Medicament for treatment and / or prevention of cancer

Abstract

The present invention relates to a medicament for the treatment and / or prevention of cancer, the medicament being characterized by comprising an antibody having an immunological reactivity with CAPRIN-1 protein or a fragment of the antibody and an MAPK pathway inhibitor which are combined with each other in a blended or separated form.

Description

Medicines for the treatment and / or prevention of cancer

[0001] The present invention relates to a pharmaceutical for treating and / or preventing cancer, which uses an antibody against CAPRIN-1 protein or a fragment thereof and a MAPK pathway inhibitor.

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

[0003] In recent clinical trials, in order to enhance the efficacy of cancer therapeutic drugs, a combination of multiple cancer therapeutic drugs has become the standard treatment. For example, for breast cancer, it has become common to treat the disease using multiple anticancer drugs, such as a combination of doxorubicin and cyclophosphamide, or paclitaxel, trastuzumab, and pertuzumab. It has also been confirmed that cancer therapeutic drugs containing anti-CAPRIN-1 antibodies as active ingredients have excellent cancer therapeutic effects when used in combination with chemotherapeutic agents (Patent Document 2). However, cancer treatments using a combination of chemotherapeutic agents are not effective against all cancers, and while some may additively enhance therapeutic effects, few significantly synergistically enhance therapeutic effects.

[0004] The MAPK (Mitogen-activated Protein Kinase) signaling pathway plays a central role in regulating cell proliferation, differentiation, and survival. It is composed of four proteins: RAS, RAF, MEK, and ERK (Non-Patent Document 1). RAS activates RAF, which functions as a MAP kinase kinase kinase (MAPKKK or MAP3K). RAF then phosphorylates and activates a MAP kinase kinase (MAPKK). This MAP kinase kinase (MAPKK) is called MEK (MAPK or ERK kinase) in this pathway. MEK phosphorylates and activates the third and final enzyme in this pathway, a MAP kinase (MAPK) called ERK (extracellular signal-regulated kinase). Upon activation, ERK can translocate into the nucleus, where it phosphorylates transcription factors, thereby controlling their activity in important cellular processes such as gene regulation, cell cycle transition, or cell differentiation (Non-Patent Document 2).

[0005] While MAPK signaling is important for normal cellular physiological functions, its abnormal activation and the emergence of mutant proteins are closely related to the onset and progression of cancer, and it is said that abnormal MAPK signaling is present in approximately 85% of all cancers (Non-Patent Document 1). Given this background, MAPK signaling has been positioned as an important target in cancer treatment. For example, inhibitors targeting MEK, which is located downstream of MAPK signaling, have been used as anticancer drugs (Non-Patent Document 1). However, while MEK inhibitors show high efficacy initially, further abnormalities in MAPK signaling components and activation of other signaling pathways that bypass MAPK signaling can cause cancer cells to become unresponsive to the inhibitors, making MEK inhibitors alone ineffective in curing cancer (Non-Patent Document 3). Similarly, RAF inhibitors have shown significant clinical activity in patients with BRAF V600E or BRAF V600K melanoma, but the emergence of drug resistance limits the efficacy of RAF inhibitors alone (Non-Patent Document 4).

[0006] WO2010 / 016526 WO2011 / 096535

[0007] J. Hematol. Oncol. , 2020, 17; 13 (1): 113 Biol Cell. , 2001, 93(1-2):53-62. Int. J. Mol. Sci. , 2020, 21(3):1102. Nat Med. 2013, 19(11):1401-9.

[0008] 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.

[0009] As a result of extensive 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 MAPK pathway inhibitor exhibits an extremely strong antitumor effect, leading to the completion of the present invention.

[0010] Specifically, the present invention relates to the following embodiments (1) to (18).

[0011] (1) A pharmaceutical for treating and / or preventing cancer, comprising a combination, either together or separately, of an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein and a MAPK (Mitogen-activated Protein Kinase) pathway inhibitor.

[0012] (2) The pharmaceutical according to (1), wherein the MAPK pathway inhibitor comprises a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, an ERK inhibitor, or a combination of any two or more thereof.

[0013] (3) The pharmaceutical according to (2), wherein the MEK inhibitor is at least one selected from the group consisting of trametinib, cobimetinib, selumetinib, refametinib, SL-327, and derivatives thereof.

[0014] (4) The pharmaceutical according to (2), wherein the RAS inhibitor is at least one selected from the group consisting of sotorasib, lonafarnib, salirasib, and derivatives thereof.

[0015] (5) The pharmaceutical according to (2), wherein the RAF inhibitor is at least one selected from the group consisting of dabrafenib, ZM 336372, and derivatives thereof.

[0016] (6) The pharmaceutical according to (2), wherein the ERK inhibitor is at least one selected from the group consisting of bosutinib, SCH772984, and derivatives thereof.

[0017] (7) The pharmaceutical according to any one of (1) to (6), wherein the antibody or fragment thereof 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.

[0018] (8) The pharmaceutical according to any one of (1) to (7), wherein the antibody or fragment thereof has immunological reactivity with the extracellular domain of CAPRIN-1 protein present on the surface of cancer cells.

[0019] (9) The pharmaceutical according to any one of (1) to (8), 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.

[0020] (10) The pharmaceutical according to any one of (1) to (9), wherein the antibody is a monoclonal antibody or a polyclonal antibody.

[0021] (11) The pharmaceutical product according to any one of (1) to (10), wherein the antibody or a fragment thereof is any one of the following (A) to (M): (A) an antibody or a fragment thereof 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 a fragment thereof 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 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 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.

[0022] (12) The pharmaceutical according to any one of (1) to (11), 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.

[0023] (13) The pharmaceutical according to any one of (1) to (12), wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, or a single-chain antibody.

[0024] (14) The pharmaceutical agent according to any one of (1) to (13), wherein the cancer is a cancer that expresses CAPRIN-1 protein on the cell membrane surface.

[0025] (15) The pharmaceutical according to any one of claims (1) to (14), wherein the cancer is melanoma, lung cancer, thyroid cancer, colon cancer, prostate cancer, ovarian cancer, pancreatic cancer, kidney cancer, breast cancer, gastric cancer, bile duct cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck 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, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, basal cell carcinoma, Paget's disease, or skin cancer.

[0026] (16) 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 MAPK pathway inhibitor.

[0027] (17) A drug efficacy enhancer for a pharmaceutical composition for treating and / or preventing cancer, which comprises as an active ingredient a MAPK pathway inhibitor, and which comprises as an active ingredient an antibody or a fragment thereof immunologically reactive with CAPRIN-1 protein.

[0028] (18) 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 MAPK pathway inhibitor, together or separately.

[0029] This specification includes the disclosure of Japanese Patent Application No. 2021-122072, which is a priority document of the present application.

[0030] The combined use of the antibody against the CAPRIN-1 protein or a fragment thereof according to the present invention and a MAPK pathway inhibitor exhibits a stronger antitumor effect than the use of an antibody against the CAPRIN-1 protein alone or an existing chemotherapeutic agent alone. Therefore, the combined use of an antibody against the CAPRIN-1 protein and a MAPK pathway inhibitor is effective in treating or preventing cancer.

[0031]

[0033] Figure 1 shows human monocyte (THP-1)-mediated phagocytic activity by a combination of an anti-CAPRIN-1 antibody and trametinib against human cancer cell lines. Reference number 1 shows phagocytic activity against a human melanoma cell line (A375), reference number 2 shows phagocytic activity against a human colon cancer cell line (HCT116), reference number 3 shows phagocytic activity against a human prostate cancer cell line (DU145), and reference number 4 shows phagocytic activity against a human lung cancer cell line (A549). Hatched bars show a test group where no concomitant drug was added (DMSO was added instead of the drug). Black bars show a test group where trametinib was added.

[0034] Figure 1 shows human monocyte (THP-1)-mediated phagocytic activity by a combination of an anti-CAPRIN-1 antibody and various drugs against the human colon cancer cell line HCT116. 5 shows the phagocytic activity in the following test groups: Reference No. 5; no combined drug added test group (DMSO was added to each cell instead of a drug); Reference No. 6; trametinib combined test group (50 nM); Reference No. 7; fluorouracil (5-FU) combined test group (0.4 μg / mL); and Reference No. 8; irinotecan combined test group (15 μM). This figure shows the phagocytic activity mediated by human monocyte cells (THP-1) in the combined use of an anti-CAPRIN-1 antibody and various drugs against the human colon cancer cell line HCT116. Reference number 9: no combined drug added test group, Reference number 10: lonafarnib combined test group (10 μM), Reference number 11: sotorasib combined test group (10 μM), Reference number 12: salirasib combined test group (100 μM), Reference number 13: selumetinib combined test group (10 μM), Reference number 14: refametinib combined test group (1000 nM), Reference number 15: SL-327 combined test group (10 μM), Reference number 16: cobimetinib combined test group (800 nM), Reference number 17: bosutinib combined test group (10 μM). Error bars indicate standard deviation (S.D.). Student's t test showed that the phagocytic activity in the drug combination test group was significantly higher than that in the drug-free test group (significance level 5%). **: p<0.01, ***: p<0.001.

[0033] Figure 1 shows the phagocytic activity mediated by human monocyte cells (THP-1) in the human colon cancer cell line HCT116 when an anti-CAPRIN-1 antibody is used in combination with various drugs. Reference number 18 shows the phagocytic activity in a test group with no combined drug, Reference number 19 shows the phagocytic activity in a test group with combined drug administration (10 μM), and Reference number 20 shows the phagocytic activity in a test group with combined drug administration (100 μM). Figure 1 shows the phagocytic activity mediated by human monocyte cells (THP-1) in the human colon cancer cell line HCT116 when an anti-CAPRIN-1 antibody is used in combination with various drugs. Reference number 21 shows the phagocytic activity in a test group with no combined drug administration, and Reference number 22 shows the phagocytic activity in a test group with combined drug administration (10 μM). Error bars indicate standard deviation (S.D.). As a result of Student's t test, the phagocytic activity in the SCH772984 combined test group was significantly higher than that in the combined drug-free test group (p<0.001; significance level 5%).

[0032] The antitumor effect of the antibody against the CAPRIN-1 protein or a fragment thereof (hereinafter referred to as "anti-CAPRIN-1 antibody") used in the present invention in combination with a MAPK pathway inhibitor is preferably evaluated by examining the phagocytic activity of cancer cells by immune cells when cancer cells are co-cultured with immune cells in vitro, as described below. Here, the immune cells used in evaluating the antitumor effect in vitro may be any blood cells that have phagocytic activity, and are preferably human monocytes (THP-1 or U937). When an antibody binds to cancer cells, it is recognized by the immune cells and kills the cancer cells via the phagocytic activity of the immune cells. Therefore, it is possible to predict the antitumor effect in vivo by evaluating the antitumor effect in vitro.

[0033] As used herein, the terms "coadministration" and "combination" refer to the administration or addition of an anti-CAPRIN-1 antibody and a MAPK pathway inhibitor as independent active ingredients to the same organism or cell simultaneously or at a predetermined interval. The intervals may be simultaneous administration, or may be 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 2 weeks, 3 weeks, or 4 weeks later. Either the anti-CAPRIN-1 antibody or the MAPK pathway inhibitor may be administered or added when it exhibits its anti-tumor effect.

[0034] The term "comprising a combination of drugs together or separately" as used herein means that multiple drugs are contained in a form that can be administered to a patient simultaneously or separately, and this form may be, for example, the form of a so-called mixed preparation in which multiple drugs are mixed, or the form of a so-called kit preparation (pharmaceutical kit) in which multiple drugs are contained as individual preparations. This form also includes the form of a kit preparation in which multiple drugs are contained in any combination in two or more preparations.

[0035] Such a kit preparation according to the present invention may be, for example, a kit preparation comprising a preparation (or pharmaceutical composition) containing an anti-CAPRIN-1 antibody and a preparation (or pharmaceutical composition) containing a MAPK pathway inhibitor.

[0036] 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 as long as it can exert an anti-tumor effect, and the antibody may be a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, or a non-human animal antibody.

[0037] Furthermore, subjects to be treated and / or prevented from cancer in the present invention are mammals such as primates, pet animals, livestock, and sport animals, preferably humans, dogs, and cats, more preferably humans.

[0038] The pharmaceutical composition and method for treating and / or preventing cancer according to the present invention, which comprise an anti-CAPRIN-1 antibody and a MAPK pathway inhibitor as active ingredients, are described below.

[0039] <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, 22, 24, 26, and 28 are the amino acid sequences of mouse CAPRIN-1 protein, and the amino acid sequence represented by SEQ ID NOS: 30 is the amino acid sequence of chicken CAPRIN-1 protein.

[0040] 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.

[0041] In the present invention, an anti-CAPRIN-1 antibody refers to an antibody or a fragment thereof (antigen-binding fragment) 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 specifically binding to the CAPRIN-1 protein or a partial polypeptide thereof in vivo.

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

[0043] A polyclonal antibody (anti-CAPRIN-1 polyclonal antibody) immunologically reactive with the full-length CAPRIN-1 protein or a fragment thereof can be obtained, for example, by immunizing a mouse, a human antibody-producing mouse, a rat, a rabbit, a chicken, or the like with the natural CAPRIN-1 protein, or a fusion protein with GST or the like, or a partial peptide thereof, followed by collecting serum and purifying the obtained serum using ammonium sulfate precipitation, protein A, protein G, a DEAE ion exchange column, an affinity column to which the CAPRIN-1 protein or a partial peptide is bound, or the like.

[0044] The nucleotide sequence and amino acid sequence of CAPRIN-1 and its homologs used in the immunization can be obtained, for example, by accessing GenBank (NCBI, USA) and using algorithms such as BLAST and FASTA (Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90: 5873-5877, 1993; Altschul et al., Nucleic Acids Res. 25: 3389-3402, 1997). Methods 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.

[0045] 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.

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

[0047] 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.

[0048] 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).

[0049] 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 contain specific variable regions called complementarity-determining regions (CDRs), which confer binding specificity to the antibody. The relatively conserved portions of the variable regions are called framework regions (FRs). Complete heavy and light chain variable regions each contain four FRs connected by three CDRs (CDR1 to CDR3).

[0050] 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.

[0051] 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.

[0052] Non-human animal antibodies can be obtained by immunizing a non-human 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 then administered to the animal multiple times. After immunizing an animal and confirming that the serum contains anti-CAPRIN-1 antibodies, the serum is obtained and purified using ammonium sulfate precipitation, protein A, protein G, a DEAE ion exchange column, or an affinity column coupled with CAPRIN-1 protein or a partial peptide, as described above, to obtain non-human animal antibodies. 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).

[0053] 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).

[0054] The anti-CAPRIN-1 antibody used in the present invention may have amino acids in the variable region (e.g., FR) or constant region substituted with other amino acids. The amino acid substitutions are single or multiple, 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).

[0055] 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:

[0056] 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) and antitumor compounds (e.g., the antitumor agents exemplified below). The substance to be conjugated to 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 this field.

[0057] 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 bound to fucose.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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:

[0062] 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.

[0063] 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.

[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: 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.

[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: 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] In addition, the following anti-CAPRIN-1 antibodies are also preferably used.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] In the Examples described below, it has been confirmed that the above-mentioned polyclonal antibodies or monoclonal antibodies against the full-length CAPRIN-1 protein or a portion of the polypeptide region expressed on the cell membrane surface of cancer cells exhibit reactivity with the cell membrane surface of multiple human cancer cells, and have shown effective results in human cancer patients, with a remarkable antitumor effect that completely eliminated tumors in some cancer sites.

[0111] <MAPK Pathway Inhibitors> The MAPK pathway refers to a signal transduction pathway that involves the activation of mitogen-activated protein kinase (MAPK) in the RAS / RAF / MEK / ERK pathway and links intracellular responses to growth factor binding to cell surface receptors, and is also referred to in the literature as the MAPK signal pathway, MAPK / ERK signal transduction pathway, RAF-MEK-ERK pathway, RAS / MAPK pathway, or RAS-RAF-MEK-ERK pathway. For a review of the enzymes involved in the MAPK pathway, see, for example, Biochim Biophys Acta. 2007, 1773(8):1263-84. The term MAPK pathway encompasses the many protein components and kinase cascades that are part of this signal transduction pathway, as well as the various targets regulated by this pathway.

[0112] A MAPK pathway inhibitor refers to an inhibitor of the biological activity of any wild-type or mutant form of an enzyme involved in the MAPK pathway. Specific examples of MAPK pathway inhibitors include, but are not limited to, RAS inhibitors, RAF inhibitors, MEK inhibitors, and ERK inhibitors. Furthermore, the MAPK pathway inhibitor may be a therapeutically effective derivative of a substance known as a MAPK pathway inhibitor, provided that it has a MAPK pathway inhibitory effect.

[0113] <RAS inhibitors> RAS inhibitors are drugs that inhibit the activity of RAS, one of the proteins that make up the MAPK pathway. RAS has a molecular weight of 21 kDa and belongs to a large family of monomeric GTPases. The RAS subfamily constitutes a superfamily of small G proteins, which includes the three classical RASs, HRAS, KRAS, and NRAS, as well as R-RAS, TC21 (R-RAS2), M-RAS (R-RAS3), Rap1A, Rap1B, Rap2A, Rap2B, RalA, and RalB. RAS transitions from an inactive state bound to GDP to an activated state bound to GTP in response to various extracellular stimuli. This GDP / GTP exchange reaction is promoted by GEF(s) (guanine-nucleotide exchange factors). Furthermore, GTP-bound RAS is converted back to its GDP-bound form by endogenous GTPase, and this reaction is promoted by GTPase-activating proteins (GAPs). Activated GTP-bound RAS interacts with a wide range of downstream targets, activating downstream signals. One of its major targets is known to be RAF kinase. RAS is a frequently mutated oncogene, with mutations detected in approximately 30% of cancer patients. In recent years, drugs that specifically inhibit the growth of cancers with certain KRAS gene mutations (KRAS G12C mutations) have been approved, and the development of other RAS inhibitors is also underway.

[0114] Specific examples of RAS inhibitors include adagrasib (MRTX849), garsorasib, lonafarnib (SCH66336), salirasib, sotorasib (AMG510), sotorasib racemate, (-)-rasfonin, (Rac)-antineoplaston A10, 6H05 (TFA), antineoplaston A10, and antitumor inhibitors. agent-60, APS6-45, ARS-1620, ARS-853 (ARS853), ASP2453, AZD4625, BAY-293, BI-2852, BI-3406, CASIN, CMC2.24, Deltarasin, Deltarasin hydrochloride, diazepinomicin, farnesyl thiosalicylic acid, FTI-276 trifluoroacetate salt, FTI-277, FTI-277 hydrochloride, GDC-6036, GGTI-286, GGTI-286 hydrochloride, GGTI298 Trifluoroacetate, JDQ-443 (WO2021 / 120890), K20, Kobe0065, Kobe2602, KRAS mutant protein inhibitor 1, L-744,832 Dihydrochloride, LC-2, Manumycin A, MCP110, ML 210, MLS-573151, MRTX0902, MRTX1133, MRTX1133 formic, MRTX-1257, MRTX849 ethoxypropanoic acid, MRTX-EX185, NSC-658497, Oncrasin-1, Pan-RAS-IN-1, PHT-7.3, PROTAC K-Ras Degrader-1, PROTAC SOS1 degrader-2, RAS GTPase inhibitor 1, RAS inhibitor Abd-7, Ras Inhibitory Peptide, Ras / Rac Transformation Blocker, SCH 51344,RAS / RAS-RAF-IN-1, Rasafin, RM-018, RMC-0331, RTIL 13, SAH-SOS1A, SAH-SOS1A TFA, SCH 51344, SOS1-IN-10 (WO2022 / 017519; compound 8), SOS1-IN-11, SOS1-IN-12, SOS1-IN-13, SOS1-IN-3 (WO2019 / 122129A1; compound I-1), SOS1-IN-4 (WO2021 / 228028; example 65), SOS1-IN-5 (WO2021 / 203768; compound 4), SOS1-IN-6, SOS1-IN-7, SOS1-IN-8 (WO2022 / 017339; compound 2), SOS1-IN-9 (WO2022 / 028506; compound 302), XRp44X, KRpep-2d, KY1220, NAV-2729, Zoledronic acid (ZOL 446), BQU57, CID-1067700, Fendiline hydrochloride, ARS-1323 (WO2015 / 054572), ARS-1630 (WO2015 / 054572), KRas G12C inhibitor 1 (US2018 / 0072723), KRas G12C inhibitor 2 (WO202KRAS G12C inhibitor 21(WO2021 / 219090;example 7)、KRAS G12C inhibitor 22(WO2021 / 219072A1;example 120)、KRAS G12C inhibitor 23(WO2021 / 218939;compound 1)、KRAS G12C inhibitor 24(CN113563323A;compound 1)、KRAS G12C inhibitor 25(WO2021 / 216770;compound 3)、KRAS G12C inhibitor 26(WO2021 / 109737)、KRAS G12C inhibitor 27(WO2021 / 109737)、KRAS G12C inhibitor 28(WO2021 / 113595;Example 1)、KRAS G12C inhibitor 29(WO2021 / 252339)、KRAS G12C inhibitor 30(WO2021 / 252339A1;compound 2)、KRAS G12C inhibitor 31(WO2021 / 252339)、KRAS G12C inhibitor 32、KRAS G12C inhibitor 33(WO2021 / 244603A1;compound 1)、KRAS G12C inhibitor 34(WO2021 / 239058)、KRAS G12C inhibitor 35(CN112920183A;compound 3)、KRAS G12C inhibitor 36(WO2021 / 121367;compound 1-2)、KRAS G12C inhibitor 37(WO2018 / 143315;compound 65)、KRAS G12C inhibitor 38(WO2021 / 129820;compound 171)、KRAS G12C inhibitor 39(WO2019 / 099524;compound 494)、KRas G12C inhibitor 4(WO2020 / 233592;compound 2)、KRAS G12C inhibitor 40(WO2021 / 129824;compound 70)、KRAS G12C inhibitor 41(WO2021 / 129824;compound 121)、KRAS G12C inhibitor 42(WO2020 / 146613;compound 10)、KRAS G12C inhibitor 43、KRAS G12C inhibitor 44、KRAS G12C inhibitor 45、KRAS G12C inhibitor 46、KRAS G12C inhibitor 47、KRAS G12C inhibitor 48、KRAS G12C inhibitor 49、KRAS G12C inhibitor 5、KRAS G12C inhibitor 50、KRAS G12C inhibitor 51、KRAS G12C inhibitor 52、KRAS G12C inhibitor 53、KRAS G12C inhibitor 54、KRAS G12C inhibitor 55、K-Ras G12C-IN-1、K-Ras G12C-IN-2、K-Ras G12C-IN-3、K-Ras G12C-IN-4、KRAS G12D inhibitor 1、KRAS G12D inhibitor 10(WO2021 / 108683;compound 34)、KRAS G12D inhibitor 11(WO2021 / 108683;compound 52)、KRAS G12D inhibitor 12(WO2021 / 108683;compound 134)、KRAS G12D inhibitor 13(WO2021 / 108683;compound 142)、KRAS G12D inhibitor 14、KRAS G12D inhibitor 15(WO2022 / 042630;compound 243)、KRAS G12D inhibitor 3 TFA(WO2022 / 002102;compound 146)、KRAS G12D inhibitor 3(WO2022 / 002102;compound 146)、KRAS G12D inhibitor 5、KRAS G12D inhibitor 6(WO2021 / 108683;compound 112)、KRAS G12D inhibitor 7 (WO2021 / 108683; compound 114), KRAS G12D inhibitor 8 (WO2021 / 107160; compound 2), KRAS G12D inhibitor 9 (WO2021 / 108683; compound 20), KRAS inhibitor-10 (WO2021 / 005165), KRAS inhibitor-11, KRAS inhibitor-12, KRAS inhibitor-13, KRAS inhibitor-14, KRAS inhibitor-15, KRAS inhibitor-16, KRAS inhibitor-18, KRAS inhibitor-4, KRAS inhibitor-6 (WO2017 / 087528; compound A), KRAS inhibitor-7 (WO2017 / 087528; compound B), KRAS inhibitor-8 (WO2017 / 087528; compound C), KRAS inhibitor-9, K-Ras (G12C) inhibitor 12, K-Ras (G12C) inhibitor 6, K-Ras (G12C) inhibitor 9, K-Ras-IN-1, and pharmaceutically acceptable (known) salts or (known) derivatives thereof. Among these RAS inhibitors, preferred are adagrasib, garsolasib, lonafarnib, salirasib, sotorasib, zoledronic acid (ZOL 446), antineoplaston A10, or pharmaceutically acceptable (known) salts or (known) derivatives thereof, and more preferred are lonafarnib, salirasib, sotorasib, or pharmaceutically acceptable (known) derivatives thereof.

[0115] Lonafarnib inhibits farnesyltransferase, which activates H-ras, K-ras-4B, and N-ras. The CAS number of lonafarnib is 193275-84-2, and its IUPAC name is 4-[2-[4-[(2R)-6,15-dibromo-13-chloro-4-azatriclo[9.4.0.0 ３，８]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide, molecular formula C ２７ H ３１ Br ２ C ｌ N ４ O ２ , molecular weight is 638.8.

[0116] Salirasib (also known as farnesylthiosalicylic acid, FTS) inhibits RAS methylation (activated RAS). The CAS number of salirasib is 162520-00-5, its IUPAC name is 2-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl]sulfanylbenzoic acid, and its molecular formula is C ２２ H ３０ O ２ S, molecular weight is 358.5.

[0117] Sotorasib inhibits KRAS G12C. Its CAS number is 2252403-56-6, its IUPAC name is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one, and its molecular formula is C ３０ H ３０ F ２ N ６ O ３ , molecular weight is 560.59.

[0118] <RAF Inhibitors> RAF inhibitors are drugs that inhibit the activity of RAF, one of the proteins that make up the MAPK pathway. RAF kinase is a family of three serine / threonine kinases associated with retroviral oncogenes, consisting of three members: ARAF, BRAF, and CRAF (RAF1). BRAF contains an activation loop, a central structure in signal transduction. When BRAF is activated, this loop is usually phosphorylated at multiple sites, contributing to stabilization of the activated form. A specific amino acid (residue 600) within this loop is the site of oncogenic mutation. When the amino acid at this position is changed from valine to glutamic acid (called a V600E mutation, where V is valine and E is glutamic acid), shifting the position of this loop from its resting state, the enzyme becomes constantly active, allowing cancer cells to proliferate without any normal regulation. BRAF mutations have been observed in various cancers, including melanoma and colorectal cancer. CRAF mutations have been observed in multiple cancer types, and its activation is known to be involved in resistance to BRAF inhibitors in malignant melanoma. Activation of RAF kinase requires interaction with RAS-GTP, dephosphorylation, and phosphorylation by SRC family protein tyrosine kinases and other protein serine / threonine kinases, as well as dimerization. The activated RAF dimer then phosphorylates and activates MEK.

[0119] Specific examples of RAF inhibitors include agerafenib, agerafenib hydrochloride, hydrochloride), Belvarafenib (HM95573 / GDC-5573 / RG6185), Dabrafenib (GSK2118436A / GSK2118436), Encorafenib-13C,d3, Naporafenib (LXH254), Lineterkib, Tovorafenib (MLN2480), Vemurafenib (PLX4032 / RG7204 / RO5185426), (Z)-GW 5074, Antitumor agent-60, AZ 628, AZ304, BI-882370, B-Raf IN 1, B-Raf IN 2 (WO2021 / 116055), B-Raf IN 5, B-Raf IN 6, B-Raf IN 7, B-Raf IN 8, B-Raf IN 9, BRAF inhibitor (WO2011 / 103196; Compound P-0850), BRAF V600E / CRAF-IN-1, BRAF V600E / CRAF-IN-2, CCT196969, Doramapimod (BIRB 796), Encorafenib-13C, d3, GDC-0879, GNE-9815, GSK-114, GW 5074, HG6-64-1 (HMSL 10017-101-1, WO2011 / 090738; example 9 (XI-1)), L-779450, LXH254, LY3009120 (DP-4978), MCP110, ML786 dihydrochloride, Pan-RAF kinase inhibitor 1 (WO2021 / 110141;compound 16B), PLX-4720, PLX-4720-d7, PLX7904, PLX7922, PLX8394, PROTAC B-Raf degrader 1, Raf inhibitor 1, Raf inhibitor 1 dihydrochloride, Raf inhibitor 2 (EP1003721B1), RAF mutant-IN-1 (WO2019107987A1), RAF709, RAF-IN-1, RAS / RAS-RAF-IN-1, Ro 5126766 (CH5126766), RRD-251, SB-590885, SB-682330A, SHR902275, TAK-580 (MLN 2480 / BIIB-024), TAK-632, TBAP-001 (WO2015 / 075483), ZM 336372, and pharmaceutically acceptable (known) salts or (known) derivatives thereof. Among these RAF inhibitors, agerafenib, belbalafenib, dabrafenib, naporafenib, lineterquib, toborafenib, vemurafenib, or pharmaceutically acceptable (known) salts or (known) derivatives thereof are preferred, and dabrafenib (GSK2118436A / GSK2118436), ZM 336372, or pharmaceutically acceptable (known) derivatives thereof are more preferred;

[0120] Dabrafenib (GSK2118436A / GSK2118436) inhibits the kinase activity of mutant BRAF (V600E, V600K, and V600D). The CAS number of dabrafenib is 1195765-45-7, its IUPAC name is N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, and its molecular formula is C ２３ H ２０ F ３ N ５ O ２ S ２Dabrafenib is also used as a mesylate salt, and its CAS number is 1195768-06-9, its IUPAC name is N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide; methanesulfonic acid, and its molecular formula is C ２３ H ２０ F ３ N ５ O ２ S ２ ・CH ４ SO ３ The molecular weight is 615.7. When simply referred to as dabrafenib in this specification, it is a general term for the free form and mesylate of dabrafenib.

[0121] ZM 336372 (also known as Zinc00581684) inhibits the kinase activity of CRAF. The CAS number of ZM 336372 is 208260-29-1, its IUPAC name is 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]benzamide, and its molecular formula is C ２３ H ２３ N ３ O ３ , molecular weight is 389.4.

[0122] <MEK Inhibitors> MEK inhibitors are drugs that inhibit the activity of MEK (MAPK / ERK Kinase), one of the proteins that make up the MAPK pathway. MEK is a dual-specificity kinase (an enzyme that possesses both serine / threonine kinase and tyrosine kinase activity) that is activated upon phosphorylation downstream of RAF in the MAPK signaling pathway. A typical phosphorylation substrate for MEK is ERK (extracellular signal-regulated kinase), and one of the main effects of MEK inhibitors is the inhibition of ERK phosphorylation. ERK is primarily localized in the cytoplasm when inactive, but upon activation upon phosphorylation, it translocates into the nucleus and phosphorylates various transcription factors, including c-Jun, c-Myc, c-Fos, and ETS1. ERK regulates the expression of many genes through the control of the activity of these transcription factors. MEK has multiple isoforms, among which MEK1 and MEK2 play important roles in the development and progression of cancer and are responsible for signal transduction in the MAPK pathway. Therefore, it is preferable that the MEK inhibitor is an inhibitor of MEK1 and / or MEK2.

[0123] Specific examples of MEK inhibitors include trametinib (GSK1120212 / JTP-74057), cobimetinib (GDC-0973 / XL518), binimetinib (MEK162 / ARRY-162 / ARRY-438162), selumetinib (AZD6244 / ARRY-142886), mirdametinib, and pelitinib (EKB-569 / AS703026 / MSC1936369B / SAR 245509), Renametinib (BAY 869766 / RDEA119), Zapnometinib (PD0184264 / ATR-002), Pimasertib (AS703026 / MSC1936369B / SAR 245509), (S,R,S)-AHPC-Me-C10-Br, 1-Allylcyclopropane-1-sulfonyl Chloride, APS-2-79, APS-2-79 hydrochloride, APS-2-79 hydrochloride, Arctigenin, ARRY142866, ARRY438162, AZD6244, AZD8330 (ARRY-424704 / ARRY-704), Balamapimod (MKI 833), BAY 869766, BI-847325, C16-PAF, CH4987655, CH5126766, CHMFL-EGFR-202, CI-1040 (PD 184352), CIF, CInQ-03, CKI27, CS-3006, E6201 (ER-806201), EBI-1051, Epiberberine chloride, G-573, GDC-0623 (RG 7421 / MEK inhibitor 1), GDC0973, GSK1120212, Hypothemycin, Isorhamnetin, JTP-74057, Lidocaine, Lidocainehydrochloride, Lidocaine-d10, Lidocaine-d10 hydrochloride, Lidocaine-d10 N-Oxide, MAP855, MEK Inhibitor Set, MEK Inhibitor VIII, MEK inhibitor, MEK / PI3K-IN-1, MEK / PI3K-IN-2, MEK1 / 2 Inhibitor IV, MEK1 / 2-IN-2, MEK162 (ARRY438162), MEK-IN-1 (WO2008 / 076415), MEK-IN-5, MS432, MSC-2015103B, MSC-1936369, Myricetin, PD 184352, PD 198306, PD0325901 (MEK1 / 2 Inhibitor III), PD0325901-O-C2-dioxolane, PD184161, PD318088, PD-334581, PD98059, RDEA 119, RG7167, RG7304, RG7420, RGB-286638, RGB-286638 free base, Ro 5126766 (CH5126766), RO4987655 (CH4987655), SHR-7390, SL-327, TAK-733, TCS PIM-1 1 (SC 204330), trans-Zeatin, trans-Zeatin-d5, U0124, U0126, U0126-EtOH, XL518, and pharmaceutically acceptable (known) salts or (known) derivatives thereof. Among these MEK inhibitors, preferred are trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib, pelitinib, refametinib, zapnometinib, pimasertib, SL-327, or a pharmaceutically acceptable (known) salt or (known) derivative thereof, and more preferred are trametinib, cobimetinib, selumetinib, refametinib, SL-327, or a pharmaceutically acceptable (known) derivative thereof.

[0124] Trametinib (GSK1120212 / JTP-74057) has a CAS number of 871700-17-3, an IUPAC name of N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide, and a molecular formula of C ２６ H ２３ FIN ５ O ４ and a molecular weight of 615.4. Trametinib is poorly soluble in its pure form, so it is also used as a dimethyl sulfoxide (DMSO) adduct. The DMSO adduct of trametinib (trametinib DMSO solvate) has the CAS number 1187431-43-1, the IUPAC name is N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide; methylsulfinylmethane, and the molecular formula is C ２８ H ２９ FIN ５ O ５ S, molecular weight is 693.5. When simply referred to as trametinib in this specification, it is a general term for the free form and DMSO adduct of trametinib.

[0125] Cobimetinib inhibits the kinase activity of MEK1 and MEK2, and its CAS number is 934660-93-2. Its IUPAC name is [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanene, and its molecular formula is C ２１ H ２１ F ３ IN ３ O ２Cobimetinib is also used as a fumarate salt, and has the CAS number 1369665-02-0, IUPAC name (E)-but-2-enedioic acid; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methaneone, and molecular formula (C ２１ H ２１ F ３ IN ３ O ２ ) ２ ・C ４ H ４ O ４ The molecular weight is 1178.7. When simply referred to as cobimetinib in this specification, it is a general term for the free form and fumarate of cobimetinib.

[0126] Selumetinib inhibits the kinase activity of MEK. Its CAS number is 606143-52-6, its IUPAC name is 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide, and its molecular formula is C １７ H １５ BrClFN ４ O ３ Selumetinib is also used as a sulfate salt, and its CAS number is 943332-08-9, its IUPAC name is 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; sulfuric acid, and its molecular formula is C １７ H １５ BrClFN ４ O ３ ・H ２ SO ４ The molecular weight is 555.8. When simply referred to as selumetinib in this specification, it is a general term for the free form and sulfate of selumetinib.

[0127] Lefametinib inhibits the kinase activity of MEK1 and MEK2. The CAS number of lefametinib is 923032-37-5, its IUPAC name is N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide, and its molecular formula is C １９ H ２ 0F ３ IN ２ O ５ S, molecular weight is 572.3.

[0128] SL-327 inhibits the kinase activity of MEK1 and MEK2. The CAS number of SL-327 is 305350-87-2, its IUPAC name is (Z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile, and its molecular formula is C １６ H １２ F ３ N ３ S, molecular weight is 335.3.

[0129] <ERK inhibitors> ERK inhibitors are drugs that inhibit the activity of ERK, one of the proteins that make up the MAPK signaling pathway. ERK (extracellular signal-regulated kinase) is a serine / threonine kinase, and generally refers to the 44 kDa ERK1 and 42 kDa ERK2 isoforms. When the low-molecular-weight G protein RAS is activated, RAF and MEK are activated in sequence, and when the activated MEK phosphorylates the tyrosine and threonine in the activation loop of ERK, the kinase activity of ERK itself is turned on. This series of signal transduction flows is the mainstream of the MAP kinase pathway and is called the RAS-RAF-MEK-ERK signaling cascade. Activated ERK is known to be involved in the expression of various cellular functions such as cell proliferation, differentiation, survival, cell motility, and tumorigenesis by phosphorylating a wide variety of substrates.

[0130] Specific examples of ERK inhibitors include tizaterkib (WO2017 / 080979A1), alobresib (GS-5829), bortezomib (PS-341), bosutinib (SKI-606), edaxeterkib, ravoxertinib (GDC-0994), lineterkib, temterkib (LY3214996), ulixertinib (BVD-523), and ERK1 / 2 inhibitors. 4 (WO2020 / 238776), ERK1 / 2 inhibitor 5 (WO2020 / 238776), ERK1 / 2 inhibitor 6 (WO2021 / 063335; compound 1), ERK1 / 2 inhibitor 7 (WO2021 / 110168; WX006), ERK1 / 2 inhibitor 8 (WO2021 / 110168; WX007), ERK1 / 2 inhibitor 3 (WO2021 / 218912; compound 1), (E)-Osmundacetone, (rel)-AR234960, 2,5-Dihydroxyacetophenone, ACA-28, Adjudin, AG126, AKT-IN-11, Astragaloside IV, ASTX-029, AZD0364 (ATG-017), Bohemine, C16-PAF, Cafetol, CC-90003, Cearoin, Chicanine, CHPG, CHPG sodium salt, CKLF1-C27 TFA, CKLF1-C27, Corynoxeine, Cucurbitacin IIb, DEL-22379, Deltonin, DMU-212, EF24, Enniatin A1, Enniatin B, Enniatin B1, epi-Eriocalyxin A, ERK1 / 2 inhibitor 1, ERK1 / 2 inhibitor 2, ERK2 IN-1, ERK-IN-2, ERK-IN-3, ERK-IN-3 benzenesulfonate, FR 180204, Gypenoside L, HIOC, Hirsutenone, HI-TOPK-032,Honokiol, I-191, KO-947, Lidocaine, LM22B-10, Longdaysin, Loureirin B, Magnolin, Methylthiouracil, MK-8353 (SCH900353), Mogrol, Motixafortide (BL-8040), MRTX-1257, Mulberroside A, Nitidine chloride, NMDAR / TRPM4-IN-2 free base, Otriptolide, Pachymic acid, Pamoic acid disodium, Pamoic acid, PD98059, Piperlongumine, Pluripotin (SC1), SCH772984, Tauroursodeoxycholate, TBHQ, TCS ERK 11e, Tenufoliside A, TIC10 (ONC201), trans-Zeatin, trans-Zeatin-d5, Urolithin B, VX-11e, Withanolide B, Xantocillin, Yoda 1, ZM 241385, and pharmaceutically acceptable (known) salts or (known) derivatives thereof. Among these ERK inhibitors, preferred are tizatatorquib, allobresib, bortezomib, bosutinib, edaxeterquib, lavoxertinib, lineterquib, lineterquib hydrochloride, temterquib, ulixertinib, SCH772984, or pharmaceutically acceptable (known) salts or (known) derivatives thereof, and more preferred are bosutinib, SCH772984, or pharmaceutically acceptable (known) derivatives thereof.

[0131] Bosutinib (SKI-606) is an Src / Abl inhibitor and also inhibits MAPK / ERK. The CAS number of bosutinib is 380843-75-4, its IUPAC name is 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, and its molecular formula is C ２６ H ２９ Cl ２ N ５ O３ Bosutinib is also used as a hydrate, and its CAS number is 918639-08-4, its IUPAC name is 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; hydrate, and its molecular formula is C ２６ H ２９ Cl ２ N ５ O ３ ・H ２ The molecular weight is 548.5 and the molecular weight is 548.5. When simply referred to as bosutinib in this specification, it is a general term for the free form and hydrate of bosutinib.

[0132] SCH772984 inhibits the kinase activity of ERK1 / 2, and its CAS number is 942183-80-4. Its IUPAC name is (3R)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide, and its molecular formula is C ３３ H ３３ N ９ O ２ , molecular weight is 587.7.

[0133] <Other Drugs> In addition to the anti-CAPRIN-1 antibody and MAPK pathway inhibitor, the active ingredient of the pharmaceutical of the present invention may also contain an antitumor agent 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 the known antitumor agent, and specific examples include 5-fluorouracil, irinotecan, oxaliplatin, carboplatin, cisplatin, nedaplatin, gemcitabine, paclitaxel, nab-paclitaxel, imiquimod, immune checkpoint inhibitors, doxorubicin, daunorubicin, cyclophosphamide, methotrexate, thiotepa, busulfan, improsulfan, piposulfan, benzodopa, carboquone, metholedopa, and benzodiazepam. uredopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, bryostatin, calystatin, cryptophycin 1, cryptophycin 8, dolastatin tin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine prednimustine), trophosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, dynemycin, clodronate, esperamicin, aclacinomycin, actinomycin, ausramycin, 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, ansamitocin, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid acid), 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, vinbucil, These include prasugrel, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, difluoromethylolnithine (DMFO), topoisomerase inhibitors, retinoic acid, folinic acid, and pharmaceutically acceptable (known) salts or (known) derivatives thereof.

[0134] <Anti-tumor effect of the present invention> The anti-tumor effect of the combined use of an anti-CAPRIN-1 antibody and a MAPK pathway inhibitor of the present invention can be evaluated in vivo or in vitro. The in vivo anti-tumor effect can be evaluated by administering an anti-CAPRIN-1 antibody and a MAPK pathway 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 in vivo anti-tumor effect can also be evaluated by examining the survival rate of the living body. It can also be evaluated by examining the ability to produce cytokines or chemokines. It can also be evaluated by examining the prevention of cancer, metastasis, or recurrence.

[0135] In vitro antitumor effects can be evaluated by examining the cytotoxicity and phagocytic activity of immune cells when cancer cells are co-cultured with immune cells. Therefore, the antitumor effect of a combination of an anti-CAPRIN-1 antibody and a MAPK pathway inhibitor can be evaluated by adding the anti-CAPRIN-1 antibody and the MAPK pathway inhibitor in combination to a co-culture system of cancer cells and immune cells and examining the cytotoxicity or phagocytic activity of the immune cells against the cancer cells. The immune cells used here may be any blood cells that have cytotoxic or phagocytic activity, preferably human NK cells when assessing cytotoxic activity, or human monocytes (THP-1 or U937) when assessing phagocytic activity. When an antibody binds to cancer cells, it is recognized by immune cells and kills the cancer cells via the cytotoxic or phagocytic activity of the immune cells. Therefore, evaluating the antitumor effect in vitro makes it possible to predict the antitumor effect in vivo.

[0136] 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.

[0137] The combination of an anti-CAPRIN-1 antibody of the present invention with a MAPK pathway inhibitor enhances the in vitro antitumor effect compared to the anti-CAPRIN-1 antibody alone, for example, by 1.1-fold or more, preferably 1.5-fold or more, more preferably 2-fold or more, and even more preferably 3-fold or more.

[0138] <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 CAPRIN-1 protein, particularly a cancer (cell) that expresses CAPRIN-1 protein on the cell membrane surface.

[0139] 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.

[0140] As used herein, the terms "tumor" and "cancer" refer to malignant neoplasms and are used interchangeably.

[0141] The cancer that is the subject of the present invention may be any cancer that expresses CAPRIN-1 protein on the cell membrane surface, preferably melanoma, lung cancer, thyroid cancer, colon cancer, prostate cancer, ovarian cancer, pancreatic cancer, kidney cancer, breast cancer, gastric cancer, bile duct cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck 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, leukemia, lymphoma, liver cancer, sarcoma, fibrosarcoma, mast cell tumor, adrenocortical carcinoma, Ewing's tumor, multiple myeloma, testicular cancer, basal cell carcinoma, Paget's disease, or skin cancer, more preferably melanoma, non-small cell lung cancer, thyroid cancer, colon cancer, or prostate cancer. Furthermore, these cancers may be primary cancers, metastatic cancers, metastatic or recurrent cancers, postoperative cancers, or unresectable cancers. Furthermore, these cancers may have specific gene mutations. Examples of gene mutations include BRAF gene mutations, KRAS gene mutations, and EGFR gene mutations. Note that melanoma is often used synonymously with malignant melanoma or malignant melanoma.

[0142] More specifically, examples of the cancer include Bowen's disease, 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, and neuroepithelial tissue tumors such as glioma and glioblastoma. , neuroblastoma, ependymoma, 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 Tumor, mucinous cystadenocarcinoma, pancreatoblastoma, pancreatic head cell tumor, Frant's tumor, 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, endometrial cancer, fibrosarcoma, bone and joint sarcoma, Ewing's sarcoma, Wilms' tumor, hepatoblastoma, soft tissue sarcoma, acute leukemia, chronic leukemia, spinal cord tumor, soft tissue malignant tumor, Teratomas and head and neck cancers include, but are not limited to, hypopharyngeal cancer, oropharyngeal cancer, tongue cancer, nasopharyngeal cancer, oral cancer, lip cancer, 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 for metastasis or recurrence), pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, retinoblastoma, central nervous system germ cell tumor, Ewing's sarcoma family tumors), etc. Also included are palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, non-parenchymal cancers, and progressive cancers that originate from the above cancers. Furthermore, palpable cancers, subcutaneous cancers, intracutaneous cancers, superficial cancers, dermal cancers, and non-parenchymal cancers that have metastasized or recurred from the above cancers are also included.

[0143] Furthermore, preferred subjects (patients) are mammals, including, for example, primates, pet animals, livestock, sport animals, etc., with humans, dogs, and cats being particularly preferred.

[0144] 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 pharmaceuticals of the present invention, the active ingredient (at least one of an anti-CAPRIN-1 antibody and a MAPK pathway inhibitor) may be appropriately combined with, for example, a pharmacologically acceptable carrier, vehicle, or additive, specifically, sterilized water, physiological saline, an isotonic solution, a buffer (such as a buffer solution), a vegetable oil, an oily liquid, an antioxidant, a solubilizer, an emulsifier, a suspending agent, a surfactant, a stabilizer, a flavoring agent, an excipient, a binder, or the like, 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.

[0145] 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.

[0146] 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.

[0147] 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 MAPK pathway 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 of each active ingredient can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, or from 0.1 to 300 mg, or from 1 mg to 30 mg per kg of body weight per patient, 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.

[0148] <Administration Method> The treatment and / or prevention of cancer using the pharmaceutical preparation for cancer treatment and / or prevention of the present invention includes various forms in addition to the administration as a pharmaceutical preparation described above. For example, each active ingredient of the pharmaceutical preparation of the present invention can be administered simultaneously, in parallel, or separately in a sequential manner. 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 may be performed following a surgical procedure, or a surgical procedure may be performed between the administration of the first and second agents. Furthermore, the pharmaceutical preparation for cancer treatment and / or prevention of the present invention may be administered in multiple administration cycles. For example, when the active ingredients of the pharmaceutical preparation for cancer treatment and / or prevention 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, this 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 covers the same period. The interval between cycles can vary from 0 to 2 months. The dosage of each active ingredient of the pharmaceutical product 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 the above-mentioned pharmaceutical composition.

[0149] <Pharmaceutical Kit> The pharmaceutical 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 (formulations) in a method for treating and / or preventing cancer, and the package may include instructions for administering each active ingredient. Each active ingredient of the 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. Furthermore, the pharmaceutical kit contains sufficient amounts of each active ingredient for one or more doses so that each active ingredient can be administered according to the administration method described above. <Treatment and / or Prevention Method> Based on the details specifically described above, the present invention provides a method for treating and / or preventing cancer, comprising administering the pharmaceutical of the present invention or the anti-CAPRIN-1 antibody of the present invention and a MAPK pathway inhibitor to a subject (patient). For example, the present invention further provides a method for treating and / or preventing cancer, comprising administering the pharmaceutical of the present invention, etc. to a subject (patient) who has or is suspected of having cancer. Furthermore, in this embodiment, for example, the anti-CAPRIN-1 antibody (antibody or fragment thereof), MAPK pathway inhibitor, and optionally the anti-tumor agent contained in the pharmaceutical product of the present invention may be administered simultaneously or separately to the subject (patient).

[0150] 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.

[0151] Example 1: Preparation of anti-CAPRIN-1 antibodies 100 μg of human CAPRIN-1 recombinant protein prepared according to Example 3 of WO 2010 / 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.

[0152] 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 a heavy chain variable region represented by SEQ ID NO: 114 and the amino acid sequence of a light chain variable region represented by SEQ ID NO: 115.

[0153] 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. This was then inserted into a mammalian expression vector containing the heavy chain constant region of human IgG1. 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. This was then inserted into a mammalian expression vector containing the light chain constant region of human IgG1. The above two recombinant expression vectors were transfected into mammalian cells according to standard methods to obtain a culture supernatant containing humanized monoclonal antibody #1 against CAPRIN-1 (humanized antibody #1). The amino acid sequences of CDR1, CDR2, and CDR3 of the heavy chain of humanized monoclonal antibody #1 are set forth in SEQ ID NOs: 272, 273, and 274, respectively. The amino acid sequences of CDR1, CDR2, and CDR3 of the light chain of humanized monoclonal antibody #1 are shown in SEQ ID NOs: 275, 276, and 277, respectively.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] The expression of the CAPRIN-1 gene has been confirmed by flow cytometry in human cancer cells, including breast cancer cells (BT-474), colon cancer cells (HT-29, HCT116), lung cancer cells (QG56, H1650, A549), gastric cancer cells (NCI-N87), uterine cancer cells (HEC-1-A), prostate cancer cells (22Rv1, DU145), 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 (OC It was confirmed that humanized antibody #1 had stronger fluorescence intensity than the negative control human IgG control antibody, which shows no reactivity to cancer cells, and the rabbit IgG antibody against any of the following cancer cells: lymphoma cells (Ramos), gallbladder cancer cells (TGBC14TKB), fibrosarcoma cells (HT-1080), melanoma cells (G-361, A375), mouse renal cancer cells (Renca), and mouse breast cancer cells (4T1), in which expression of the CAPRIN-1 gene has been confirmed, and that it strongly reacts with the cell membrane surface of the above cancer cells in which CAPRIN-1 is expressed.

[0158] Also, WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO2013 / 018891, W It was also confirmed that the anti-CAPRIN-1 antibodies described in WO2013 / 018889, 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.

[0159] Example 2: In vitro antitumor effect of a combination of an anti-CAPRIN-1 antibody and trametinib The antitumor effect of a combination of an anti-CAPRIN-1 antibody and the MEK inhibitor trametinib was evaluated in vitro. The antitumor effect of a combination of an anti-CAPRIN-1 antibody and the existing chemotherapeutic agents fluorouracil (5-FU) or irinotecan (CPT-11) was also evaluated and compared with the antitumor effect of a combination of an anti-CAPRIN-1 antibody and trametinib. Trametinib (Cat. No. CS-0060) purchased from ChemScene was used.

[0160] Specifically, in each of the trametinib combination test group, the fluorouracil combination test group, and the irinotecan combination test group, human cancer cells pretreated with each combination drug were co-cultured with human monocyte cells (THP-1) in the presence of an anti-CAPRIN-1 antibody, and the antibody-mediated phagocytic activity of the cancer cells by THP-1 was evaluated. The human-derived cancer cells used were the melanoma cell line A375 (used only in the trametinib combination test group), the colon cancer cell line HCT116, the prostate cancer cell line DU145 (used only in the trametinib combination test group), and the lung cancer cell line A549 (used only in the trametinib combination test group). In the trametinib combination test group, human-derived cancer cells were cultured in the presence of trametinib for two days on a 6-well plate, and in the fluorouracil combination test group and the irinotecan combination test group, human-derived cancer cells were cultured in the presence of each combination drug for two days. The concentrations of each concomitant drug were determined so that the proliferation rate of each cancer cell line was reduced by approximately half at the end of the culture. Specifically, trametinib was added at 50 nM, fluorouracil at 0.4 μg / mL, and irinotecan at 15 μM to HCT116, trametinib at 50 nM to A375, trametinib at 250 nM to DU145, and trametinib at 250 nM to A549. A control group was also prepared in which only DMSO (dimethyl sulfoxide), the solvent for each concomitant drug, was added to a final concentration of 0.1% and the cancer cells were cultured for two days.

[0161] The cultured cancer cell lines were detached using TrypLE Express (Thermo), and calcein-AM was added at a final concentration of 0.02 μg / mL, followed by incubation at 37° C. for 30 minutes to stain the cancer cells. Next, the cells were plated at 1×10 per well. ４ The cells were dispensed into a 96-well plate so that the total number of cells was 10. The cells were then treated with anti-CAPRIN-1 antibody at a final concentration of 5 μg / mL and 1×10 ５ THP-1 was added, and the mixture was incubated at 37°C, 5% CO ２ The cells were cultured for 2.5 hours under the conditions of

[0014] . Thereafter, the cells were washed with PBS (phosphate buffered saline) containing 1% FBS (fetal bovine serum) and reacted with APC (allophycocyanin)-labeled anti-human CD45 antibody at a final concentration of 0.25 μg / mL to stain human monocytes. Dead cells were further stained with propidium iodide (PI) at a final concentration of 0.1 μg / mL, and the fluorescence of each cell was measured by flow cytometry. PI-positive dead cells were excluded during analysis. THP-1, a type of human monocyte, recognizes antibodies bound to cancer cells and phagocytose them. If the cancer cells are stained with calcein-AM, the monocytes that engulf them by phagocytosis will also be calcein-AM positive. Therefore, the phagocytic activity in this evaluation system was calculated as the ratio (%) of APC-positive / Calcein-AM-positive cells to the total Calcein-AM-positive population.

[0162] Evaluation was performed using the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 as the anti-CAPRIN-1 antibody. Results showed that in the test group without concomitant drug, A375, HCT116, DU145, and A549 had cancer cell phagocytic activity of 18%, 11%, 4%, and 4%, respectively. In contrast, in the test group with trametinib, A375, HCT116, DU145, and A549 had cancer cell phagocytic activity of 49%, 45%, 9%, and 7%, respectively. Therefore, the antitumor effect of the anti-CAPRIN-1 antibody against the above four types of human cancer cells was enhanced by approximately 1.8- to 4-fold when used in combination with trametinib ( FIG. 1 ).

[0163] Furthermore, in HCT116, the trametinib combination test group increased the cancer cell phagocytic activity to 45%, while the fluorouracil and irinotecan combination test groups reduced the cancer cell phagocytic activity to 16% and 14%, respectively. In other words, the combination of an anti-CAPRIN-1 antibody and trametinib strongly enhanced the cancer cell phagocytic activity compared to the combination of an anti-CAPRIN-1 antibody and the above-mentioned existing chemotherapeutic agents (Figure 2).

[0164] Also, 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 / 0 The combined use of trametinib with the anti-CAPRIN-1 antibodies described in WO 2013 / 18883, WO 2013 / 125636, WO 2013 / 125654, WO 2013 / 125640, WO 2013 / 147169, WO 2013 / 147176, and WO 2015 / 020212 also results in an enhancement of cancer cell phagocytic activity against human cancer cells similar to the combined use of anti-CAPRIN-1 humanized antibody #1 with trametinib.

[0165] Example 3 In Vitro Antitumor Effect of Combination Use of Anti-CAPRIN-1 Antibody and RAS Inhibitor The antitumor effect of combination use of an anti-CAPRIN-1 antibody and a RAS inhibitor was evaluated in vitro. The RAS inhibitors used were lonafarnib (Cat. No. S2797), sotorasib (Cat. No. S8830), and salirasib (Cat. No. S7684), all purchased from Selleck.

[0166] Specifically, in each RAS inhibitor combination test group, human cancer cells that had been previously treated with each combination drug were co-cultured with human monocyte cells (THP-1) in the presence of an anti-CAPRIN-1 antibody, and the antibody-mediated phagocytic activity of cancer cells by THP-1 was evaluated.

[0167] HCT116, a colon cancer cell line, was used as the human cancer cells. For the lonafarnib combination test group, sotorasib combination test group, and salirasib combination test group, human cancer cells were cultured for two days in the presence of each of the combination drugs on a 6-well plate. Specifically, lonafarnib was added to HCT116 at concentrations of 10 μM, sotorasib at 10 μM, and salirasib at 100 μM. A control group without the addition of any of the combination drugs was also set up, and cancer cells were cultured for two days in advance in the absence of any of the combination drugs.

[0168] The cultured cancer cell lines were detached using TrypLE Express (Thermo), and calcein-AM was added at a final concentration of 0.04 μg / mL, followed by incubation at 37° C. for 10 minutes to stain the cancer cells. Next, the cells were plated at 5×10 per well. ３ The cells were then dispensed into a 96-well plate so that the total number of cells was 1.25 × 10 cells / well. The final concentration of the anti-CAPRIN-1 antibody was 1 μg / mL. ５ THP-1 was added, and the mixture was incubated at 37°C, 5% CO ２ The cells were cultured for 1 hour under the conditions of

[0000] . Thereafter, the cells were washed with PBS (phosphate buffered saline) containing 1% FBS (fetal bovine serum) and reacted with an APC (allophycocyanin)-labeled anti-human CD45 antibody at a final concentration of 0.25 μg / mL to stain the human monocytes. Dead cells were further stained with propidium iodide (PI) at a final concentration of 0.1 μg / mL, and the fluorescence of each cell was measured by flow cytometry. PI-positive dead cells were excluded during analysis. THP-1, a type of human monocyte, recognizes antibodies bound to cancer cells and phagocytose them. If the cancer cells are stained with calcein-AM, the monocytes that engulf them by phagocytosis will also be calcein-AM positive. Therefore, the phagocytic activity in this evaluation system was calculated as the ratio (%) of APC-positive / Calcein-AM-positive cells to the total Calcein-AM-positive population.

[0169] Evaluation using the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 as the anti-CAPRIN-1 antibody showed 50% cancer cell phagocytic activity in HCT116 in the test group without concomitant drug. In contrast, in the test groups with lonafarnib, sotorasib, and salirasib, cancer cell phagocytic activity was 59% to 80%. Student's t test showed that the phagocytic activity in the test group with lonafarnib, sotorasib, and salirasib combined was significantly higher than that in the test group without concomitant drug (p<0.001, p<0.01, and p<0.001, respectively; significance level 5%). Therefore, the antitumor effect of the anti-CAPRIN-1 antibody against the above-mentioned human cancer cells was significantly enhanced by about 1.2 to 1.6 times when used in combination with lonafarnib, sotorasib, or salirasib (FIG. 3).

[0170] Also, 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 / The combined use of the anti-CAPRIN-1 antibodies described in WO 2013 / 125636, WO 2013 / 125654, WO 2013 / 125640, WO 2013 / 147169, WO 2013 / 147176, and WO 2015 / 020212 with lonafarnib, sotoranib, or salirasib also results in an enhancement of cancer cell phagocytic activity against human cancer cells similar to the combined use of anti-CAPRIN-1 humanized antibody #1 with lonafarnib, sotoranib, or salirasib.

[0171] Example 4 In Vitro Antitumor Effect of Combination Use of Anti-CAPRIN-1 Antibody and RAF Inhibitor The antitumor effect of combination use of an anti-CAPRIN-1 antibody and a RAF inhibitor was evaluated in vitro. The RAF inhibitors used were dabrafenib (Cat. No. CS-0692) and ZM 336372 (Cat. No. CS-0693) purchased from ChemScene.

[0172] Specifically, in each RAF inhibitor combination test group, human cancer cells that had been previously treated with each combination drug were co-cultured with human monocyte cells (THP-1) in the presence of an anti-CAPRIN-1 antibody, and the antibody-mediated phagocytic activity of cancer cells by THP-1 was evaluated.

[0173] HCT116, a colon cancer cell line, was used as the human cancer cells. For the dabrafenib combination test group and the ZM 336372 combination test group, human cancer cells were cultured for two days in the presence of each of the combination drugs on a 6-well plate. Specifically, dabrafenib was added to HCT116 at a concentration of 10 μM, and ZM 336372 was added at a concentration of 100 μM. A control group was also set up, in which cancer cells were cultured for two days in the absence of any of the combination drugs.

[0174] The cultured cancer cell lines were detached using TrypLE Express (Thermo), and calcein-AM was added at a final concentration of 0.04 μg / mL, followed by incubation at 37° C. for 10 minutes to stain the cancer cells. Next, the cells were plated at 5×10 per well. ３ The cells were then dispensed into a 96-well plate so that the total number of cells was 1.25 × 10 cells / well. The final concentration of the anti-CAPRIN-1 antibody was 1 μg / mL. ５ THP-1 was added, and the mixture was incubated at 37°C, 5% CO ２ The cells were cultured for 1 hour under the conditions of

[0000] . Thereafter, the cells were washed with PBS (phosphate buffered saline) containing 1% FBS (fetal bovine serum) and reacted with an APC (allophycocyanin)-labeled anti-human CD45 antibody at a final concentration of 0.25 μg / mL to stain the human monocytes. Dead cells were further stained with propidium iodide (PI) at a final concentration of 0.1 μg / mL, and the fluorescence of each cell was measured by flow cytometry. PI-positive dead cells were excluded during analysis. THP-1, a type of human monocyte, recognizes antibodies bound to cancer cells and phagocytose them. If the cancer cells are stained with calcein-AM, the monocytes that engulf them by phagocytosis will also be calcein-AM positive. Therefore, the phagocytic activity in this evaluation system was calculated as the ratio (%) of APC-positive / Calcein-AM-positive cells to the total Calcein-AM-positive population.

[0175] Evaluation was performed using the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 as the anti-CAPRIN-1 antibody. Results showed that 23% cancer cell phagocytic activity was observed in HCT116 in the test group without concomitant drug. In contrast, in the test group with dabrafenib and ZM 336372, cancer cell phagocytic activity of 75% or more was observed. Therefore, the antitumor effect of the anti-CAPRIN-1 antibody against the above-mentioned human cancer cells was enhanced by approximately 3.3- to 3.5-fold when used in combination with dabrafenib and ZM 336372 ( FIG. 4 ).

[0176] Also, WO2010 / 016526, WO2011 / 096517, WO2011 / 096528, WO2011 / 096519, WO2011 / 096533, WO2011 / 096534, WO2011 / 096535, WO2013 / 018886, WO2013 / 018894, WO2013 / 018892, WO20 When the anti-CAPRIN-1 antibodies described in WO2013 / 018891, WO2013 / 018889, WO2013 / 018883, WO2013 / 125636, WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212 are used in combination with dabrafenib and ZM 336372, an enhancement in cancer cell phagocytic activity similar to that observed in the combination of anti-CAPRIN-1 humanized antibody #1 with dabrafenib and ZM 336372 against human cancer cells is observed.

[0177] (Example 5) In vitro antitumor effect of combined use of anti-CAPRIN-1 antibody and MEK inhibitor 2 The antitumor effect of combined use of anti-CAPRIN-1 antibody and MEK inhibitors other than trametinib was evaluated in vitro. The MEK inhibitors used were selumetinib (Cat. No. S1008), refametinib (Cat. No. S1089), and SL-327 (Cat. No. S1066), all purchased from Selleck, and cobimetinib (Cat. No. 19563), all purchased from Cayman.

[0178] Specifically, human cancer cells that had been previously treated with each of the combination drugs in each MEK inhibitor combination test group were co-cultured with human monocyte cells (THP-1) in the presence of an anti-CAPRIN-1 antibody, and the antibody-mediated phagocytic activity of the cancer cells by THP-1 was evaluated.

[0179] The human cancer cells used were the colon cancer cell line HCT116. For the selumetinib combination test group, refametinib combination test group, SL-327 combination test group, and cobimetinib-bosutinib combination test group, human cancer cells were cultured for two days in the presence of each combination drug on a 6-well plate. Specifically, selumetinib was added to HCT116 at concentrations of 10 μM, refametinib at 1000 nM, SL-327 at 10 μM, and cobimetinib at 800 nM. A control group was also set up, where cancer cells were cultured for two days in the absence of any combination drug.

[0180] The cultured cancer cell lines were detached using TrypLE Express (Thermo), and calcein-AM was added at a final concentration of 0.04 μg / mL, followed by incubation at 37° C. for 10 minutes to stain the cancer cells. Next, the cells were plated at 5×10 per well. ３ The cells were then dispensed into a 96-well plate so that the total number of cells was 1.25 × 10 cells / well. The final concentration of the anti-CAPRIN-1 antibody was 1 μg / mL. ５ THP-1 was added, and the mixture was incubated at 37°C, 5% CO ２The cells were cultured for 1 hour under the conditions of

[0000] . Thereafter, the cells were washed with PBS (phosphate buffered saline) containing 1% FBS (fetal bovine serum) and reacted with an APC (allophycocyanin)-labeled anti-human CD45 antibody at a final concentration of 0.25 μg / mL to stain the human monocytes. Dead cells were further stained with propidium iodide (PI) at a final concentration of 0.1 μg / mL, and the fluorescence of each cell was measured by flow cytometry. PI-positive dead cells were excluded during analysis. THP-1, a type of human monocyte, recognizes antibodies bound to cancer cells and phagocytose them. If the cancer cells are stained with calcein-AM, the monocytes that engulf them by phagocytosis will also be calcein-AM positive. Therefore, the phagocytic activity in this evaluation system was calculated as the ratio (%) of APC-positive / Calcein-AM-positive cells to the total Calcein-AM-positive population.

[0181] Evaluation using the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 as the anti-CAPRIN-1 antibody revealed that 50% cancer cell phagocytic activity was observed in HCT116 in the test group without concomitant drug addition. In contrast, in the test groups with selumetinib, refametinib, SL-327, and cobimetinib addition, cancer cell phagocytic activity of 93% or more was observed in all cases. Therefore, the antitumor effect of the anti-CAPRIN-1 antibody against the above-mentioned human cancer cells was significantly enhanced by 1.8-fold or more when used in combination with selumetinib, refametinib, SL-327, or cobimetinib (Figure 3).

[0182] Also, 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, WO2 When the anti-CAPRIN-1 antibodies described in WO2013 / 125654, WO2013 / 125640, WO2013 / 147169, WO2013 / 147176, and WO2015 / 020212 are used in combination with selumetinib, refametinib, SL-327, or cobimetinib, an enhancement in cancer cell phagocytic activity is observed similar to that observed in the above-mentioned combination of anti-CAPRIN-1 humanized antibody #1 with selumetinib, refametinib, SL-327, or cobimetinib against human cancer cells.

[0183] (Example 6) In vitro antitumor effect of combined use of anti-CAPRIN-1 antibody and ERK inhibitor The antitumor effect of combined use of anti-CAPRIN-1 antibody and ERK inhibitor was evaluated in vitro. The ERK inhibitors used were bosutinib (Cat. No. S1014) purchased from Selleck and SCH772984 (Cat. No. 19166) purchased from Cayman.

[0184] Specifically, in each ERK inhibitor combination test group, human cancer cells that had been previously treated with each combination drug were co-cultured with human monocyte cells (THP-1) in the presence of an anti-CAPRIN-1 antibody, and the antibody-mediated phagocytic activity of cancer cells by THP-1 was evaluated.

[0185] The human cancer cells used were the colon cancer cell line HCT116. For the SCH772984 combination test group and the bosutinib combination test group, human cancer cells were cultured for two days in the presence of each combination drug on a 6-well plate. Specifically, SCH772984 was added to HCT116 at a concentration of 10 μM, and bosutinib was added at a concentration of 10 μM. A control group was also set up, in which cancer cells were cultured for two days in advance without the addition of any combination drug.

[0186] The cultured cancer cell lines were detached using TrypLE Express (Thermo), and calcein-AM was added at a final concentration of 0.04 μg / mL, followed by incubation at 37° C. for 10 minutes to stain the cancer cells. Next, the cells were plated at 5×10 per well. ３ The cells were then dispensed into a 96-well plate so that the total number of cells was 1.25 × 10 cells / well. The final concentration of the anti-CAPRIN-1 antibody was 1 μg / mL. ５ THP-1 was added, and the mixture was incubated at 37°C, 5% CO ２ The cells were cultured for 1 hour under the conditions of

[0000] . Thereafter, the cells were washed with PBS (phosphate buffered saline) containing 1% FBS (fetal bovine serum) and reacted with an APC (allophycocyanin)-labeled anti-human CD45 antibody at a final concentration of 0.25 μg / mL to stain the human monocytes. Dead cells were further stained with propidium iodide (PI) at a final concentration of 0.1 μg / mL, and the fluorescence of each cell was measured by flow cytometry. PI-positive dead cells were excluded during analysis. THP-1, a type of human monocyte, recognizes antibodies bound to cancer cells and phagocytose them. If the cancer cells are stained with calcein-AM, the monocytes that engulf them by phagocytosis will also be calcein-AM positive. Therefore, the phagocytic activity in this evaluation system was calculated as the ratio (%) of APC-positive / Calcein-AM-positive cells to the total Calcein-AM-positive population.

[0187] Evaluation was performed using the anti-CAPRIN-1 antibody (anti-CAPRIN-1 humanized antibody #1) prepared in Example 1 as the anti-CAPRIN-1 antibody. Results showed that 39% of HCT116 cells in the non-combined drug-containing test group exhibited phagocytic activity against cancer cells. In contrast, 90% of HCT116 cells in the SCH772984-containing test group exhibited phagocytic activity against cancer cells (Figure 5). Student's t test showed that the phagocytic activity in the SCH772984-containing test group was significantly higher than that in the non-combined drug-containing test group (p<0.001; significance level 5%). Furthermore, 50% of HCT116 cells in the non-combined drug-containing test group exhibited phagocytic activity against cancer cells. In contrast, 82% of HCT116 cells in the bosutinib-containing test group exhibited phagocytic activity against cancer cells (Figure 3). A Student's t test showed that the phagocytic activity in the bosutinib combination test group was significantly higher than that in the non-combined drug test group (p<0.001; significance level 5%). Therefore, the antitumor effect of the anti-CAPRIN-1 antibody on the above-mentioned human cancer cells was significantly enhanced by approximately 1.7 to 2.3 times when used in combination with bosutinib and SCH772984.

[0188] Also, 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, WO2 When the anti-CAPRIN-1 antibodies described in WO 2013 / 125636, WO 2013 / 125654, WO 2013 / 125640, WO 2013 / 147169, WO 2013 / 147176, and WO 2015 / 020212 are used in combination with bosutinib and SCH772984, an enhancement in cancer cell phagocytic activity similar to that observed in the above-mentioned combination of anti-CAPRIN-1 humanized antibody #1 with bosutinib and SCH772984 against human cancer cells is observed.

[0189] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical for the treatment and / or prevention of cancer, comprising an antibody or a fragment thereof having immunological reactivity with CAPRIN-1 protein and a MAPK (Mitogen-activated Protein Kinase) pathway inhibitor, either together or separately.

2. The pharmaceutical according to claim 1, wherein the MAPK pathway inhibitor comprises a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, an ERK inhibitor, or a combination of any two or more thereof.

3. The pharmaceutical according to claim 2, wherein the MEK inhibitor is at least one selected from the group consisting of trametinib, cobimetinib, selumetinib, refametinib, SL-327, and derivatives thereof.

4. The pharmaceutical according to claim 2, wherein the RAS inhibitor is at least one selected from the group consisting of sotorasib, lonafarnib, salirasib, and derivatives thereof.

5. The pharmaceutical according to claim 2, wherein the RAF inhibitor is at least one selected from the group consisting of dabrafenib, ZM 336372, and derivatives thereof.

6. The pharmaceutical according to claim 2, wherein the ERK inhibitor is at least one selected from the group consisting of bosutinib, SCH772984, and derivatives thereof.

7. The pharmaceutical according to claim 1, wherein the antibody or its fragment has immunological reactivity with a CAPRIN-1 protein having an amino acid sequence represented by any of the even sequence numbers among SEQ ID NOs: 2 to 30, or an amino acid sequence having at least 80% sequence identity with the amino acid sequence.

8. The pharmaceutical according to claim 1, wherein the antibody or its fragment has immunological reactivity with the extracellular region of the CAPRIN-1 protein present on the cancer cell surface.

9. The pharmaceutical product according to claim 1, wherein the antibody or a fragment thereof has immunological reactivity 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, 309, or an amino acid sequence having 80% or more sequence identity with the amino acid sequence.

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

11. The pharmaceutical product according to claim 1, wherein the antibody or a fragment thereof is any one of the following (A) to (M): (A) An antibody or a fragment thereof comprising a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 36, 37, and 38 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 40, 41, and 42, and having immunological reactivity with a CAPRIN-1 protein (B) An antibody or a fragment thereof comprising a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 44, 45, and 46 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 48, 49, and 50, and having immunological reactivity with a CAPRIN-1 protein (C) An antibody or a fragment thereof comprising a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 52, 53, and 54 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 56, 57, and 58, and having immunological reactivity with a CAPRIN-1 protein (D) An antibody or a fragment thereof comprising a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 60, 61, and 62 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 64, 65, and 66, and having immunological reactivity with a CAPRIN-1 protein (E) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 170, 171, and 172 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 173, 174, and 175, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein (F) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 176, 177, and 178 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 179, 180, and 181, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein (G) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 182, 183, and 184 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 185, 186, and 187, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein (H) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 188, 189, and 190 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 191, 192, and 193, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein (I) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 146, 147, and 148 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 149, 150, and 151, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein (J) A heavy chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 272, 273, and 274 and a light chain variable region comprising complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 275, 276, and 277, and an antibody or a fragment thereof having immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that includes a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 290, 291, and 292 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 293, 294, and 295, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that includes a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 300, 301, and 302 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 304, 305, and 306, and has immunological reactivity with the CAPRIN-1 protein An antibody or a fragment thereof that includes a heavy chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 134, 135, and 136 and a light chain variable region containing complementarity-determining regions (CDR1, CDR2, and CDR3, respectively) of SEQ ID NOs: 137, 138, and 139, and has immunological reactivity with the CAPRIN-1 protein. The pharmaceutical according to claim 1, wherein the antibody or the fragment thereof is any one of the following (a) to (al): (a) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 39 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 43 (b) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 47 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 51 (c) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 55 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 59 (d) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 63 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 67 (e) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 68 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 69 (f) An antibody or a fragment thereof, wherein the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 70 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 71 ​ An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 72 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 73 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 75 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 79 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 82 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 84 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 85 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 86 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 87 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 88 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 89 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 90 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 91 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 93 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 94 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 95 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 96 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 98 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 99 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 100 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 101 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 102 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 103 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 104 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 105 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 108 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 111 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 112 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 114 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 115 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 116 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 117 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 118 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 119 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 120 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 121 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 122 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 123 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 124 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 125 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 126 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 127 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 129 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 130 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 131 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 132 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133 An antibody or a fragment thereof, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 303 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

307.

13. The pharmaceutical product according to claim 1, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody or a single-chain antibody.

14. The pharmaceutical product according to claim 1, wherein the cancer is a cancer that expresses CAPRIN-1 protein on the cell membrane surface.

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

16. A potency enhancer for a pharmaceutical composition for the treatment and / or prevention of cancer, which comprises, as an active ingredient, an antibody or a fragment thereof that has immunological reactivity with CAPRIN-1 protein and a MAPK pathway inhibitor.

17. A potency enhancer for a pharmaceutical composition for the treatment and / or prevention of cancer, which comprises, as an active ingredient, an antibody or a fragment thereof that has immunological reactivity with CAPRIN-1 protein and a MAPK pathway inhibitor.