of humanized antibody #1 prepared in Example 1 and low-dose etoposide was 18%, and the group administered a combination of humanized antibody #1 prepared in Example 1 and high-dose etoposide was 30%. In all treatment groups, the tumor volume had increased from the start of administration.

[0146] Compared with the evaluation results of the antitumor effect in combination with topotecan shown in Example 2, the antitumor effect was low when an antibody against CAPRIN-1 was treated in combination with etoposide, whereas it was shown that a significantly stronger synergistic antitumor effect was achieved when an antibody against CAPRIN-1 was treated in combination with topotecan, a topoisomerase I inhibitor.

Claims

1. A pharmaceutical for treating and / or preventing cancer, comprising a combination, together or separately, of an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein and a topoisomerase I inhibitor.

2. The pharmaceutical product of claim 1 , wherein the topoisomerase I inhibitor is topotecan or irinotecan.

3. The pharmaceutical product according to claim 1 or 2, wherein the antibody or fragment is an antibody or a fragment thereof that is immunologically reactive with a CAPRIN-1 protein having an amino acid sequence represented by any of the even-numbered SEQ ID NOs: 2 to 30, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.

4. The pharmaceutical product according to claim 1 or 2, wherein the antibody or a fragment thereof is immunologically reactive with the extracellular domain of CAPRIN-1 protein present on the surface of cancer cells.

5. The pharmaceutical product according to claim 1 or 2, wherein the antibody or a fragment thereof is immunologically reactive with a partial polypeptide of a CAPRIN-1 protein having an amino acid sequence represented by any one of SEQ ID NOs: 31 to 35, 296 to 299, 308, and 309, or an amino acid sequence having 80% or more sequence identity with said amino acid sequence.

6. The pharmaceutical product according to claim 1 or 2, wherein the antibody is a monoclonal antibody or a polyclonal antibody.

7. The pharmaceutical product according to claim 1 or 2, wherein the antibody or fragment thereof is any one of the following (A) to (M): (A) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 36, 37 and 38, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 40, 41 and 42, respectively, and having immunological reactivity with a CAPRIN-1 protein. (B) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 44, 45 and 46, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 48, 49 and 50, respectively, and having immunological reactivity with a CAPRIN-1 protein. (C) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 52, 53 and 54, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 56, 57 and 58, respectively, and having immunological reactivity with a CAPRIN-1 protein. (D) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 60, 61 and 62, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 64, 65 and 66, respectively, and having immunological reactivity with a CAPRIN-1 protein. (E) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 170, 171 and 172, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 173, 174 and 175, respectively, and having immunological reactivity with CAPRIN-1 protein. (F) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 176, 177 and 178, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 179, 180 and 181, respectively, and having immunological reactivity with CAPRIN-1 protein. (G) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 182, 183 and 184, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 185, 186 and 187, respectively, and having immunological reactivity with CAPRIN-1 protein. (H) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 188, 189 and 190, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 191, 192 and 193, respectively, and having immunological reactivity with CAPRIN-1 protein. (I) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 146, 147 and 148, respectively, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 149, 150 and 151, respectively, and having immunological reactivity with CAPRIN-1 protein. (J) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 272, 273 and 274, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 275, 276 and 277, respectively, and having immunological reactivity with CAPRIN-1 protein. (K) An antibody or fragment thereof having immunological reactivity with a CAPRIN-1 protein, comprising a heavy chain variable region having the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 290, 291 and 292 and a light chain variable region having the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 293, 294 and 295. (L) An antibody or fragment thereof having immunological reactivity with CAPRIN-1 protein, comprising a heavy chain variable region having the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 300, 301 and 302 and a light chain variable region having the complementarity determining regions (CDR1, CDR2 and CDR3, respectively) of SEQ ID NOs: 304, 305 and 306. (M) An antibody or fragment thereof comprising a heavy chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 134, 135 and 136, and a light chain variable region comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of SEQ ID NOs: 137, 138 and 139, and having immunological reactivity with CAPRIN-1 protein.

8. The pharmaceutical product according to claim 1 or 2, wherein the antibody or fragment thereof is any one of the following (a) to (al): (a) an antibody or 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; (b) an antibody or fragment thereof, in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51; (c) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:55 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

59. (d) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 63 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

67. (e) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

69. (f) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 70 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

71. (g) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

73. (h) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

75. (i) an antibody or fragment thereof, in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77; (j) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

79. (k) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

81. (l) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83; (m) an antibody or 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

121. (af) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

123. (ag) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

125. (ah) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

127. (ai) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

129. (aj) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

131. (ak) an antibody or fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

133. (al) an antibody or 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.

9. The pharmaceutical product of claim 1 or 2, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody or a single chain antibody.

10. The pharmaceutical composition according to claim 1 or 2, wherein the cancer expresses CAPRIN-1 protein on the cell membrane surface.

11. The pharmaceutical composition according to claim 1 or 2, wherein the cancer is ovarian cancer, bile duct cancer, breast cancer, kidney cancer, pancreatic cancer, colon cancer, melanoma, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, gastric cancer, mesothelial carcinoma, colorectal cancer, esophageal cancer, gastroesophageal 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's tumor, multiple myeloma, testicular cancer, thyroid cancer, basal cell carcinoma, Paget's disease or skin cancer.

12. An efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises as an active ingredient an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein, and which comprises as an active ingredient a topoisomerase I inhibitor.

13. An efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises as an active ingredient a topoisomerase I inhibitor, and which comprises as an active ingredient an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein.