TW201825119A - Method of treating cancer using anti-ccr4 antibody and anti-pd-1 antibody - Google Patents

Method of treating cancer using anti-ccr4 antibody and anti-pd-1 antibody Download PDF

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TW201825119A
TW201825119A TW106142006A TW106142006A TW201825119A TW 201825119 A TW201825119 A TW 201825119A TW 106142006 A TW106142006 A TW 106142006A TW 106142006 A TW106142006 A TW 106142006A TW 201825119 A TW201825119 A TW 201825119A
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Taiwan
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antibody
cancer
seq id
set forth
sequence set
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TW106142006A
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Chinese (zh)
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川上哲義
大山行也
玄元一人
亞蘭 J 寇曼
尼爾斯 隆伯格
新达 郑
史帝芬 D 艾爾布奇
瑪格麗特 馬歇爾
丹尼斯 海利
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日商協和醱酵麒麟有限公司
日商小野藥品工業股份有限公司
美商必治妥美雅史谷比公司
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Priority to US201762554486P priority
Priority to US62/554,486 priority
Application filed by 日商協和醱酵麒麟有限公司, 日商小野藥品工業股份有限公司, 美商必治妥美雅史谷比公司 filed Critical 日商協和醱酵麒麟有限公司
Publication of TW201825119A publication Critical patent/TW201825119A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507Comprising a combination of two or more separate antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Abstract

The present invention provides a method of treating cancer comprising administering an anti-CC chemokine receptor 4 (CCR4) antibody and an anti-apoptotic 1 (PD-1) antibody to an individual. Also provided is a composition or kit for treating cancer, the composition or kit comprising an anti-CCR4 antibody and an anti-PD-1 antibody.

Description

Method for treating cancer using anti-CCR4 antibody and anti-PD-1 antibody

The present invention relates to a method of treating cancer in an individual in need thereof, which comprises administering an anti-CCR4 antibody and an anti-PD-1 antibody to an individual. The invention further provides a pharmaceutical composition for treating cancer in an individual in need thereof, the pharmaceutical composition comprising an anti-CCR4 antibody and an anti-PD-1 antibody.

CC chemokine receptor 4 (CCR4) is known as the chemokine receptor of two chemokines, the thymus and activation-regulating chemokine (TARC) (also known as CCL17). And macrophage-derived chemokine (MDC) (also known as CCL22). Furthermore, it is well known that CCR4 is expressed in Th2 cells, CD4 + regulatory T cells (Treg) and T lymphoma cells, such as adult T cell leukemia lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma ( On PTCL). Recently, most of the promising anti-CCR4 humanized antibodies, mogamulizumab have been approved by the Ministry of Health, Labour and Welfare in Japan (MHLW) to pass the marketing approval to treat CCR4. Positive adult T cell leukemia lymphoma (ATL) (Non-Patent Document 1) and CCR4 + relapse/refractory CTCL and PTCL (Non-Patent Document 2). In addition, recent immune checkpoint molecules such as programmed cell death-1 (PDCD1, PD-1), programmed cell death ligand 1 (PD-L1), cytotoxic T lymphocyte associated 4 (CTLA-4), and Killer-inhibitory receptor (KIR) has become available to trigger anti-tumor immune responses in some cancers. PD-1 (CD279) is a 55 kDa type I transmembrane protein belonging to the immunoglobulin family and is reported to be expressed in immune cells (especially including activated T cells, regulatory T cells (Treg), B cells, and NK cells) on. One of its ligands, PD-L1 (B7 homolog-1); B7-H1; CD274, is a 53 kDa type I transmembrane protein that contributes to immunosuppression or T cell deactivation. PD-L2 (B7-DC or CD273) is identified as a second ligand for PD-1, which has inhibitory activity on T cells similar to PD-L1. In contrast, CTLA-4 specifically appears on activated CD4 + T cells, has a structure similar to CD28 and binds antigen-presenting cells (APC) by binding CD80/CD86 (B7-1, B7-2) , such as on dendritic cells to regulate T cell activity. Therapeutic antibodies for the treatment of different cancers have been approved and/or have been developed for use in multiple immune checkpoint molecules. In the United States, anti-PD-1 human IgG4 antibody, which has been approved to block PD-1 activity, has been approved (next to 5C4, BMS-936558, MDX-1106 or ONO-4538) (Patent Document 1 and Non-patent) Document 3) Following iprelimumab and if BRAF V600 mutation positive, BRAF inhibitors are used to treat patients with unresectable or metastatic melanoma and progressive disease. It has also been approved in the United States for the treatment of metastatic squamous non-small cell lung cancer with or after platinum-based chemotherapy. OPDIVO (registered trademark) is approved for administration at 3 mg/kg once every two weeks. In Japan, OPDIVO (registered trademark) has also been approved for the treatment of patients with unresectable melanoma and can be administered every 2 weeks at 2 mg/kg. In addition, in the United States has approved the approval of another anti-PD-1 antibody, pembrolizumab (previously referred to as lambrolizumab or MK-3475), followed by Iplibumab and ruo BRAF The V600 mutation is positive, and the BRAF inhibitor is used to treat patients with unresectable or metastatic melanoma and progressive disease. Other checkpoint inhibitor antibodies in development include anti-CTLA-4 antibodies (eg, iprezumab and trimeumab, active ingredients of YERVOY (registered trademark)), anti-PD-1 antibodies (eg, MEDI0608), Anti-PD-L1 antibodies (eg, MEDI4736, MPDL3280A, and MSB0010718C) and PD-L2Ig (eg, AMP-224). [ Citation List ] [ Patent Literature ] PTL 1: U.S. Patent No. 8,008,449 [ Non-Patent Document ] NPL1: Ishida et al., J. Clin. Oncol., 2012; 30; 837-842 NPL 2: Ogura et al., J. Clin .Oncol., 2014; 32; 1157-1163 NPL 3: Wang et al, Cancer Immunol Res., 2014; 2: 846-56

The invention provides a method of treating cancer in an individual in need thereof, the method comprising administering an anti-PD-1 antibody in combination with an anti-CCR4 antibody to the individual. In one embodiment, the invention comprises a method of treating cancer in an individual, the method comprising: an antibody or antigen binding portion thereof that specifically binds to human CC chemokine receptor 4 (CCR4) ("anti-CCR4 antibody or The antigen-binding portion thereof) and the antibody or antigen-binding portion thereof ("anti-PD-1 antibody or antigen-binding portion thereof") which specifically binds to human programmed death-1 (PD-1) are administered to the individual. In another embodiment, the invention comprises a method of reducing the size of a tumor in an individual having cancer by at least about 1%, 5%, 10%, 15%, 20% or 30%, the method comprising The CCR4 antibody or antigen binding portion thereof and the anti-PD-1 antibody or antigen binding portion thereof are administered to the individual. In some embodiments, the anti-CCR4 antibody is a chimeric antibody, a human antibody, or a humanized antibody. In other embodiments, the anti-CCR4 antibody or antigen binding portion thereof for use in the method is selected from the group consisting of: (i) an antibody or antigen binding portion thereof that binds to the same epitope as the antibody, comprising: comprising The heavy chain variable region ("VH") complementarity determining region (CDR) of the sequence set forth in SEQ ID NO: 1, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and comprising SEQ ID NO: One or more of the VH CDR3s of the sequences set forth in 3, and the light chain variable region ("VL") CDR1 comprising the sequence set forth in SEQ ID NO: 4, comprising the set forth in SEQ ID NO: a sequence of VL CDR2 and one or more of the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) an antibody or antigen binding portion thereof comprising: comprising the set forth in SEQ ID NO: The VH CDR1 of the sequence, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, the VL CDR1 comprising the sequence set forth in SEQ ID NO: a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (iii) an antibody or an antibody thereof a binding portion comprising: a VH comprising the sequence set forth in SEQ ID NO: 7 and a VL comprising the sequence set forth in SEQ ID NO: 8; (iv) an antibody comprising: comprising SEQ ID NO: a heavy chain of the sequence set forth and a light chain comprising the sequence set forth in SEQ ID NO: 10; (v) an antibody or antigen binding portion thereof, which competes with (ii) the antibody; and (vi) Moglia Monoclonal antibody or antigen binding portion thereof. In other embodiments, the anti-PD-1 antibody is a chimeric antibody, a humanized antibody, or a human antibody. In some other embodiments, the anti-PD-1 antibody or antigen binding portion thereof is selected from the group consisting of: (i) an antibody or antigen binding portion thereof that binds to the same epitope as the antibody, comprising: comprising the SEQ ID One or more of the VH CDR1 of the sequence set forth in NO:11, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and the VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, and comprising VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and one or more of VL CDR3 comprising the sequence set forth in SEQ ID NO: 16; (ii) an antibody or antigen-binding portion thereof comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, comprising SEQ ID NO: 13 The VH CDR3 of the sequence set forth, the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and the sequence set forth in SEQ ID NO: a VL CDR3; (iii) an antibody or antigen binding portion thereof comprising: comprising the set forth in SEQ ID NO: a VH of the sequence and a VL comprising the sequence set forth in SEQ ID NO: 18; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising the set forth in SEQ ID NO: a light chain of the sequence; (v) an antibody or antigen-binding portion thereof, which competes with (ii) the antibody; (vi) nalumab or an antigen-binding portion thereof; (vii) peizumab or an antigen thereof a binding moiety; and (viii) MEDI0608 or an antigen binding portion thereof. In certain embodiments, the cancer treatable by the methods of the invention is selected from the group consisting of melanoma cancer, liver cancer, hepatocellular cell carcinoma, cholangiocarcinoma, renal cancer, prostate cancer, breast cancer. , colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, cervical cancer, endometrial cancer, rectal cancer, anal area Cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's Disease, non-Hodgkin's lymphoma ), esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, including acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytes Chronic or acute leukemia of leukemia, solid tumor in children, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal pelvic cancer, central nervous system (CNS) swelling Tumor, primary CNS lymphoma, tumor angiogenesis, glioblastoma, spinal axis tumor, brain stem neurotroph, pituitary adenoma, mesothelioma, Kapo's sarcoma Kaposi's sarcoma), epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and any combination thereof. In some embodiments, the cancer is lung cancer, gastrointestinal cancer, or both. In other embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer, the gastrointestinal cancer is esophageal cancer or gastric cancer, and the T cell lymphoma is ATL, CTCL or PTCL. In still other embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer or squamous non-small cell lung cancer. In a specific embodiment, the cancer is melanoma. In still other embodiments, the cancer is a progressive, metastatic, and/or unresectable cancer. In some embodiments, the anti-CCR4 antibody is administered at least about 0.1, 0.3, 0.5, 0.75, 1.0, 2.0, or 3.0 mg/kg. In certain embodiments, the anti-CCR4 antibody or antigen binding portion thereof is administered at least once a week, at least once every two weeks, or at least once a week followed by once every two weeks. In a specific embodiment, the anti-CCR4 antibody or antigen binding portion thereof is administered once a week for four weeks after the first administration, followed by administration once every two weeks. In certain embodiments, the anti-PD-1 antibody or antigen binding portion thereof is at least about 1 mg/kg, 2.0 mg/kg, 3.0 mg/kg or 5 mg/kg, or at least about 240 mg/body as a level Dosing dose administration. In other embodiments, the anti-PD-1 antibody or antigen binding portion thereof is administered at least once a week, at least once every two weeks, or at least once every three weeks. In still other embodiments, the anti-PD-1 antibody or antigen binding portion thereof is administered at 2.0 mg/kg once every two weeks or at 3.0 mg/kg every two weeks, or at 240 mg/body as a flat dose every two weeks. Once cast. In some embodiments, an anti-CCR4 antibody or antigen binding portion thereof and an anti-PD-1 antibody or antigen binding portion thereof are administered to the individual in parallel or sequentially. In other embodiments, the anti-CCR4 antibody or antigen binding portion thereof is administered before or after the anti-PD-1 antibody. In other embodiments, administration results in one or more of the following effects: (i) reduced CCR4 + T cells, (ii) reduced regulatory T cells, (iii) enhanced PD-L1 expression in tumor tissue (iv) reduced PD-1 positive T cells, (v) increased tumor infiltrating lymphocytes (TIL), and (vi) any combination thereof. In certain other embodiments, the methods further comprise an additional anticancer agent. In a particular embodiment, one or more of the tumors in the cancer exhibit PD-L1, PD-L2, CCR4, or any combination thereof. In certain embodiments, the invention also encompasses a kit for treating an individual afflicted with cancer, the kit comprising: (a) a dose specific to a dose ranging from 0.1 to 10 mg/kg body weight to PD -1 antibody or antigen-binding portion thereof ("anti-PD-1 antibody or antigen-binding portion thereof"); (b) a dose of 0.1 to 10 mg/kg body weight specifically binding to CCR4 antibody or An antigen binding portion ("anti-CCR4 antibody or antigen binding portion thereof"); and (c) instructions for using the anti-PD-1 antibody and the anti-CCR4 antibody in such methods. In other embodiments, the invention includes a pharmaceutical composition for treating cancer comprising (a) an antibody or antigen-binding portion thereof that specifically binds to PD-1 and inhibits PD-1 activity ("anti- A PD-1 antibody or antigen-binding portion thereof) and an antibody or antigen-binding portion thereof ("anti-CCR4 antibody or antigen-binding portion thereof") that specifically binds to CCR4 and inhibits CCR4.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning The following references provide the skilled person with a general definition of the various terms used in the present invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker Edition, 1988). The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings attributed below, unless otherwise specified. By "administering" is meant the use of any of a variety of methods and delivery systems known to those skilled in the art to physically introduce a composition comprising a therapeutic agent into an individual. Routes of administration of anti-PD-1 antibodies include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. As used herein, the phrase "parenteral administration" means a mode of administration other than injection and local administration by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial. , intrathecal, lymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural And intrasternal injection and infusion, as well as in vivo electroporation. In some embodiments, the agent is administered orally via a parenteral route, in certain embodiments. Other parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, transvaginal, transrectal, sublingual or topical. The voting may also be performed, for example, once, in multiples, and/or over one or more extended periods of time. "Adverse events" (AE) as used herein are any unfavorable and generally undesirable or undesirable signs (including abnormal laboratory findings), symptoms or diseases associated with the use of medical treatment. For example, an adverse event can be associated with activation of the immune system or amplification of immune system cells (eg, T cells) in response to treatment. Medical treatment can have one or more related AEs and each AE can have the same or a different severity. Reference to a method of "changing an adverse event" means a therapeutic treatment that reduces the incidence and/or severity of one or more AEs. By "isolated antibody" is meant an antibody that is substantially free of other antibodies having different antigenic specificities (eg, an isolated antibody that specifically binds to PD-1 is substantially free of specific binding to PD-1 other than PD-1). Antigen antibody). However, an isolated antibody that specifically binds to PD-1 can cross-react with other antigens, such as PD-1 molecules from different species. Furthermore, the isolated antibodies may be substantially free of other cellular materials and/or chemicals. An "anti-antigen" anti-system refers to an antibody that specifically binds to an antigen. For example, an anti-PD-1 antibody specifically binds to PD-1 and an anti-CTLA-4 antibody specifically binds to CTLA-4. An "antigen-binding portion" of an antibody (also referred to as "antigen-binding fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by the entire antibody. In the present invention, "comprises/comprising", "including" and "having" and the like may have the meaning attributed to them in the U.S. Patent Law and may mean "includes/including" and Similarly, "consisting essentially of" or "substantially composed" has the same meaning as belonging to the US patent law and the term is open, as long as the basic or novel features cited are not greater than the cited content. The existence and variation, but excluding prior art embodiments, allows for greater than the presence of the cited content. "Cancer" refers to a wide variety of disease groups characterized by uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth division and growth result in the formation of malignant tumors that invade adjacent tissues and can also be transferred to the distal portion of the body via the lymphatic system or blood flow. After cancer metastasis, the distal tumor can be called "derived from" primitive, precancerous metastatic tumor. Since the distal tumor is derived from a pre-cancerous tumor, the "derived from" tumor may also include a pre-metastatic tumor. The term "immunotherapy" refers to an individual who is treated by a method comprising inducing, ameliorating, inhibiting, or otherwise modifying an immune response to treat a disease or to be at risk of contracting or suffering from a disease. "Treatment" or "therapy" of an individual means any type of intervention or treatment performed on an individual, or administration of an active agent to an individual with the goal of reversing, alleviating, ameliorating, inhibiting, slowing or preventing symptoms, complications or diseases. The onset, progression, progression, severity, or recurrence of a biochemical marker associated with a disease or disease. "Therapeutically effective amount", "effective amount", "effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is to protect an individual from the onset of disease or to promote disease by disease when used alone or in combination with another therapeutic agent. The severity of the symptoms is reduced, the frequency and duration of the period of absence of the symptoms of the disease are evidence of a regression of the disease, or any amount of the drug that is damaged or disabled due to the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to those skilled in the art, such as evaluation in a human subject during clinical trials, in an animal model system that predicts efficacy in humans, or in vivo. The reagent activity was evaluated in an external assay. In one embodiment, the antibodies or combinations of antibodies described herein promote cancer regression or prevent other tumor growth in an individual. In certain embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating cancer. "Promoting cancer regression" means administering an effective amount of a drug, alone or in combination with an anti-tumor agent, such that tumor growth or size reduction, tumor necrosis, reduction in the severity of at least one disease symptom, frequency of disease-free symptoms, and Increase in duration or prevent damage or disability due to illness or illness. In addition, the terms "effective" and "utility" in relation to treatment include both pharmacological effects and physiological safety. Pharmacological utility refers to the ability of a drug to promote the resolution of cancer in a patient. Physiological safety refers to the degree of toxicity due to administration of a drug, or other undesirable physiological effects (bad effects) on the level of cells, organs and/or organisms. For example, for treating a tumor, a therapeutically effective amount of an antibody or combination thereof, relative to an untreated individual or in certain embodiments, relative to a patient treated with standard care therapy, can inhibit cell growth or tumor growth at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the invention, tumor regression is observable and lasts for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Regardless of the final measurement of therapeutic utility, the evaluation of immunotherapeutic drugs must also take into account the "immune-related" response pattern. An "immune-related" response pattern refers to a pattern of clinical response commonly observed in cancer patients treated with immunotherapeutics that induce resistance by inducing a cancer-specific immune response or by modifying the native immune process. Tumor effect. This mode of response is characterized by a beneficial therapeutic effect after an initial increase in tumor burden or the appearance of a new lesion, which will be classified as disease progression in the assessment of traditional chemotherapeutic agents and will be synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of such agents on the target disease. A therapeutically effective amount of a drug includes a "prophylactically effective amount" which, when administered alone or in combination with an antitumor agent, is at risk of developing cancer (eg, an individual having a precancerous condition) or an individual suffering from a cancer recurrence. Any amount of a drug that inhibits the development or recurrence of cancer. In certain embodiments, a prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" the development or recurrence of cancer means reducing the likelihood of progression or recurrence of cancer or completely preventing the development or recurrence of cancer. It will be understood that the use of an alternative (such as "or") means one of the alternatives, or a combination of the two or any combination thereof. As used herein, the indefinite article "a" or "an" The term "about" or "substantially encompasses" means a value or composition within the acceptable tolerances of the value or composition as determined by those skilled in the art, which will depend in part on how it is measured or The decision value or composition, ie the limitations of the measurement system. For example, "about" or "substantially encompasses" may mean within one or more than one standard deviation according to the practice in the art. Alternatively, "about" or "substantially encompasses" may mean a range of up to 10% (ie, +10% to -10%). For example, about 3 mg can include any value between 2.7 mg and 3.3 mg (for 10%). Moreover, particularly in the context of biological systems or methods, the terms may mean up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in the application and the scope of the patent application, the meaning of "about" or "substantially encompasses" should be assumed to be within the tolerance of a particular value or composition, unless otherwise stated. . As used herein, the term "about once a week" means an approximate value, and "about once a week" may include every six days to every eight days. Therefore, the frequency of "once a week" can be every six days, every seven days or every eight days. As used herein, unless otherwise specified, any range of ranges, percentage ranges, ranges of ranges, or ranges of integers are understood to include any integer value within the recited range and, where appropriate, its fraction (such as an integer One and one percent). The terms "CC chemokine receptor 4", "CCR4", "CCR4 peptide", "CCR4 protein" or "CCR4 polypeptide" as used herein are used interchangeably and are meant to include SEQ ID NO:22. a polypeptide of the amino acid sequence or a functional fragment thereof; a polypeptide comprising the amino acid sequence of GenBank Accession No. NP_005499.1, comprising a deletion or substitution in the amino acid sequence represented by SEQ ID NO: 22 or NP_005499.1 Or a polypeptide having an amino acid sequence of one or more amino acid residues and having CCR4 activity; comprising at least about 85% homology to at least about 90% of the amino acid sequence represented by SEQ ID NO: a polypeptide having homology, at least about 93% homology, and at least about 95%, about 96%, about 97%, about 98% or about 99%, more homologous amino acid sequence and having CCR4 activity; Related polypeptides of SNP variants and the like. Related polypeptides include SNP variants, splice variants, fragments, surrogates, deletions, and insertions that retain CCR4 activity and/or function. Furthermore, the CCR4 polypeptide comprises a polypeptide encoded by the nucleotide sequence of SEQ ID NO: 21 or GenBank Accession No. NM_005508.4. In some embodiments, the gene encoding CCR4 comprises a nucleotide having one or more nucleotide deletions, substitutions or additions in the nucleotide sequence of SEQ ID NO: 21 or GenBank Accession No. NM_005508.4 sequence. In other embodiments, the CCR4 gene encodes a polypeptide having CCR4 function and comprises at least about 60% or more homology to the nucleotide sequence of SEQ ID NO: 21 or GenBank Accession No. NM_005508.4, in some embodiments A nucleotide sequence that is at least about 80% or more homologous, and in other embodiments at least about 95%, about 96%, about 97%, about 98% or about 99%, more homologous. In some embodiments, the CCR4 gene encodes a polypeptide having the function of CCR4 and comprises a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 21 or GenBank Accession No. NM_005508.4. The term "CCR4 nucleic acid molecule" as used herein refers to a polynucleotide that encodes a CCR4 polypeptide. An exemplary CCR4 nucleic acid molecule is provided in SEQ ID NO: 21 or GenBank Accession No. NM_005508.4. Gene polymorphism is often recognized in the nucleotide sequence of a gene encoding a protein of eukaryotes. The CCR4 gene used in the present invention also includes a gene which produces a small modification in a nucleotide sequence by this polymorphism, and is used as a gene used in the present invention. CCR4 is a G-protein-coupled seven transmembrane receptor cloned from the human immature basophilic cell line KU-812 to K5-5, and may have the amino acid sequence represented by SEQ ID NO:22. The extracellular region of CCR4 is in positions 1 to 39, positions 99 to 111, positions 176 to 206, and positions 268 to 284 in the amino acid sequence, and the intracellular region is in the amino acid sequence (GenBank Accession No. NP_005499.1). Positions 68 to 77, positions 134 to 150, positions 227 to 242, and positions 309 to 360. CCR4 specifically binds to different molecules including, but not limited to, TARC (thymus and activation-regulating chemokines) produced by thymocytes (J. Biol. Chem., 271, 21514, 1996) and is isolated from macrophages. MDC (macrophage-derived chemokine) (J. Exp. Med., 185, 1595, 1997), also known as STCP-1 (stimulated T cell chemotactic protein-1) (J. Biol.Chem) ., 272, 25229, 1997). TARC and MDC are also referred to as CCL17 and CCL22, respectively. One or more of the functions of CCR4 include its ability to combine with TARC and/or MDC. Other functions of CCR4 in the present invention include Ca on CCR4 cells depending on the expression of a CCR4 ligand such as CCL17 and/or CCL22.2 + The function of influx and cell migration of CCR4 cells. The terms "programmed cell death-1", "PD-1", "PD-1 polypeptide" or "CD279" are used interchangeably herein and mean at least one function of PD-1 activity (eg, by PD) The -1 pathway activates T cells and/or binds to a polypeptide of PD-L1 or PD-L2) or a fragment thereof. In one embodiment, PD-1 comprises at least about 85%, at least about 90%, at least about 93%, at least about 95%, about 96%, about 97%, about 98%, about 99% with NCBI accession number NP_005009. Or an amino acid sequence of about 100% sequence identity or the amino acid sequence set forth in SEQ ID NO: 24, wherein the PD-1 protein has binding activity to PD-L1 and PD-L2 and/or PD- 1 activity. In some embodiments, PD-1 also includes SNP variants, splice variants, fragments, surrogates, deletions, and insertions that preserve PD-1 activity and/or function. In other embodiments, PD-1 comprises a polypeptide encoded by the nucleotide sequence of SEQ ID NO: 23 or GenBank Accession No. NM_005018.2. The PD-1 gene also includes a DNA-containing gene comprising a nucleoside having one or more nucleotide deletions, substitutions or additions in the nucleotide sequence of SEQ ID NO: 23 or GenBank Accession No. NM_005018.2 Acid sequence. In some embodiments, PD-1 is at least about 60%, about 70%, about 80%, about 90%, about 95%, having a nucleotide sequence of SEQ ID NO: 23 or GenBank Accession No. NM_005018.2, Approximately 96%, about 97%, about 98%, about 99%, or about 100% of the identical nucleotide sequence encodes and has at least one function of PD-1 (eg, activation of T cells by the PD-1 pathway and/or Or combined with PD-L1 or PD-L2). In other embodiments, PD-1 is encoded by a nucleotide sequence that hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 23 or GenBank Accession No. NM_005018.2 and has a function of PD-1 . The term "PD-1 nucleic acid molecule" refers to a polynucleotide that encodes a PD-1 polypeptide. An exemplary PD-1 nucleic acid molecule is provided in SEQ ID NO: 23 or GenBank Accession No. NM_005018.2. Gene polymorphism is often recognized in the nucleotide sequence of a gene encoding a protein of eukaryotes. The PD-1 gene used in the present invention also includes a gene which produces a small modification in the nucleotide sequence by the polymorphism, and is used as the gene used in the present invention. PD-1 was cloned into a 55 kDa type I membrane protein belonging to the immunoglobulin family (Ishida et al., 1992; 11; 3887-3895). PD-1 is expressed on activated T lymphocytes. The intracellular domain of PD-1 contains an ITSM motif (an immunoreceptor tyrosine-based exchange motif) and an ITIM motif (based on an immunoreceptor tyrosine-based inhibitory motif) that can be a suppressor domain for an immune response. Since mice lacking PD-1 develop lupus autoimmune diseases such as glomerulonephritis and arthritis and diseases similar to dilated cardiomyopathy, PD-1 appears to be a negative regulator of immune response. Other PD-1 ligands, PD-L1, are referred to as ligands for PD-1 and type I transmembrane proteins that act as inhibitors of T cell proliferation by binding to PD-1. It has an immunoglobulin V-domain, a C-domain, and a cytoplasmic tail. PD-L1 is known to be expressed on antigen presenting cells and on some cancer cells. "Anti-CCR4 antibody" refers to an antibody that selectively binds to a human CCR4 polypeptide. Provided herein are exemplary anti-CCR4 antibodies, eg, an anti-CCR4 antibody consisting of amino acid residues 2 to 29 of SEQ ID NO: 22 that bind to an epitope. In one embodiment, the anti-CCR4 antibody is moglizumab (POTELIGEO (registered trademark)). In another embodiment, an anti-CCR4 antibody reduces, inhibits or prevents one or more functions of CCR4. In other embodiments, the anti-CCR4 antibody cross-competes with moglizumab. "Anti-PD-1 antibody" refers to an antibody that selectively binds to a PD-1 polypeptide. An exemplary anti-PD-1 antibody is described in, for example, U.S. Patent No. 8,008,449, incorporated herein by reference. In one embodiment, the anti-PD-1 antibody is navobizumab (OPDIVO (registered trademark)). In another embodiment, the anti-PD-1 antibody reduces, inhibits or prevents one or more functions of PD-1. In other embodiments, the anti-PD1 antibody cross-competes with navobizumab. As used in this disclosure, the term "antibody" refers to an immunoglobulin or a fragment or derivative thereof, and encompasses any polypeptide comprising an antigen binding site, whether produced in vitro or in vivo. The term includes, but is not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, humanized antibodies, single chain antibodies, chimeric antibodies, synthetic antibodies, recombinant antibodies, hybrid antibodies, mutant antibodies, and Transplant the antibody. The term "antibody" also encompasses the preservation of antigen binding function (ie, capable of specifically binding to CCR4 or PD-1) for the purposes of this disclosure, unless otherwise modified by the term "intact" as "intact antibody". Antibody fragments (or antigen-binding fragments), such as Fab, F(ab')2 , Fv, single chain Fv (scFv), Fd, dAb and other antibody fragments. Typically, such fragments will comprise an antigen binding domain (or portion). The antibody molecule is formed of a polypeptide called a heavy chain (hereinafter referred to as an H chain) and a light chain (hereinafter referred to as an L chain). In addition, the H chain is derived from the H chain variable region from its N-terminus (also known as VH Or VH) and the region of the H chain constant region (also referred to as CH), and the L chain consists of the L chain variable region from its N terminus (also known as VL Or a region of the VL) and L chain constant region (also referred to as CL). Regarding CH, α, δ, ε, γ, and mu chains are known for each subcategory. Regarding CL, λ and κ are known. An IgG antibody has two heavy chains and two light chains and forms two antigen binding sites consisting of VH and VL. Therefore, the IgG antibody is a bivalent antibody. The terms "antibody fragment", "antigen binding domain", "antigen-binding fragment", "antigen-binding portion" and "binding fragment" refer to a portion of an antibody molecule comprising an amino acid responsible for specific binding between an antibody and an antigen. . For example, where the antigen is large, the antigen binding domain may only bind to a portion of the antigen. A part of an antigen molecule responsible for specific interaction with an antigen-binding domain is called an "antigenic determinant" or an "antigenic determinant". The antigen binding domain typically comprises an antibody light chain variable region (V)L Or VL) and antibody heavy chain variable region (VH Or VH). However, it is not necessary to include both. For example, Fd antibody fragments are only made up of VH Domain composition, but still retains certain antigen binding functions of intact antibodies. The term "complementarity determining region" or "CDR" refers to an essential portion of the antigen binding function of an antibody contained in the variable region of an antibody. Three CDRs are present in VH and VL, respectively, and these are defined as CDR1 to CDR3 in each variable region. Antigen-binding fragments of antibodies can be produced by recombinant DNA techniques or by enzymatic cleavage or chemical cleavage of intact antibodies. Antigen-binding fragments include Fab, Fab', F(ab')2 , Fv and single chain antibodies. It should be understood that the binding sites of the antibodies other than the "bispecific" or "bifunctional" antibodies are identical. The same antigen-binding fragment, also referred to as a "Fab" fragment and an "Fc" fragment, is produced by the enzyme (papaya enzyme) decomposing antibody, and the two antigen-binding fragments have no antigen-binding activity but have crystallization ability. Decomposition of antibodies by leaven (pepsin) to produce F(ab')2 A fragment wherein the two arms of the antibody molecule remain linked and comprise two antigen binding sites. F(ab')2 The fragment is capable of cross-linking with the antigen. As used herein, "Fv" refers to the smallest fragment of an antibody that retains both an antigen recognition site and an antigen binding site. As used herein, "Fab" refers to a fragment comprising an antibody of the constant domain of the light chain and the CH1 domain of the heavy chain. The term "mAb" refers to a monoclonal antibody. Antibodies useful in the present invention include, but are not limited to, all natural antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and non-proprietary antibodies. A domain refers to a functional building block that constitutes each polypeptide of an antibody molecule. Further, Fc which can be used in the present invention means a partial sequence and a partial structure of an H chain constant region formed by a hinge domain, a CH2 domain, and a CH3 domain. Further, CH is formed by a CH1 domain, a hinge domain, a CH2 domain, and a CH3 domain from the N-terminus. The CH1 domain, the hinge domain, the CH2 domain, the CH3 domain, and the Fc region of the present invention can be recognized by a plurality of amino acid residues from the N-terminus according to the EU index [Kabat et al., Sequences of Proteins of Immunological Interest, US Dept .Health and Human Services (1991)]. A plurality of amino acid residues are indicated by Kabat et al. by the EU index and in the present invention, the first plurality of amino acid residues indicate the original or parent residues of the polypeptide and the latter plurality of amino acid residue indicator polypeptides Substituting or replacing an amino acid residue. Specifically, CH1 is identified by the amino acid sequence from positions 118 to 215 of the EU index, the hinge is identified by the amino acid sequence from positions 216 to 230 of the EU index, and CH2 is from position 231 from the EU index to The amino acid sequence of 340 is recognized, and CH3 is recognized by the amino acid sequence from positions 341 to 447 of the EU index. As used herein, the term "recombinant antibody" refers to an antibody produced by recombinant techniques and monoclonal antibodies obtained from fusion tumors. Recombinant antibodies include chimeric antibodies prepared by binding a human antibody constant region to a non-human antibody variable region, and a framework of a human antibody variable region by CDRs of a H-chain and an L-chain of a variable region of a non-human antibody A humanized antibody (or CDR-grafted antibody) prepared in a region (hereinafter abbreviated as FR), and a human antibody prepared by using an animal producing a human antibody or the like. The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequences of VH and VL of a non-human animal antibody are grafted into the corresponding VH and VL of a human antibody. Chimeric antibodies can be obtained by inserting cDNA encoding VH and VL from a fusion tumor derived from a non-human animal to produce a monoclonal antibody, and inserting the cDNA into an animal having DNA encoding the CH and CL of the human antibody. The expression vector of the cell is used to construct a human chimeric antibody expression vector, and then the vector is introduced into an animal cell to express the antibody. The term "humanized antibody" refers to an antibody in which the amino acid sequence of the CDRs of VH and VL of a non-human animal antibody is grafted into the corresponding CDRs of VH and VL of a human antibody. This area is called FR except for the CDRs of VH and VL. A humanized antibody can be produced by (i) constructing an amino acid of VH composed of an amino acid sequence of a CDR of a VH of a non-human antibody and an amino acid sequence of a framework region (FR) of a VH of any human antibody. The cDNA encoding the sequence and the cDNA encoding the amino acid sequence of VL consisting of the amino acid sequence of the CDR of the VL of the non-human animal antibody and the amino acid sequence of the FR of any human antibody; (ii) These cDNAs are separately inserted into expression vectors of animal cells having DNA encoding the CH and CL of human antibodies to construct a humanized antibody expression vector; and (iii) the vector is introduced into animal cells to express the antibody. As used herein, the term "human antibody" refers to an antibody having a variable region in which both the framework region and the CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. Human antibodies of the invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations induced by in vitro random or site-specific mutagenesis or introduced by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The term "human" antibody is used synonymously with "fully human" antibody. Human antibodies also include antibodies obtained from human antibody phage libraries, colonized immortalized human peripheral blood lymphocytes, or human antibody-producing transgenic animals prepared according to recent technological improvements in genetic engineering, cell modification, and research and development. Human antibodies can be obtained by immunizing mice having human immunoglobulin genes (Tomizuka K et al, Proc Natl Acad Sci USA. 97, 722 -7, 2000) with the desired antigen. Furthermore, by using a phage display library formed by amplification of an antibody gene of human B cells to select a human antibody having a desired binding activity, it is possible to obtain a human antibody without immunization (Winter G et al. Annu Rev Immunol. 12: 433-55. 1994). Furthermore, by using Epstein-Barr (EB) virus to immortalize human B cells to produce human antibody-producing cells with the desired binding activity, it is possible to obtain human antibodies (Rosen A et al., Nature 267, 52-54. 1977). The human antibody phage library is a phage library in which antibody fragments such as Fab and scFv are expressed on the surface thereof by inserting an antibody gene prepared from human B cells into a gene of a phage. It is possible to recover from the library the phage displaying the antibody fragment having the desired antigen-binding activity by using the binding activity with respect to the immobilized antigen substrate as an index. Antibody fragments can also be converted to human antibody molecules consisting of two intact H chains and two intact L chains by genetic engineering techniques. A transgenic animal that produces a human antibody refers to an animal obtained by integrating a human antibody gene into the chromosome of a host animal. Specifically, human antibody genes are introduced into mouse ES cells. The ES cells are then transplanted to an early embryo of another mouse. A transgenic animal that produces a human antibody can be produced from the embryo. For the production of human antibodies from a transgenic animal producing a human antibody, a fusion cell producing a human antibody is obtained by a normal fusion tumor preparation method. After culturing a fusion tumor obtained from a mammal other than a human, a human antibody can be produced and expressed in the culture. In particular, antibodies suitable for use in the present disclosure may include non-human animal antibodies, humanized antibodies, and any of the methods known in the art, such as VH and VL of human antibodies produced by fusion tumors or antibody-producing cells. Amino acid sequence. The amino acid sequence of CL in the antibody of the present invention may be any of an amino acid sequence of a human antibody or an amino acid sequence of a non-human animal antibody. In certain embodiments, the amino acid sequence of the Ck or Cλ of a human antibody is used. The CH in the antibody of the present invention may be any of immunoglobulins. In certain embodiments, any of γ1 (IgG1), γ2 (IgG2), and γ4 (IgG4), and variants thereof, may be suitable for use in the antibodies of the invention. The term "effector function" as used in the present invention refers to cytotoxic activity induced by an antibody, including antibody-dependent cellular cytotoxicity (ADCC) by effector cells such as natural killer (NK) cells, complement-dependent cytotoxicity ( CDC), antibody dependent phagocytosis (ADP) or any combination thereof. The effector function of the antibody can be modulated by known methods. For example, ADCC activity is known in the art to be regulated by controlling the amount of trehalose (also referred to as "nuclear trehalose") which is reduced by complex N-glycosidically linked sugar chains. The α1-6 bond in the end binds to N-ethinylglucosamine (GlcNAc), and the complex N-glycosidically linked sugar chain binds to the EU index in the Fc region of the antibody (Kabat et al., Sequence) Asparagine (Asn) at position 297 of the Proteins of immunological interests, 5th edition, 1991) (see WO2005/035586, WO2002/31140, WO00/61739), each of which is incorporated by reference in its entirety. The manner is incorporated herein. Furthermore, it is known in the art to modulate ADCC and/or CDC, for example, by modifying the amino acid residues of the Fc region of an antibody. The effector activity of the antibody can be enhanced or decreased by controlling the amount of nuclear trehalose bound to the complex N-glycosidically linked sugar chain of the Fc region of the antibody. To reduce the trehalose content of the complex N-glycosidically linked sugar chain bound to the Fc of the antibody, CHO cells lacking the α1,6-trehalyltransferase gene (FUT8) can be used to express the antibody. An antibody that does not bind trehalose is obtained. Antibodies that do not contain trehalose have higher ADCC activity. To increase the trehalose content of the complex N-glycosidically linked sugar chain bound to the Fc of the antibody, trehalose can be obtained by expressing the antibody using a host expressing the α1,6-trehalyltransferase gene. Antibody. Antibodies with trehalose have lower ADCC activity than antibodies without trehalose. In one embodiment, an anti-CCR4 antibody for use in the invention is an antibody having a de-fucosylated N-glycosidically linked sugar chain that binds to the Fc region of an antibody. In certain embodiments, an anti-CCR4 antibody for use in the invention is an antibody having a de-fucosylated N-glycosidically linked sugar chain that binds to the Fc region of an antibody, in some embodiments, about 50% or Bigger. In other embodiments, the de-fucosylation of the antibody ranges from about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% or more. Furthermore, ADCC activity or CDC activity can be increased or decreased by modifying the amino acid residues in the Fc region of the antibody. The amino acid residues in the Fc region are modified to increase or decrease the binding activity to the FcyR, thereby controlling ADCC activity. The amino acid residues in the Fc region are modified to increase or decrease the binding activity of complement, thereby controlling CDC activity. For example, the CDC activity of an antibody can be increased by using the amino acid sequence of the Fc region described in the specification of US 2007/0148165. In addition, the ADCC activity or the CDC activity can be as described in the specification of US 6,737,056, US 7,297,775, US 7,317,091, WO 2005/070963, and Oganesyan et al. (Biol. Crystal., 2008; 64; 700-704). The amino acid residue is increased or decreased. In some embodiments, the anti-PD-1 antibody has no effector function and neutralizes PD-1 function only by PD-L1 or PD-L2 binding. In certain embodiments, an anti-PD1 antibody suitable for use in the invention can be an IgG2 or IgG4 subclass that exhibits reduced effector function or no effector function. In one embodiment, an anti-PD-1 antibody for use in the present invention may be provided with an Fc variant having a reduced effector function or no effector function. As used herein, the term "individual" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like. Unless otherwise stated, the terms "patient" or "individual" are used interchangeably herein. The term "flat dose" or "flat dose" as used in relation to the compositions of the present invention means the dose administered to a patient regardless of the patient's body weight or body surface area (BSA). Thus, the leveling dose is not provided in the form of a mg/kg dose, but rather in an absolute amount of a reagent (eg, an anti-CCR4 antibody and/or an anti-PD-1 antibody). For example, a 60 kg person and a 100 kg person will receive the same dose of the composition (eg, 240 mg of anti-PD1 antibody and 80 mg of anti-CCR4 antibody). As referred to herein, the term "weight-based dose" means that the dose administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg/kg of anti-PD-1 antibody and 1 mg/kg of anti-CCR4 antibody, we can take an appropriate amount of anti-PD-1 antibody (ie, 180 mg). And anti-CCR4 antibody (ie, 60 mg). Various aspects of the invention are described in further detail in the following subsections.CCR4 CCR4 is a member of the seven transmembrane G-type protein-coupled receptor family of the lymphocyte chemokine receptors that act as two chemokines, TARC (CCL17) and MDC (CCL22). CCR4 is shown to include CD4+ Regulatory T cell (Treg) CD4+ On Th2 cells. In addition, some cancers including adult T-cell leukemia lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and several solid tumors have been shown to exhibit CCR4. Induction of Ca by ligands bound by CCR42 + Flowing into CCR4+ The cells are induced on the cells and the cells migrate toward the ligand-secreting tissues. CD4+ Th2 cells are regulatory cells in humoral immunity. Th2 cells also inhibit Th1 cell function when Th2 cells promote antibody production to additional antigens by B cells. Th2 cells act as helper T cells by producing immunosuppressive interleukins, such as interleukin (IL)-10, thereby inhibiting cellular immunity. CD4, CD25, CTLA-4, and GITR (glucocorticoid-induced tumor necrosis factor receptor family-associated genes) are known Treg markers (Journal of Allergy and Clinical Immunology, 110: 693-701, 2002). In addition, the FoxP3 (fork box protein 3) transcription factor is a major gene involved in the differentiation and functional expression of regulatory T cells (Science, 299: 1057-61, 2003). In addition, CCR4 is also expressed on Treg cells (US Publication No. 2006/0034841). Treg cells are one of the T cell populations that inhibit the activation of autoreactive T cells and are responsible for immunizing self-tolerance and preventing the immune system from attacking self-organized tissues in healthy individuals (Immunological Review, 182: the whole volume, 2001). . Treg cells secrete inhibitory chemokines, interleukin-10 (IL-10), and transforming growth factor (TGF)-beta via direct and/or indirect pathways, such as cell-cell interactions, depletion of T cell stimulation Sex chemokines and IL-2 inhibit immunostimulation. Exemplary cells that exhibit CCR4 targeting in the methods provided herein are selected from the group consisting of CCR4+ Immune cells and CCR4+ Cells in tumor cells. In some embodiments, CCR4+ The cell is a cell selected from the group consisting of CCR4+ T cell, CCR4+ Th2 cells, CD4+ CD25+ CCR4+ T cell, CCR4+ Foxp3+ T cells, CD4+ CD25+ CCR4+ Foxp3+ T cells, CD4+ CD25+ CCR4+ CD127Low T cells and CD4+ CD25+ CD45RA- CCR4+ Foxp3+ T cells (referred to as effector Treg) (Miyara et al, Immunity, 2009; 30: 899-911), and "Treg cells" are defined as regulatory T cells. In other embodiments, CCR4+ Treg is defined by at least one flag set selected from the following: CD4+ CD25+ CCR4+ CD25+ Foxp3+ , CCR4+ Foxp3+ CD4+ CD25+ CCR4+ Foxp3+ CD4+ CD25+ CCR4+ CD127Low And CD4+ CD25+ CD45RA- CCR4+ Foxp3+ It can be exemplary.PD-1 The activation and deactivation of T cells in the human body is simultaneously complicated by multiple membrane proteins. One of these membrane proteins, PD-1 was cloned into a 55 kDa type I membrane protein (Ishida et al., EMBO J., 1992; 11; 3887-3895). PD-1 is expressed on multiple cell types of activated T cells, regulatory T cells (Treg), activated B cells, and natural killer (NK) cells and is known to bind PD-1 by binding to its ligand, PD-L1. And PD-L2 to regulate T cell activation. The intracellular domain of PD-1 contains an ITSM motif and an ITIM motif that can be an inhibitory domain of the immune response. PD-1 binds to PD-1 to induce inhibition signals in T cells or other PD-1 expressing cells, thereby blocking the activation, cell proliferation and/or inflammatory cells of T cells or other PD-1 expressing cells. Interleukin release or disable T cells. On the other hand, PD-L1 (human PD-L1 cDNA, AF233516) and PD-L2 (human PD-L2 NM_025239) are ligands for PD-1. PD-L1 is expressed on a plurality of cells, including antigen presenting cells such as activated mononuclear cells and dendritic cells (Freeman et al, Journal of Experimental Medicine (2000), 19; 1027-1034). PD-L1 expression and PD-L2 expression were confirmed not only in normal cells but also in several cancers. In the present invention, PD-1 expression on normal cells and PD-L1 expression on cancer tissues or cancer cells can be detected by known assays such as flow cytometry, immunohistochemistry (IHC). By "PD-1 positive" is meant a cell, tissue, body fluid of at least about 0.1%, at least about 1%, at least about 5%, at least about 10%, or at least about 20% or more of a stained human subject. "PD-L1 positive" or "PD-L2 positive" as used herein may be used interchangeably with "at least about 1% of PD-L1 and/or PD-L2 performance". In one embodiment, PD-L1 performance and/or PD-L2 performance can be used by any method known in the art. In another embodiment, PD-L1 expression and/or PD-L2 expression is measured by in situ hybridization (IHC). The PD-L1 and/or PD-L2 positive tumor may thus have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about as measured by automated IHC. 30%, at least about 40%, or at least about 50% of tumor cells expressing PD-L1.anti- CCR4 antibody An anti-CCR4 antibody suitable for use in the present invention can specifically bind to human CCR4. In one embodiment, an anti-CCR4 antibody can attenuate, inhibit or prevent at least one function of a CCR4 protein. In one embodiment, the anti-CCR4 antibody reduces or depletes CCR4+ Immunosuppressive cells and / or CCR4+ cancer cell. In another embodiment, the anti-CCR4 antibody binds to CCR4 expressed on immunosuppressive cells or cancer cells and reduces or depletes the number of cells by the following antibody effector functions: for example, induction by major natural killer (NK) cells Antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or antibody-dependent phagocytosis (ADP) and/or neutralization of CCR4 coordination by phagocytic cells such as macrophages or dendritic cells body. In one embodiment, an anti-CCR4 antibody used in the method binds to the extracellular region of a CCR4 molecule and exhibits ADCC activity. In another embodiment, the anti-CCR4 antibody binds to an epitope in amino acids 2 to 29 of the CCR4 protein (eg, corresponding to amino acids 2 to 29 of SEQ ID NO: 22) and exhibits ADCC activity. In other embodiments, the anti-CCR4 antibody binds to an epitope in amino acids 12 to 29 of the CCR4 protein (eg, amino acids 12 to 29 of SEQ ID NO: 22) and exhibits ADCC activity. In other embodiments, the anti-CCR4 antibody is cross-competing with an antibody comprising: CCR4: VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, VH CDR2 comprising the sequence set forth in SEQ ID NO: a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and comprising SEQ ID NO The VL CDR3 of the sequence set forth in :6. In one embodiment, an anti-CCR4 antibody or antigen binding portion thereof for use in the invention binds to the same epitope that is bound by an antibody comprising the following or moglizumab: comprising comprising SEQ ID NO: The VH CDR1 of the sequence set forth, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, and the VL comprising the sequence set forth in SEQ ID NO: CDR1, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6. In another embodiment, an anti-CCR4 antibody suitable for use in the invention comprises: a VH CDR comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and comprising the SEQ ID One or more of the VH CDR3s of the sequence set forth in NO: 3, and the VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and One or more of the VL CDR3s of the sequences set forth in SEQ ID NO: 6. In other embodiments, the anti-CCR4 antibody comprises: VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, comprising the set forth in SEQ ID NO: a sequence of VH CDR3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: . In some embodiments, the anti-CCR4 antibody comprises: VH comprising the sequence set forth in SEQ ID NO: 7 and VL comprising the sequence set forth in SEQ ID NO: 8. In certain embodiments, an anti-CCR4 antibody comprises: a heavy chain comprising the sequence set forth in SEQ ID NO: 9 and a light chain comprising the sequence set forth in SEQ ID NO: 10. In other embodiments, the Fc region of the anti-CCR4 antibody comprises nuclear trehalose that does not bind to N-ethyl glucosamine at position 297 of the Fc region. In a specific embodiment, the anti-CCR4 antibody is moglizumab (POTELIGEO (registered trademark)). In certain embodiments, an anti-CCR4 antibody for use in the methods or compositions has a lower fucosylation, de-fucosylation or no aglycosylation-free N-glycosidic linkage to the Fc region of the antibody Sugar chain. Lower fucosylated, de-fucosylated or non-fucosylated antibodies may have higher ADCC activity than trehalosylated antibodies. Thus, in one embodiment, an anti-CCR4 antibody for use in the present methods or in a composition of the invention can be produced from cells having lower or no alpha 1,6-trehalyl transferase (FUT8) activity. In another embodiment, the anti-CCR4 antibody used in the methods or compositions of the invention is substantially free of nuclear trehalose by binding an N-glycosidically linked sugar chain of Asn 297 in the Fc region. The α1,6 bond is bonded to N-ethinylglucosamine. In certain embodiments, the method further comprises identifying CCR4 expression prior to administration of the anti-CCR4 antibody. In other embodiments, CCR4 infiltrating the tumor tissue of the patient and/or tissue effluent such as the abdomen, pleura may be monitored before, during, and/or after treatment.+ T cell or CCR4+ Treg cell population, CCR4+ T cell or CCR4+ The reduction/consumption level of Treg. In addition, CCR4 expression can also be analyzed on cancer cells themselves by any method known in the art.anti- PD-1 antibody In one embodiment, an antibody or antigen binding portion thereof ("anti-PD-1 antibody") that specifically binds to human PD-1 and inhibits hPD-1 activity is used in the methods of the invention. In another embodiment, the anti-PD-1 antibody or antigen binding portion thereof blocks, inhibits, prevents or neutralizes PD-1 expression on a cell or a PD-1 associated tumor immune response function. The anti-PD-1 antibody used in the method of the present invention binds to PD-1 having higher specificity and affinity, blocks the binding of PD-L1, and/or inhibits the immunosuppressive effect of the PD-1 signaling pathway. In any of the therapeutic methods or compositions disclosed herein, the anti-PD-1 antibody comprises an antigen binding that binds to PD-1 and exhibits a functional property similar to that of a whole antibody inhibiting ligand binding and upregulating the immune system. Fragment. In some embodiments, an anti-PD-1 antibody of the invention comprises: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and comprising SEQ ID NO One or more of the VH CDR3s of the sequence set forth in 13 and the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, and the VL CDR2 comprising the sequence set forth in SEQ ID NO: 15 and comprising the SEQ ID NO: One or more of the VL CDR3 of the sequence set forth in 16. In certain embodiments, the anti-PD-1 antibody comprises: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and comprising SEQ ID NO: The sequence VH CDR3 set forth in 13 , the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and the sequence set forth in SEQ ID NO: 16 VL CDR3. In other embodiments, the anti-PD-1 antibody comprises: a VH comprising the sequence set forth in SEQ ID NO: 17 and a VL comprising the sequence set forth in SEQ ID NO: 18. In still other embodiments, the anti-PD-1 antibody comprises: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and a light chain comprising the sequence set forth in SEQ ID NO: 20. In still other embodiments, the anti-PD-1 antibody is IgG2, IgG4, or a variant thereof having reduced effector activity. In certain embodiments, the anti-PD-1 antibody or antigen binding portion thereof competes with navobizumab for binding to human PD-1 and the anti-PD-1 antibody or antigen-binding fragment thereof, such as nabumab, binds to human The same epitope region of PD-1. In other embodiments, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is a chimeric, humanized or human monoclonal antibody or fragment thereof. In certain embodiments of treating a human subject, the monoclonal antibody is a humanized antibody. In other embodiments of treating a human subject, the antibody is a human antibody. In other embodiments, antibodies of the IgGl, IgG2, IgG3 or IgG4 isotype or antibody Fc variants thereof can be used in the methods and compositions. In certain embodiments, the anti-PD-1 antibody or antigen binding portion thereof comprises a heavy chain constant region that belongs to a human IgGl or IgG4 isotype or any applicable IgG variant. In other embodiments, the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen binding portion thereof comprises a S228P mutation that utilizes a proline residue normally found at a corresponding position in the IgG1 isotype antibody to replace the hinge a serine residue in the region. This mutation present in navobizumab prevents Fab arms from exchanging with endogenous IgG4 antibodies while maintaining a lower affinity for activating Fc receptors associated with wild-type IgG4 antibodies (Wang et al, 2014 Cancer Immunol Res. 2 (9): 846-56). In still other embodiments, the antibody comprises a light chain constant region that is a human kappa or lambda constant region. A humanized antibody or human antibody (HuMab) that specifically binds to PD-1 with higher affinity has been disclosed in U.S. Patent No. 8,008,449 or No. 8,779,105. Other anti-PD-1 monoclonal antibodies are described, for example, in U.S. Patent Nos. 6,808,710, 7,488,802, 8, 168,757 and 8,354,509, and PCT Publication No. WO 2012/145493. Each of the anti-PD-1 HuMAbs disclosed in U.S. Patent No. 8,008,449 has been shown to exhibit one or more of the following features: (a) binding to have 1 x 10-7 M or less than 1×10- 7 M of KD Human PD-1, as determined by surface plasmon resonance using the Biacore biosensor system; (b) substantially not bound to human CD28, CTLA-4 or ICOS; (c) increased mixed lymph T cell proliferation in sphere reaction (MLR) analysis; (d) increased interferon gamma production in MLR assay; (e) increased IL-2 secretion in MLR assay; (f) binding to human PD-1 and Crab-fed macaque PD-1; (g) inhibits PD-L1 and/or PD-L2 binding to PD-1; (h) stimulates antigen-specific memory response; (i) stimulates antibody response; and (j) inhibits activity Tumor cell growth in vivo. Anti-PD-1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one (in some embodiments, at least five) of the foregoing features. In some embodiments, the anti-PD-1 antibody is nalumumab. In one embodiment, the anti-PD-1 antibody is patizumab. In one embodiment, the anti-PD-1 antibody is navumab. Navobizumab (also known as "OPDIVO (registered trademark)"; previously specifically referred to as 5C4, BMS-936558, MDX-1106 or ONO-4538) to selectively prevent ligands with PD-1 (PD-L1 and PD-L2) interaction, thereby blocking the whole human IgG4 (S228P) PD-1 immunological checkpoint inhibitory antibody that down-regulates anti-tumor T cell function (U.S. Patent No. 8,008,449; Wang et al, 2014 Cancer Immunol Res. 2 ( 9): 846-56). In some embodiments, the anti-PD-1 antibody cross-competes or binds to the same epitope as the paclizumab. In a specific embodiment, the anti-PD-1 antibody is nalumumab. Pacliizumab (also known as "KEYTRUDA (registered trademark)", lerizumab and MK-3475) is directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) Humanized monoclonal IgG4 antibody. Pacliizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587; see also http://www.cancer.gov/drugdictionary?cdrid=695789 (last visit: December 14, 2014). Pacliizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma. In other embodiments, the anti-PD-1 antibody cross-competes or binds to the epitope of MEDI0608 (previously AMP-514) that is the same as the monoclonal antibody. In still other embodiments, the anti-PD-1 antibody is MEDI0608. MEDI 0608 is described, for example, in U.S. Patent No. 8,609,089 B2 or http://www.cancer.gov/drugdictionary?cdrid=756047 (last visit: December 14, 2014). Anti-PD-1 antibodies useful in the disclosed methods or compositions disclosed also include isolated antibodies that specifically bind to human PD-1 and cross-compete with navobizumab to bind to human PD-1 (see For example, U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013/173223). The ability of antibodies to cross-compete to bind to an antigen can indicate that such antibodies bind to the same epitope region of the antigen and sterically hinder binding of other cross-competing antibodies to a particular epitope region. By virtue of binding to the same epitope region of PD-1, it is expected that such cross-competing antibodies will have functional properties very similar to those of Navuzumab. The cross-competing antibody can be readily identified based on the ability of a cross-competing antibody to cross-compete with Navuzumab in a standard PD-1 binding assay, such as a Biacore assay, an ELISA assay, or a flow cytometry (see, for example, WO 2013/ 173223). In certain embodiments, the anti-PD-1 antibody is nalumumab (OPDIVO (registered trademark)). In other embodiments, the anti-PD-1 antibody is patizumab (KEYTRUDA (registered trademark)). In other embodiments, the anti-PD-1 antibody is selected from the group consisting of human antibody 17D8, human antibody 2D3, human antibody 4H1, human antibody 4A11, human antibody 7D3, and human antibody 5F4, described in U.S. Patent No. 8,008,449. In still other embodiments, the anti-PD-1 antibody is MEDI0608 (previously AMP-514) or AMP-224. In certain embodiments, an anti-PD-1 antibody for use in the methods or compositions that specifically binds to PD-1 and inhibits PD-1 activity (eg, binds to PD-L1 and/or PD-L2) Suitable for treating cancer, such as lung cancer (eg, non-small cell lung cancer), esophageal cancer, or gastric cancer. In one embodiment, an anti-PD-1 antibody for use in a method or composition of the invention comprises: (i) an antibody that cross-competes with the antibody to bind to human PD-1, the antibody comprising: comprising SEQ ID NO The heavy chain CDR1 of the sequence set forth in 11; the heavy chain CDR2 comprising the sequence set forth in SEQ ID NO: 12, and one or more of the heavy chain CDR3 comprising the sequence set forth in SEQ ID NO: 13, And a light chain CDR1 comprising the sequence set forth in SEQ ID NO: 14, a light chain CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a light chain CDR3 comprising the sequence set forth in SEQ ID NO: One or more; (ii) an antibody that binds to the same epitope region as the epitope region of the antibody, the antibody comprising: a heavy chain CDR1 comprising the sequence set forth in SEQ ID NO: 11, comprising SEQ The heavy chain CDR2 of the sequence set forth in ID NO: 12, the heavy chain CDR3 comprising the sequence set forth in SEQ ID NO: 13, the light chain CDR1 comprising the sequence set forth in SEQ ID NO: 14, comprising SEQ ID NO a light chain CDR2 of the sequence set forth in 15 and a light chain CDR3 comprising the sequence set forth in SEQ ID NO: 16; (iii) an antibody thereof Included: a heavy chain CDR1 comprising the sequence set forth in SEQ ID NO: 11, a heavy chain CDR2 comprising the sequence set forth in SEQ ID NO: 12, a heavy chain CDR3 comprising the sequence set forth in SEQ ID NO: 13, a light chain CDR1 comprising the sequence set forth in SEQ ID NO: 14, a light chain CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a light chain CDR3 comprising the sequence set forth in SEQ ID NO: 16; Iv) an antibody comprising: a VH comprising the sequence set forth in SEQ ID NO: 17 and a VL comprising the sequence set forth in SEQ ID NO: 18; or (v) an antibody comprising: comprising SEQ ID NO: 19 The heavy chain of the sequence set forth in the sequence and the light chain comprising the sequence set forth in SEQ ID NO: 20. The anti-PD-1 antibody used in the present invention can exert neutralizing or blocking activity on PD-1; that is, the anti-PD-1 antibody can block PD-1 activity and inhibit T cell proliferation by PD-L1 binding. , interleukin release and any combination thereof. In one embodiment, the anti-PD-1 antibody ONO-4538, BMS-936558, nabuumumab/OPDIVO (registered trademark) specifically binds to PD-1 and blocks PD-1 binding to PD-L1 and PD An exemplary anti-PD-1 antibody of -L2. Navobizumab attenuates PD-1 mediated inhibition of human T cell activation in vitro and inhibits tumor growth in xenograft models via a T cell-dependent mechanism.( i ) anti- CCR4 Antibody and ( Ii ) anti- PD - 1 Combination therapy of antibodies The invention relates to a method of treating cancer comprising administering a CCR4 antagonist and a PD-1 antagonist, wherein the CCR4 antagonist comprises binding to CCR4, interfering with CCR4 or otherwise blocking CCR4 binding to its ligand ( For example, any smaller or larger molecule of CCL17 and/or CCL22) (eg, an anti-CCR4 antibody), and the PD-1 antagonist comprises binding to PD-1, interfering with PD-1, or otherwise blocking PD- 1 Any smaller or larger molecule (eg, an anti-PD-1 antibody) that binds to its ligand (eg, PD-L1). In one embodiment, the invention comprises a method of treating at least one cancer in an individual in need thereof, the method comprising administering an anti-CCR4 antibody and an anti-PD-1 antibody. In another embodiment, the dosing schedule of the method comprises a dosing schedule for a cancer patient comprising administering an anti-CCR4 antibody and an anti-PD-1 antibody. In certain embodiments, an anti-CCR4 antibody and an anti-PD-1 anti-system are administered in an amount effective to treat cancer. Also provided herein is a method of reducing the size of a tumor in an individual having cancer by at least about 1%, 5%, 10%, 15%, 20%, or 30%, the method comprising: (i) an anti-CCR4 antibody or The antigen binding portion and (ii) the anti-PD-1 antibody or antigen binding portion thereof are administered to the individual. In other embodiments, the combination methods of the invention enhance anti-tumor efficacy compared to monotherapy with anti-CCR4 antibodies or anti-PD-1 antibodies. In certain embodiments, the anti-CCR4 antibody and the anti-PD-1 antibody are administered in an effective amount to reduce the tumor size of the cancer. These combined methods of the invention can reduce or deplete CCR4, which inhibits anti-tumor immune responses+ Treg cells bring one or more beneficial effects in anti-tumor immunotherapy of cancer patients; therefore anti-CCR4 antibodies counteract CCR4+ The immunosuppressive effect of Treg cells and causes and enhances the anti-tumor immune response. At the same time, anti-PD-1 antibodies block or neutralize negative regulators of T cells and PD-1 against cytotoxic T cells that attack tumor cells in the tumor microenvironment; thus anti-PD-1 antibodies counteract negative signals against T cells And cause an anti-tumor immune response. Dosages for administration of the anti-CCR4 antibody in the method include any dose of from about 0.1 mg/kg to about 10.0 mg/kg per administration. In one aspect, the dose of the anti-CCR4 antibody used in the method comprises at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg. /kg, at least about 0.6 mg/kg, at least about 0.7 mg/kg, at least about 0.8 mg/kg, at least about 0.9 mg/kg, at least about 1.0 mg/kg, at least about 2.0 mg/kg, and at least about 3.0 mg/ Kg. Dosages for administration of the anti-PD-1 antibody in the method include any dose of from about 1.0 mg/kg to about 10.0 mg/kg per administration. In one aspect, the dose of the anti-PD-1 antibody used in the method comprises at least about 1 mg/kg, at least about 2 mg/kg, at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 6 mg/kg, at least about 7 mg/kg, at least about 8 mg/kg, at least about 9 mg/kg, or at least about 10 mg/kg. In other embodiments, the dose of the anti-PD-1 antibody is about 2.0 mg/kg. In a specific embodiment, the dose of the anti-PD-1 antibody is about 3.0 mg/kg. In a particular embodiment, the dose of the anti-PD-1 antibody is about 240 mg/body as a flat dose. In some embodiments, the dose of the anti-PD-1 antibody is at least about at least about 100 mg/body, 120 mg/body, 140 mg/body, 160 mg/body, 180 mg/body, 200 mg/body, 220 mg. / Body, 240 mg / body, 260 mg / body, 280 mg / body, 300 mg / body, 400 mg / body, 420 mg / body, 440 mg / body, 460 mg / body, 480 mg / body, 500 mg / Body, 520 mg / body, 540 mg / body, 560 mg / body or 600 mg / body. In certain embodiments, the dose of the anti-PD-1 antibody is a 480 mg/body dose. The administration cycle of the antibody used in the method includes any suitable administration cycle for each antibody. The dosing cycle is defined as about once a week (Q1W), about every two weeks (Q2W), about once every three weeks (Q3W), or about once every four weeks or about once a month (Q4W). The administration cycle of the anti-CCR4 antibody used in the method includes one week (Q1W) for four weeks to eight weeks, once a week (Q1W) for four weeks and once every two weeks (Q2W). In one aspect, the anti-CCR4 antibody is administered once a week for four weeks (induction phase) and then every two weeks (maintenance phase) after the first administration. The administration cycle of the anti-PD-1 antibody used in the method includes once every two weeks, once every three weeks, or once every four weeks. In another embodiment, the method of the invention comprises a method of treating at least one cancer in an individual comprising administering about 0.1 mg once every week for about four weeks after the first administration and then about once every two weeks. /kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg of anti-CCR4 antibody, and about every two weeks Administer about 2.0 mg/kg, or about 3.0 mg/kg, or at least about 100 mg/body, 120 mg/body, 140 mg/body, 160 mg/body, 180 mg once, every three weeks, or once every four weeks. / body, 200 mg / body, 220 mg / body, 240 mg / body, 260 mg / body, 280 mg / body, 300 mg / body, 400 mg / body, 420 mg / body, 440 mg / body, 460 mg / Body, 480 mg / body, 500 mg / body, 520 mg / body, 540 mg / body, 560 mg / body, 580 mg / body or 600 mg / body as a flat dose of anti-PD-1 antibody combination. In other embodiments, the methods of the invention comprise treating at least one cancer in an individual, the method comprising administering; (i) about one week after the first administration for about four weeks and then about every two weeks about 0.1 Mg/kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and about every two weeks Administration of an anti-PD-1 antibody combination of about 2.0 mg/kg once; (ii) about 0.1 mg/kg, about 0.3 mg/kg, about once a week for the first time after the first administration and then about once every two weeks. , about 0.75 mg/kg, about 1.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and administered about 3.0 mg/kg of anti-PD-1 antibody combination about once every two weeks; (iii) at About 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 after about once a week for about four weeks and then about once every two weeks. Mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and administered at least about 100 mg/body, 120 mg/body, 140 mg/body, 160 mg/body, 180 mg/body, about once every two weeks. 200 mg / body, 220 mg / Body, 240 mg / body, 260 mg / body, 280 mg / body, 300 mg / body, 400 mg / body, 420 mg / body, 440 mg / body, 460 mg / body, 480 mg / body, 500 mg / Body, 520 mg/body, 540 mg/body, 560 mg/body, 580 mg/body or 600 mg/body as a flat dose of anti-PD-1 antibody combination; (iv) about one week after the first dose An anti-CCR4 antibody that lasts for about four weeks and then about every two weeks, about 0.1 mg/kg, about 0.3 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg. And administering about 2.0 mg/kg of anti-PD-1 antibody combination about once every four weeks; (v) about 0.1 mg/kg for about four weeks after the first administration and then about once every two weeks. , about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and about 3.0 mg/kg of anti-drug administered about once every four weeks. The PD-1 antibody combination or (vi) is about one week after the first administration for about four weeks and then about once every four weeks, about 0.1 mg/kg, about 0.3 mg/kg, about 0.75 mg/kg, about 1.0. Mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and administered at least about 100 mg/body, 120 mg/body, 140 mg/body, 160 mg/body with about once every two weeks. , 180 mg / body, 200 mg / body, 220 mg / body, 240 mg / body, 260 mg / body, 280 mg / body, 300 mg / body, 400 mg / body, 420 mg / body, 440 mg / body , 460 mg / body, 480 mg / body, 500 mg / body, 520 mg / body, 540 mg / body, 560 mg / body, 580 mg / body or 600 mg / body as a flat dose of anti-PD-1 antibody combination. In one embodiment, the method of the invention comprises a method of treating at least one cancer in an individual comprising administering about 0.1 mg per week for about four weeks after the first administration and then about once every two weeks. Kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and administered about once every two weeks Anti-PD-1 antibody with a dose of about 2.0 mg/kg or about 3.0 mg/kg, or about 240 mg/body as a flat dose, or about 480 mg/body as a flat dose of anti-PD-1 antibody Combination, wherein the anti-CCR4 antibody competitively binds to CCR4 with an antibody comprising: VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, comprising The VH CDR3 of the sequence set forth in SEQ ID NO: 3, the VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and comprising SEQ ID NO: VL CDR3 of the sequence set forth in 6 and wherein the anti-PD-1 antibody competitively binds to PD-1 with an antibody comprising: SEQ ID NO: 11 The VH CDR1 of the sequence set forth, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, and the sequence set forth in SEQ ID NO: 14. VL CDR1, VL CDR2 comprising the sequence set forth in SEQ ID NO: 15 and VL CDR3 comprising the sequence set forth in SEQ ID NO: 16. In one embodiment, the method of the invention comprises a method of treating a cancer patient, the method comprising administering about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg, about once a week for about four weeks and then about every two weeks. /kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and about 2.0 mg/kg or about 3.0 mg/about once every two weeks. Kg, or about 240 mg/body as a flat dose of anti-PD-1 antibody, or about 480 mg/body as a flat-tune dose of anti-D-1 antibody combination every four weeks, wherein the anti-CCR4 antibody binds to the antibody The same epitope, the antibody comprising: a VH CDR comprising the sequence set forth in SEQ ID NO: 1, a VH CDR comprising the sequence set forth in SEQ ID NO: 2, comprising the set forth in SEQ ID NO: a VH CDR3 of the sequence, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6, And wherein the anti-PD-1 antibody binds to the same epitope as the antibody, the antibody comprising: comprising the sequence set forth in SEQ ID NO: The VH CDR1, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, VL CDR2 of the sequence set forth in SEQ ID NO: 15 and VL CDR3 comprising the sequence set forth in SEQ ID NO: 16. In one embodiment, the method of the invention comprises a method of treating a cancer patient, the method comprising administering about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg, about once a week for about four weeks and then about every two weeks. /kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody, and about 2.0 mg/kg, or about 3.0 mg, administered about once every two weeks. /kg, or a combination of anti-PD-1 antibodies at a dose of about 240 mg/body, or a combination of anti-PD-1 antibodies at a dose of about 480 mg/body once every four weeks, wherein the anti-CCR4 antibody Included: VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, comprising SEQ ID VL CDR1 of the sequence set forth in NO: 4, VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and VL CDR3 comprising the sequence set forth in SEQ ID NO: 6, and wherein the anti-PD-1 antibody Including: VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, comprising the set forth in SEQ ID NO: Column of VH CDR3, comprising SEQ ID NO: VL CDR1 sequences 14 set forth, the comprising SEQ ID NO: VL sequences 15 set forth the CDR2 and comprising SEQ ID NO: VL CDR3 sequences 16 as set forth in the. In another embodiment, the method of the invention comprises a method of treating a cancer patient, the method comprising administering about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 about once a week for about four weeks and then about once every two weeks. Mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg of anti-CCR4 antibody (moglixizumab), and administered about once every two weeks. 2.0 mg/kg, or about 3.0 mg/kg, or a dose of about 240 mg/body of anti-PD-1 antibody (Narubizumab) or about 480 mg/body as a leveling agent every about four weeks A combination of anti-PD-1 antibody (nabuzumab). In the methods or compositions described herein, antibody combinations can be administered to a cancer patient in parallel (or simultaneously) or sequentially. The term "parallel" or "simultaneously" means that at least two antibodies are dissolved in a pharmaceutically acceptable aqueous liquid, such as physiological saline or Ringer's solution or a mixture thereof, and at the same time by intravenous and/or infusion. The bag is administered to the patient. The term "sequential" means that an antibody is administered to a cancer patient, and then the second antibody is administered to the cancer patients at a later time allowed after administration of the first antibody. In certain embodiments, the present disclosure includes a method of treating a patient having HCC, wherein the progression free survival (PFS) is at least 100 days, at least 101 days, at least 102 days, at least 103 days, at least 104 days, At least 105 days, at least 106 days, at least 107 days, at least 108 days, at least 109 days, at least 110 days, at least 111 days, at least 112 days, at least 113 days, at least 114 days, at least 115 days, at least 116 days, at least 117 Day, at least 118 days, at least 119 days, at least 120 days, at least 125 days, at least 130 days, at least 135 days, at least 140 days, at least 145 days, at least 150 days, at least 155 days, at least 160 days, at least 165 days, At least 170 days, at least 175 days, at least 180 days, at least 185 days, at least 190 days, at least 195 days, at least 200 days, at least 205 days, at least 210 days, at least 215 days, or at least 220 days. In other embodiments, the PFS of the present combination therapy with an anti-CCR4 antibody and an anti-PD-1 antibody is higher than the PFS of the anti-CCR4 antibody monotherapy and/or anti-PD-1 antibody monotherapy (above at least one week, at least two) Week, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine Months, or at least ten months). In other embodiments, the present disclosure provides a method of treating a patient having HCC, wherein the overall survival is at least about 200 days, at least about 210 days, at least about 220 days, at least about 230 days, at least about 240 days, At least about 250 days, at least about 260 days, at least about 270 days, at least about 280 days, at least about 290 days, at least about 300 days, at least about 310 days, at least about 320 days, at least about 330 days, at least about 340 days, At least about 350 days, at least about 360 days, at least about 370 days, at least about 380 days, at least about 390 days, or at least about 400 days. In still other embodiments, the OS of the method is higher than the OS of anti-CCR4 antibody monotherapy and/or anti-PD-1 antibody monotherapy (above at least about one month, at least about two months, at least about three) Month, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about 11 months, At least about 12 months, at least about 15 months, at least about 20 months, at least about two years, at least about 25 months, at least about 30 months, at least about 35 months, at least about three years, at least about 40 Months, at least about 3.5 years, at least about 4 years, at least about 4.5 years, or at least about 5 years).Inclusion resistance for the treatment of cancer CCR4 Antibody and resistance PD - 1 Antibody set The invention also encompasses a kit for treating an individual suffering from cancer, the kit comprising: (a) a specific binding to PD-1 at a dose ranging from about 0.1 mg/kg to about 10 mg/kg body weight and / or an antibody or antigen-binding portion thereof that inhibits PD-1 activity ("anti-PD-1 antibody or antigen-binding portion thereof"); (b) a dose ranging from about 0.1 mg/kg to about 10 mg/kg body weight An antibody or antigen-binding portion thereof ("anti-CCR4 antibody or antigen-binding portion thereof") that specifically binds to CCR4 and/or inhibits CCR4 activity; and (c) uses an anti-PD-1 antibody and any of the methods disclosed herein Instructions for anti-CCR4 antibodies. The kit typically includes a label indicating the intended use of the contents of the kit and instructions for use. The term label includes any written or recorded material that is supplied on or in conjunction with the kit or otherwise. In other embodiments, the anti-CCR4 antibody or antigen binding portion thereof is selected from the group consisting of: (i) an antibody or antigen binding portion thereof that binds to the same epitope as the antibody, comprising: comprising SEQ ID NO:1 The VH CDR1 of the sequence set forth in the sequence, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and one or more of the VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, and comprising SEQ ID NO The VL CDR 1 of the sequence set forth in 4, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and one or more of the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; An antibody or antigen binding portion thereof comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, comprising the set forth in SEQ ID NO: a sequence of VH CDR3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL comprising the sequence set forth in SEQ ID NO: CDR3; (iii) an antibody or antigen binding portion thereof comprising: VH comprising the sequence set forth in SEQ ID NO: 7 and comprising SEQ ID NO: VL of the sequence set forth in 8; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 9 and a light chain comprising the sequence set forth in SEQ ID NO: 10; (v) an antibody or antigen binding portion thereof, which cross-competes with the antibody of (ii); and (vi) moglizumab or an antigen binding portion thereof. In certain embodiments, the anti-PD-1 antibody or antigen binding portion thereof is selected from the group consisting of: (i) an antibody or antigen binding portion thereof that binds to the same epitope as the antibody, comprising: comprising the SEQ ID One or more of the VH CDR1 of the sequence set forth in NO:11, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and the VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, and comprising VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and one or more of VL CDR3 comprising the sequence set forth in SEQ ID NO: 16; (ii) an antibody or antigen-binding portion thereof comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, comprising SEQ ID NO: 13 The VH CDR3 of the sequence set forth, the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and the sequence set forth in SEQ ID NO: a VL CDR3; (iii) an antibody or antigen binding portion thereof comprising: comprising the sequence set forth in SEQ ID NO: a VH and a VL comprising the sequence set forth in SEQ ID NO: 18; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising the set forth in SEQ ID NO: a light chain of the sequence; (v) an antibody that cross-competes with the antibody of (ii); (vi) nalumumab or an antigen binding portion thereof; (vii) a platizumab or an antigen binding portion thereof; ) MEDI0608 or an antigen binding portion thereof.Inclusion resistance for the treatment of cancer CCR4 Antibody and resistance PD - 1 Antibody composition In one embodiment, the compositions of the invention comprise an anti-CCR4 antibody and an anti-PD-1 antibody for use in the treatment of cancer. In one embodiment, the composition for use in the present invention is prepared to be administered about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/kg, about once a week for about four weeks, and then about every two weeks. An anti-CCR4 antibody at a dose of about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg, and about 2.0 mg/kg, or about 3.0 mg/kg or about once every two weeks. 240 mg/body as a flat dose of anti-PD-1 antibody or a combination of anti-PD-1 antibodies at about 480 mg/body as a flat dose every four weeks. In certain embodiments, the composition is prepared as a level-adjusted dose of an anti-PD-1 antibody at about 2.0 mg/kg, or about 3.0 mg/kg, or about 240 mg/body, about once every two weeks, or About 480 mg/body as a flat dose of anti-PD-1 antibody every about four weeks and about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg, about once a week for about four weeks and then about once every two weeks. The anti-CCR4 antibody is administered in a dose of /kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg or about 3.0 mg/kg. In some embodiments, the composition is prepared to be about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about once a week for about four weeks and then about once every two weeks. An anti-CCR4 antibody at a dose of about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg is about 2.0 mg/kg or about 3.0 mg/kg or about 240 mg/body as a flat dose every about two weeks. The anti-PD-1 antibody is administered in a combination of about 480 mg/body as a flat dose of anti-PD-1 antibody approximately once every four weeks. In other embodiments, the composition is prepared to be about once a week for about 2.0 mg/kg, or about 3.0 mg/kg or about 240 mg/body as a flat dose of anti-PD-1 antibody and about once a week. An anti-CCR4 antibody dose of about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg is administered in combination for about four weeks and then about once every two weeks. In one embodiment, the composition for use in the present invention comprises an anti-CCR4 antibody (moglinizumab) for about four weeks at about once a week and then about once every two weeks at about 0.1 mg/kg, about 0.3 mg/ A dose of kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg is about 2.0 mg/kg or about 3.0 mg/about once every two weeks. A dose of kg or about 240 mg/body is a flat dose or about once every four weeks, a combination of anti-PD-1 antibody (nabuzumab) at a dose of about 480 mg/body is used to treat cancer in an individual. In another embodiment, the composition comprises an anti-PD-1 antibody (nabuzumab) at a dose of about 2.0 mg/kg or about 3.0 mg/kg or about 240 mg/body, about once every two weeks. A flat dose or about once every four weeks at a dose of about 480 mg/body and about once a week for about four weeks and then about once every two weeks about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/kg, A combination of anti-CCR4 antibody (moglinizumab) at a dose of about 0.75 mg/kg, about 1.0 mg/kg, or about 3.0 mg/kg. In certain embodiments, the compositions for use in the present invention are prepared as a puffed dosage composition; for example, a flat dosage of an anti-CCR4 antibody can be at least about 5 mg, at least about 10 mg, at least about 15 mg, at least About 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least About 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least About 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, at least about 290 mg, or at least about 300 mg. In some embodiments, the dose of the anti-CCR4 antibody ranges from about 1 mg to about 200 mg, from about 2 mg to about 180 mg, from about 3 mg to about 170 mg, or from about 6 mg to about 160 mg. In another embodiment, the composition comprises an anti-CCR4 antibody at a dose ranging from about 6 mg to about 60 mg, from about 10 mg to about 80 mg, or from about 20 mg to about 70 mg. In other embodiments, the dose of the anti-CCR4 antibody is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110. Mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, or about 180 mg. In other embodiments, the compositions for use in the invention are administered in a controlled dose wherein the dose of the anti-PD-1 antibody is at least about 1 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least About 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least About 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least About 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, at least about 290 mg, at least about 300 mg, at least about 310 mg, at least About 320 mg, at least about 330 mg, at least about 340 mg, at least about 350 mg, at least about 360 mg, at least about 370 mg, at least about 380 mg, at least about 390 mg, at least about 400 mg, at least about 410 mg, at least About 420 mg, at least about 430 mg, at least about 440 mg, at least about 450 mg, at least about 460 mg, at least about 470 mg, at least 480 mg, at least about 490 mg, at least about 500 mg, at least about 510 mg, at least about 520 mg, at least about 530 mg, at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 570 mg, at least about 580 mg, at least about 590 mg or at least about 600 mg. In some embodiments, the anti-PD-1 antibody dose is between 20 mg to 300 mg, 30 mg to 280 mg, 40 mg to 270 mg, 50 mg to 270 mg, 60 mg to 260 mg, 70 mg to 250 mg Or in the range of 80 mg to 240 mg. In still other embodiments, the dose of the anti-PD-1 antibody is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg. , about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, 400 mg, about 410 mg, about 420 mg, About 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 Mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. The composition of the present invention comprises any composition for use comprising a combination of an anti-CCR4 antibody and an anti-PD-1 antibody having the above activity as an active ingredient, and in one embodiment, the combination is in the form of a pharmaceutical formulation. It is provided that the pharmaceutical formulation is typically prepared by mixing each antibody with one or more pharmaceutically acceptable carriers according to any of the well known methods in the art of pharmacy. Furthermore, the antibodies used in the present invention are also provided in the form of a pharmaceutical formulation which is usually administered with one or more pharmaceutically acceptable carriers by any of the well-known methods in the field of pharmacy. Mix to prepare. In some embodiments, the anti-system of the invention is provided as a sterile solution, wherein the antibody is dissolved in an aqueous carrier such as water, or an aqueous solution of a salt, glycine, glucose or human albumin. Pharmaceutically acceptable additives such as buffers or tonicity agents may also be added for the preparation of solutions more similar to physiological conditions and examples thereof, including sodium acetate, sodium chloride, sodium lactate, potassium chloride, sodium citrate or analog. It can also be stored by freeze-drying and, in actual use, can be used by dissolving in a suitable solvent. With regard to the route of administration of the antibodies used in the present invention or compositions of the invention, in certain embodiments, the most effective route for treatment is used. Examples include oral administration and parenteral administration, such as intraoral, tracheobronchial, intrarectal, subcutaneous, intramuscular, intrathecal, and intravenous administration. It can be administered intrathecally or intravenously. Capsules, lozenges, powders, granules or the like may be used as excipients such as lactose, glucose, sucrose, mannitol, or the like; disintegrating agents such as starch, sodium alginate or the like; lubricating Agents such as magnesium stearate, talc or the like; binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin or the like; surfactants such as fatty acid esters or the like; plasticizers For example, glycerol or the like is prepared as an additive. Examples of formulations suitable for parenteral administration may include injectable formulations, suppositories, air sprays, or the like. For example, injectable formulations are prepared using carriers including a saline solution, a dextrose solution, or mixtures thereof. Suppositories are prepared using a carrier such as cocoa butter, hydrogenated fat, carboxylic acid or the like. The air spray is prepared using, for example, a carrier which does not irritate the antibody itself and the mouth and respiratory mucosa to be administered to a human, and which disperses the antibody into fine particles to make it easy to absorb. Specific examples of the carrier include lactose, glycerol or the like. An aerosol, a dry powder or the like can be prepared depending on the characteristics of the antibody and carrier used. Further, even in the parenteral preparation, a component exemplified as an additive in oral preparation may be added. In one embodiment, a cancer patient of the invention comprises any cancer patient capable of being effectively treated by the compositions or methods of the invention. For example, in one embodiment of the present invention, the cancer patient is at least one cancer patient having cancer selected from the group consisting of lung cancer, gastrointestinal cancer, gastric cancer (or gastric cancer), colon cancer, colorectal cancer, esophageal cancer, and pancreas Cancer, liver cancer, kidney cancer, ovarian cancer, breast cancer, head and neck cancer, skin cancer, melanoma, and hematopoietic cancer including leukemia and lymphoma. In another embodiment, the cancer of the invention includes any stage of cancer, primary/metastatic cancer, locally advanced/cancerous metastatic cancer, relapsed/refractory cancer, and surgically resectable/unresectable cancer . In one embodiment, the cancer patient has at least one cancer selected from the group consisting of small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) lung cancer, squamous cell carcinoma, adenocarcinoma, large cell Carcinoma, adenosquamous carcinoma, carcinoma with pleomorphic sarcomatoid or sarcoma, cartinoid tumor and classifieds of salivary-gland type, gastric cancer, liver cancer, liver cells Cell carcinoma, cholangiocarcinoma, breast cancer, kidney cancer, melanoma and any combination thereof. In another embodiment, the cancer patient has pancreatic cancer selected from the group consisting of pancreatic ductal cancer, pancreatic head cancer, pancreatic body cancer, pancreatic tail cancer, and any combination thereof. In another embodiment, the patient has a head and neck cancer selected from the group consisting of oral cancer, pharyngeal cancer, laryngeal cancer, cervical cancer, salivary gland cancer, and any combination thereof. In the present invention, a cancer patient can be diagnosed prior to administration of the combination therapy. In one embodiment, the diagnostic method can be performed by methods known in the background art, such as X-ray imaging, computed tomography (CT), positron emission tomography (PET-CT), magnetic resonance imaging (MRI). And/or performing an analysis of one or several biomarkers in the patient's plasma, serum, peripheral blood, tumor tissue. In addition, cancer progression, disease stage, and/or response to treatment can be analyzed by known methods and parameters in combination with the above-described imaging and biomarkers. For example, tumor metabolism with respect to glucose consumption is typically based on up-regulated radioisotope-labeled glucose consumption on FDG-PET, such as18 F-fluorodeoxyglucose (FDG) was analyzed for cancer tissue. FDG is highly accumulated in cancer tissues because cancer cells metabolize glucose and require a greater amount of glucose than normal tissues. In addition, analysis of peripheral blood lymphocytes (PBL), lymphocytes in the pleural effluent (LPE), and/or tumor infiltrating lymphocytes (TIL) can be used to assess each tissue and/or the entire body of each patient. The state of immune response. For example, several markers, such as CD4, CD8, CD25, CD45RA, CD45RO, CCR4, CD127, PD-1, PD-L1 (B7-H1, CD274), PD-L2, CTLA-4 (CD152), IFN - γ, IL-2, IL-4, IL-12 and Foxp3 can be used to predict the immune response status of each patient. Detected performance CD4+ CD25+ CD8+ CD25+ PD-1+ And / or CTLA-4+ Activated T cells, showing CD4+ CD25+ CCR4+ CD25+ Foxp3+ , CCR4+ Foxp3High CD4+ CCR4+ Foxp3+ Or CD4+ CD25+ CD45RA- CCR4+ Foxp3+ Treg cells, and when the patient's activated T cells increase and / or Treg cells decrease, the immune response in the patient is considered to be enhanced. In one assay, analysis by CD4, CD8, CD25, CD45RA, CD45RO, CCR4, CD127, PD-1, PD-L1 (B7-H1, CD274), PD before and/or after administration of the combination therapy T cells, effector Treg, depletion recognized by -L2, CTLA-4 (CD152), IFN-γ, IL-2, IL-4, IL-12 and/or Foxp3, or expression of peripheral/microenvironmental interleukins T cells, activated T cells, effector T cells, non-allergic T cells or bone marrow derived suppressor cells (MSDC). In some embodiments, combination therapy with an anti-CCR4 antibody and an anti-PD-1 antibody can reduce Treg cells and/or activate T cells in peripheral blood, pleural effusion, and/or tumor tissue of a patient. Thus, the combination of antibodies enhances the immune response to cancer cells in a patient. Moreover, in one embodiment, the method further comprises analyzing or measuring the PD-L1, PD-L2 or CCR4 performance level on the tumor cells prior to administration to determine that the patient is suitable for the combination therapy. In another embodiment, PD-L1 or PD-L2 performance in a patient can be considered a marker for the patient's combination therapy for use in the present invention. In addition, the indoleamine 2,3-dioxygenase (IDO) activity in the patient's plasma sample can be analyzed in the present invention. It is known in the art that IDOs present in various organs, such as the lung, small intestine, and placenta, are involved in inducing Treg differentiation, thereby causing immune tolerance. In addition, the molecules are highly expressed on a plurality of cancer cells, inhibiting the immune response and inducing immune tolerance of the cancer cells. Therefore, analysis of IDO activity can detect the state of the immune response. IDO activity is usually detected by analyzing changes in the levels of tryptophan, kynurenine, and kynurenine metabolites. When the IDO activity in the patient is enhanced, tryptophan, kynurenine, and kynurenine metabolites are also increased, thereby causing a decrease in the immune response in the patient. In other embodiments, combination therapy with an anti-CCR4 antibody and an anti-PD-1 antibody increases the amount of Treg cells in a patient and/or reduces IDO activity in a patient. The clinical medicinal assessment of treatment will usually be assessed by the Solid Cancer Response Assessment Criteria (RECIST) version 1.1 guidelines and by the immune-related response criteria (irRC) (Wolchok et al, Clin. Cancer Res.; 2009, 15: 7412-7420). ).Instance 1 Combination therapy with moglizumab and navobizumab in individuals with advanced solid tumors 1 the study 1. Summary of the study This study is an anti-CCR4 antibody, moglizumab, in combination with an anti-PD-1 antibody, navobizumab, in an adult individual with a histologically or cytologically diagnosed locally advanced or metastatic solid tumor. Two-part, multi-center, stage 1, open-label, dose-increasing group amplification studies. Study population: a locally advanced or metastatic solid tumor that was confirmed by histology or cytology. Dose escalation phase: Individuals with histologically or cytologically confirmed locally advanced or metastatic solid tumors will be enrolled. Group amplification stage: registration for advanced or metastatic solid tumors (including but not limited to non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), gastric cancer (GC), hepatocellular carcinoma, pancreatic cancer, and esophagus Individuals of cancer). 2. Research Objectives: Main objective: The primary objective is to characterize the safety and tolerability of a combination of loglizumab and navobizumab in individuals with locally advanced or metastatic solid tumors and to determine the combination Maximum tolerated dose (MTD) or recommended fixed dose. Secondary Objectives: The first objective is to evaluate the combination of moglizumab and navobizumab in individuals with locally advanced or metastatic solid tumors based on solid-state tumor response assessment criteria (RECIST version 1.1). Tumor activity. The optimal overall response rate (BOR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were assessed against anti-tumor activity. The second objective was to characterize the pharmacokinetic (PK) properties of moglizumab and navobizumab in a combination of moglizumab and navumab. Another goal was to evaluate the immunogenicity of moglizumab and nuumumab. 3. Inclusion Criteria: Includes individuals who have voluntarily signed the informed consent form approved by the Institutional Review Board and dated in accordance with the guidelines of the regulatory body. Written informed consent must be obtained prior to performing any research-related steps. The inclusion criteria include the following: - Individuals 20 years of age or older, with informed consent. - Individuals with evaluable lesions according to RECIST version 1.1 guidelines. - Life expectancy > 12 weeks of individuals. - ECOG function status is (performance status) 0 to 1 individual.Dose escalation phase : The individual may have been histologically or cytologically diagnosed as a locally advanced or metastatic solid tumor (excluding primary CNS or hematological malignancies).Group amplification stage : Individuals may have been histologically or cytologically diagnosed as locally advanced or metastatic solid tumors including, but not limited to, NSCLC, SCLC, GC, liver cancer, hepatocellular carcinoma, pancreatic cancer, and esophageal cancer (excluding primary CNS or hematological malignant disease). 4. Exclusion criteria Exclusion criteria include pregnant or lactating women or all individuals who are expected to become pregnant. Exclusion criteria further include individuals with uncontrolled and apparently inter-current diseases. Exclusion criteria further include individuals with known CNS metastases and/or pial metastases. Individuals who have been treated with asymptomatic brain metastases are considered stable and may include individuals who have not received a corticosteroid or anticonvulsant for at least 28 days prior to day 1 of the first cycle. Exclude anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies or specifically target T cell co-stimulation or examination Any other antibody or drug treatment individual of the route. Individuals who have been previously treated with moglizumab are excluded. Individuals who have any previous grade 3 or greater immune-related adverse events (irAE) while receiving any prior immunotherapeutic agents or any undetermined irAE are excluded. Individuals with a history of severe allergic reactions to the drug are excluded. Individuals who received attenuated live vaccinia vaccine within 28 days prior to the first day of the first cycle were excluded. Individuals with a history of organ transplantation or allogeneic bone marrow transplantation are excluded. Exclude receiving chemotherapy, immunotherapy, biological or hormonal therapy, another research drug, radiation or major surgery for cancer treatment within 28 days or 42 days prior to the first day of Cycle 1 (for nitrosourea or Individuals of mitomycin C). Individuals with any undetermined toxicity level 1 or less (defined by CTCAE version 4.03) according to previous anti-cancer therapies were excluded. Excluding individuals with irreversible toxicity, this irreversible toxicity (eg, hearing loss) may be exacerbated by unreasonable expectations of research products that may be included by the primary or associate researcher as appropriate. Exclude individuals who have received systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first day of Cycle 1, however, may include local immunosuppressive therapy at the discretion of the primary or associate investigator individual. Exclude known autoimmune diseases or syndromes that are known to require systemic steroids or immunosuppressive agents (eg, rheumatoid arthritis, uveitis, systemic lupus erythematosus, Wegener's granulomatosis) Or an individual with sarcoma-like disease. According to this study, individuals with a history of leukoplakia, alopecia, or autoimmune disease or syndrome who had not required systemic steroids or immunosuppressive agents for 3 years prior to written informed consent would be excluded. Individuals with active inflammatory bowel disease (eg, inflammatory colitis and ulcerative colitis), Crohn's disease, irritable bowel disease, celiac disease, or other severe GI chronic conditions associated with diarrhea. However, individuals who have a history of chronic GI disease who have not received any therapy for 3 years prior to written informed consent may be included. Previously in human immunodeficiency virus (HIV), human T cell leukemia type I virus (HTLV-1), hepatitis B surface antigen, and hepatitis C virus antibody with congenital or acquired immunodeficiency and with tuberculosis or test positive An individual who clinically diagnoses a known medical history. Individuals with other traumatic malignancies within 5 years prior to the first day of the first cycle were excluded. However, individuals with non-invasive malignancies that have been surgically cured, such as cervical carcinoma in situ, non-melanoma of the skin, or breast ductal carcinoma in situ of the breast, may be enrolled. Individuals who have enrolled another clinical study are excluded unless the other clinical study is the follow-up phase of an observational (non-interventional) clinical study or intervention study. An individual having any condition that would interfere with the assessment of the research product or the interpretation of the individual's safety or findings in the opinion of the researcher and/or sponsor is excluded. 5. Research designDose escalation phase The dose escalation phase is a parallel 3+3 design that will identify the combined treatment of the MTD or the recommended fixed dose. MTD was defined as a lower dose level of studied moglizumab and navobizumab, with more than 2 individuals in 6 individual groups subjected to dose-limiting toxicity (DLT); undetermined in MTD In the case, the recommended fixed dose for the group amplification phase will be determined based on the dose level in the MTD or Group 2. Approximately 3 to 18 individuals will be enrolled in the dose escalation phase (3 to 6 individuals in each of up to 3 groups). Dosage levels and schedules are described below. See also Figure 1. [Table 1]table 1 . Moglizumab and Nafluumab in the dose escalation phase Group amplification stage : The group amplification phase will further explore the safety, PK, PD and anti-tumor activity of each combination in up to 6 tumor types. At this stage, approximately 90 individuals will be enrolled who have locally advanced or metastatic solid tumors including, but not limited to, NSCLC, SCLC, GC, hepatocellular carcinoma, pancreatic cancer, and esophageal cancer; A type of tumor can be considered as warranted by the observation of the dose escalation phase to assess other safety.Combination therapy : In the dose escalation phase and the group expansion phase, the individual will receive a combination therapy with moglizumab and navobizumab. Each individual will receive 3.0 mg/kg of navozumab on day 1 and day 15 with an intravenous (IV) infusion over a period of at least one hour. Individuals will also receive 0.1, 0.3 or 1.0 in IV infusion over a period of at least 1 hour on Days 1st, 8th, 15th and 22nd of the first cycle and on Days 1 and 15 of the subsequent cycle. Megrilizumab at mg/kg. This combination session will be repeated on day 29. On the first and the 15th day of each cycle, moglizumab will be administered after completion of the administration of navumab and one hour of observation. The individual will receive the combination therapy until the disease develops or dies.Safety and efficacy evaluation : All individuals will monitor safety on the first, eighth, fifteenth, and 22nd day of the first cycle based on the event schedule; in the subsequent cycle, every 2 weeks on the first and fifteenth days Perform a safety assessment. Disease assessment by computed tomography (CT) or magnetic resonance imaging (MRI) will continue for the first 2 cycles every 4 weeks, for the next 12 cycles every 8 weeks, and then every 12 weeks thereafter. Perform until disease progression or death. Disease progression will be defined in accordance with RECIST version 1.1 guidelines. [Table 2]table 2 . Research drug 6. Efficacy and safety variablesPrimary endpoint safety .Secondary endpoint : The following efficacy parameters will be utilized: - The best overall response (BOR) assessed using RECIST version 1.1. - Time to response (TTR): Days from the first day of the first cycle to the first assessment date of the confirmed CR/PR - duration of response (DOR): from the first assessment date of the confirmed CR/PR to death or Days of PD (whatever is earlier) - Progression free survival (PFS): Days from Day 1 of Day 1 to Death or PD (whatever is earlier) - Total Survival (OS): From 1st Days from the first day of the cycle to the date of deathStatistical Analysis : The following set of analyses will be used for the study: - Safety analysis set: Includes all individuals receiving at least one dose (even a partial dose) of the study drug. Full Analysis Set (FAS): Includes all individuals receiving at least one dose (even a partial dose) of the study drug and having at least one available post-dose efficacy data. Adverse events will be listed by body system, severity, and treatment ratio. A similar representation of serious adverse events, AEs leading to discontinuation of the study, and AEs leading to death will be provided for safety analysis and full analysis set. The individual's tumor response, TTR, DOR, PFS, and OS will be assessed. The ORR will be calculated as the proportion of individuals who are responders, ie, complete response (CR) and partial reaction (PR); an accurate confidence interval for 95% of the response will be calculated. The disease control rate (CR, PR, SD) will also be calculated. 7. Clinical Efficacy As observed during the combination therapy of this clinical trial, as of September 7, 2016, 4 PR, 6 SD, and 3 PD were observed in 15 hepatocellular carcinoma (HCC) patients. On the other hand, as of September 7, 2016, 1 PR, 5 SD, and 9 PD were observed in 15 pancreatic cancer (PA) patients. In addition, several adverse events were observed in each cancer type, however, all events may be acceptable in cancer treatment. As of November 1, 2017 (data deadline was August 31, 2017), 4 PR and 6 SD were observed in 15 HCC patients (objective response rate 26.7%, disease control rate 66.7%) (Figure 2 ) 1 PR and 5 SD were observed in 15 PA patients (objective response rate 6.7%, disease control rate 40.0%) (Fig. 3). The median progression-free survival for patients with HCC and PA was 114.5 days (95% CI, 28.0 to 223.0) and 56.0 days (95% CI, 29.0 to 115.0), respectively, and the median overall survival was 343.0, respectively. Days (95% CI, 123.0 to immeasurable) and 198.0 days (95% CI, 107.0 to 328.0). No dose limiting toxicity was observed during the dose escalation phase. Level 3 to 4 drug-related adverse events (AEs) occurred in the dose escalation phase and the group amplification portion at 25.0%. No relevant level 5 AEs were seen. The most common AEs were rash (36.5%), pimple (20.8%) and diarrhea (14.6%). Based on these clinical results of this trial, it was found that the combination of anti-CCR4 antibody and anti-PD-1 antibody is effective for several types of cancer patients (including at least HCC and PC patients).Instance 2 The multi-stage phase of the open labeling of lovizumab in combination with navobizumab in individuals with locally advanced or metastatic solid tumors 1 / 2 the study 1. Summary of the study This study is a multi-centered combination of anti-CCR4 antibodies, such as moglizumab and anti-PD-1 antibodies, such as naluzumab, in adult individuals with locally advanced or metastatic solid tumors. A phase amplification study of the phase 1/2 open-labeled discovery dose. Stage 1 will identify the MTD of the combined course of moglizumab and navobizumab or the highest regimen defined dose in the absence of MTD. Phase 1 will register up to 12 individuals. Phase 2 will explore the safety, efficacy, and anti-tumor activity of the highest tolerated dose of the combination regimen. Stage 2 will register up to 184 individuals (21 to 36 individuals/tumor types) with local advanced or metastatic disease of the following tumor types: squamous cell non-small cell lung cancer (NSCLC); Non-squamous cell NSCLC of cell death ligand 1 (PD-L1); squamous cell carcinoma of the head and neck (SCCHN); non-microsatellite instability (non-MSI) high colorectal cancer (CRC) Ovarian cancer; hepatocellular carcinoma (HCC) and pancreatic cancer (PA). 2. Research Objectives The main objective of the study is to characterize the safety and tolerability of a combination of moglizumab and navobizumab in individuals with locally advanced or metastatic solid tumors and to determine the combination therapy. The MTD or the highest regimen defined dose in the absence of MTD. Secondary Objectives The secondary objective was to evaluate the antitumor activity of a combination of moglizumab and nuumumab based on RECIST version 1.1. Antitumor activity will be assessed as overall response rate (ORR), TTR, DOR, PFS and OS. Exploring the goal of the exploration: - Analyze the serum concentrations of moglizumab and Navuzumab when administered in combination; - Evaluate the immunogenicity of loMilizumab and Navuzumab when administered in combination - Evaluate the pharmacodynamic (PD) characteristics of the combination of moglizumab and navobizumab and determine which biomarker may be associated with safety and/or antitumor activity; - immune-related RECIST (irRECIST) ) Version 1.1 evaluates the ORR of a combination of moglizumab and Navuzumab. 3. Inclusion Criteria Individuals must meet each of the following inclusion criteria during the screening phase in order to be eligible to participate in the study. In addition, individuals participating in Phase 2 must meet all inclusion criteria and do not have one of the exclusion criteria for the relevant tumor type. Individuals -18 years of age or older; - individuals with histologically or cytologically confirmed solid tumors; - individuals with locally advanced or metastatic solid tumors; - have developed or no standard treatment options Tolerant or reject standard treatment, or no individual for its appropriate standard of care; - Individual with measurable lesion/RECIST version 1.1 guidelines; - Eastern Tumor Cooperative Group (ECOG) performance status with 0 or 1 ( Individuals of PS); - if the individual is a woman who is likely to become pregnant or a male who has sexual activity with a woman who is likely to become pregnant, agree to participate in the study from the time of signing the ICF; and for the female after the final dose of the research medical product (IMP) 23 weeks or for individuals who use adequate contraception for 31 weeks after the last dose of IMP; - individuals with adequate blood, kidney, liver and respiratory function definitions; - willing to undergo a tumor biopsy during the screening phase, or if the tumor is not available Access for biopsy, archived tumor material must be available for presentation to the individual; and - voluntary signatory approval by the institutional review board in accordance with the guidelines of the regulatory body Consent and indicate the date of the individual. 4. Exclusion criteria Individuals will not be eligible to participate in this study if they meet any of the following exclusion criteria during the screening phase. In addition, individuals participating in Phase 2 must meet all inclusion criteria and do not have one of the exclusion criteria specific to the relevant tumor type. - Female individuals who are pregnant or lactating or any individual who expects to become pregnant or have children during this study; - Individuals with uncontrollable and apparent current disease. - individuals with mental illness/social conditions that would limit compliance with research requirements in the researcher's opinion; - individuals with primary CNS tumors or known CNS cancer metastasis and/or CNS cancer metastasis and/or cancerous meningitis history Exception: If the CNS cancer metastasis is adequately treated, the individual is eligible and has returned to baseline (except for residual symptoms or symptoms of CNS treatment) at least 4 weeks prior to enrollment. In addition, individuals must discontinue corticosteroids for 4 weeks prior to enrollment. - Received prior treatment for cancer before day 1 of cycle 1 or nitrosourea or mitomycin C for 28 or 42 days, or tamoxifen for 14 days Individuals of the main operations; - individuals who have received radiation therapy or radiosurgery within 14 days prior to the first day of the first cycle; - have been previously anti-PD-1, anti-PD-L1, anti-PD-L2 An individual who is anti-CD137 or anti-CTLA-4 antibody or any other antibody or drug that specifically targets a T cell costimulation or checkpoint pathway; - an individual who has been previously treated with moglizumab; - has a history of allergy or Individuals with allergic substances in the study; - individuals who have received live attenuated live vaccinia within 28 days prior to the first day of the first cycle; - individuals with a history of organ transplantation or allogeneic bone marrow transplantation; - with previous anti-cancer An individual with no unresolved toxicity of >1 level of therapy; - an individual who has used immunosuppressive therapy within 14 days prior to the first day of the first cycle. - Individuals with known active autoimmune diseases or autoimmune diseases that may affect vital organ function or need to include systemic corticosteroids; - have toxic epidermal necrolysis or Stevens Johnson syndrome (Stevens -Johnson syndrome) Individuals with a history of inflammatory bowel disease, Crohn's disease, ulcerative colitis, or Wegener's granulomatosis; - Have primary or acquired immunodeficiency or human immunodeficiency virus ( HIV) test positive for a known history or known individuals with acquired immunodeficiency syndrome; - In addition to hepatocellular carcinoma, for hepatitis B surface antigen (HBVsAg) or hepatitis C RNA test for acute or chronic infection An individual who is positive; - an individual with another active malignancy requiring simultaneous intervention; - an individual receiving any other research agent; - has an assessment or individual safety that would interfere with IMP in the opinion of the researcher and/or sponsor Or an individual with another condition as explained by the findings; and - an individual with a history of pneumonia or interstitial lung disease. 5. Study Design Phase 1: Dose Discovery Phase 1 dose discovery studies have a 3+3 design that will identify the MTD for this combination therapy or the highest protocol defined dose in the absence of MTD. Phase 1 studies will register up to 12 individuals (3 to 6 individuals/group). Plan the starting dose level and the optional dose level. The dose levels and schedules are described in Table 3. MTD is defined as a dose level below the dose level of a group in which one third or more of the individuals experience DLT. The recommended dosage regimen for Phase 2 is intended to be the MTD or highest dose level tested. [table 3]table 3 . dose level * If >1 individual experiences DLT at dose level 1, the dose level can be registered. The criteria for dose discovery are summarized in Figure 4. Stage 2: Amplification group To further characterize the safety, tolerability and anti-tumor activity of the combination, up to 184 individuals (21 to 36 individuals/) will be enrolled with local advanced or metastatic disease in the following tumor types/ Tumor type): squamous cell non-small cell lung cancer (NSCLC); non-squamous cell NSCLC that does not exhibit programmed cell death ligand 1 (PD-L1); squamous cell carcinoma of the head and neck (SCCHN); Non-microsatellite instability (non-MSI) higher colorectal cancer (CRC); ovarian cancer; hepatocellular carcinoma (HCC); and pancreatic cancer (PA). The individual is treated in stage 1 as a combination of the highest doses that can be tolerated. The safety and tolerability of the course of administration for each of the expanded groups will be monitored. Individual Therapeutic Research Drugs (IMP) The following IMP will be used for this study: - Moglizumab: On Day 1, Day 8, Day 15, and Day 22 of Cycle 1, followed by each subsequent 28 On days 1 and 15 of the day cycle, 0.3 or 1.0 mg/kg was administered as an intravenous infusion for at least 1 hour. - Navumab: 240 mg of numbumab was administered by intravenous infusion over the first day and the 15th day of each 28-day cycle for at least 30 minutes. Duration of Treatment Individuals can receive combination therapy for up to 96 weeks from Day 1 of Cycle 1. Individuals who discontinue treatment and have no disease progression and experience disease progression within 12 months of the last dose of IMP may additionally receive additional IMP for up to 48 weeks, provided that the individual has not received other systemic therapies for their cancer. Safety and efficacy assessment Individual safety will be monitored throughout the study period. Tumor assessment by CT or MRI will be performed at the screening stage, at week 10, and thereafter at least every 12 weeks until a definitive disease progression or death. Tumor biopsies will be required during the screening phase (except for individuals with archived tumor tissue) and at week 10 (unless the tumor is not accessible for biopsy). 6. Efficacy and Safety Variables Primary Endpoints Safety and tolerability will be assessed by assessing changes in AE and physical test findings, vital sign measurements, 12-lead ECG readings, and clinical laboratory assessments. The secondary endpoint will utilize the following efficacy parameters: - Best overall response (BOR) assessed using RECIST version 1.1; - Time to response (TTR): From day 1 of cycle 1 to use of RECIST version 1.1 to confirm CR/PR Days of First Assessment Date - Duration of Response (DOR): Number of days since the date of first diagnosis of CR/PR with RECIST version 1.1 to death or PD (whichever is earlier); - progression free survival (PFS): The number of days from the first day of the first cycle to the date of death or PD (whichever is earlier). For individuals using RECIST version 1.1 whose BOR is PR or CR; - Total survival (OS): Days from Day 1 of Day 1 to Day of Death Statistical Methods and Planning Analysis The assessment of the data used for this study will be primarily It consists of a list of materials and a summary display. Demographic and other baseline characteristics information will be summarized for the safety analysis and efficacy analysis set. Adverse events will be listed by body system, severity, and treatment ratio. Similar performance will be provided for SAE, AEs that cause IMP to stop, and AEs that cause death. A list of laboratory parameters will indicate the normal range for each parameter. Each value will be classified as belonging to, below or within the normal range. The individual's tumor response, TTR, DOR, PFS, and OS will be assessed. The ORR will be calculated as the proportion of individuals who are responders, ie, complete response (CR) and partial response (PR); an accurate confidence interval for 95% of the ORR will be calculated. Efficacy evaluable individuals in the combination therapy-based amplification group will be evaluated for ORR using both RECIST version 1.1 and irRECIST version 1.1, including all individuals receiving combination therapy on day 1 of the first cycle. The Kaplan-Meier methodology will be used to assess reaction duration, OS and PFS. 7. Clinical efficacy As observed during the combination therapy in this clinical trial, as of August 28, 2017, 1 of 10 HCC patients had undiagnosed PR, 2 of 21 ovarian cancer patients were diagnosed with CR and 2 were diagnosed. PR; and 1 of 29 CRC patients were diagnosed with PR. As of October 23, 2017, 1 of 10 HCC patients had undiagnosed PR and 1 confirmed PR; 2 of 21 ovarian cancer patients had confirmed CR, 2 confirmed PR, and 1 undiagnosed PR; and 29 CRC One of the patients was diagnosed with PR. On the other hand, as of October 23, 2017, no PR or CR was observed in 17 PA patients. Based on these clinical results of this trial, it was found that a combination of an anti-CCR4 antibody and an anti-PD-1 antibody is effective against several types of cancer patients including at least HCC, ovarian cancer, and CRC patients.Instance 3 Flow cytometry analysis of immune cell subsets in peripheral blood of individuals Methods In the Phase 1 study described in Example 1, the immune cell subsets were measured by FCM. Peripheral blood was collected before treatment, on the first day of treatment or on the first day of treatment and on the first day of the third cycle, and before and after treatment (from the 15th day of the 2nd cycle of treatment to the 1st day of the 3rd cycle) Or the end of treatment) separated from the new tumor biopsy sample. Analysis of the effector Treg was performed by the expression of CD4, Foxp3 and CD45RA according to the method described in Immunity, 2009, 30(6) 899-911. Analyze data using FlowJo version 7.6.5. At the same time, the percentage of each group in the peripheral blood is corrected by the number of lymphocytes. Results By the preliminary analysis of peripheral blood, the effect Treg (CD3) on the first day of the second cycle (including the end of treatment) and the first day of the third cycle was observed.+ CD4+ CD45RA-Foxp3High The downward trend has nothing to do with the best overall response. Activated T cells (CD3) on day 1 of cycle 3 were also observed in the responders compared to those in the non-responders.+ CD4+ ICOS+ T cells) increased. Effect Treg in TIL (P3) by preliminary analysis of 11 pairs of TIL before and after treatment+ CD4+ CD45RA-Foxp3High ) with total CD3+ The proportion of T cells has a decreasing trend independent of clinical response after treatment. CD3 in TIL compared to Treg+ CD8+ T cells and total CD3+ The proportion of T cells has an overall increasing trend after treatment. CD3 in TIL+ CD8+ T cells/effect Treg also have an increasing trend after treatment. Furthermore, by assessing the levels of chemokines (MIG and IP-10) in peripheral blood after treatment, it was found that the increase trend was independent of the optimal overall response. Throughout this application, various publications refer to the author's name and date in parentheses, or to a patent number or patent disclosure number. The disclosures of these publications are hereby incorporated by reference in their entirety to the extent of the extent of the disclosure of the disclosure of the disclosure of . However, the citation of the references herein is not to be construed as an admission that such reference is the prior art of the present application. This application claims the US Provisional Application Serial No. 62/428,468 and 2017, filed on November 30, 2016. U.S. Provisional Application Serial No. 62/554,486, filed on Jan. 5, the entire content of which is incorporated herein by reference.No text sequence listing SEQ ID NO. 1: Description of artificial sequence; KW-0761_VH CDR1 SEQ ID NO. 2: Description of artificial sequence; KW-0761_VH CDR2 SEQ ID NO. 3: Description of artificial sequence; KW-0761_VH CDR3 SEQ ID NO. : Description of artificial sequence; KW-0761_VL CDR1 SEQ ID NO. 5: Description of artificial sequence; KW-0761_VL CDR2 SEQ ID NO. 6: Description of artificial sequence; KW-0761_VL CDR3 SEQ ID NO. 7: Description of artificial sequence ;KW-0761_VH SEQ ID NO. 8: Description of artificial sequence; KW-0761_VL SEQ ID NO. 9: Description of artificial sequence; KW-0761_H SEQ ID NO. 10: Description of artificial sequence; KW-0761_L SEQ ID NO. 11: Description of artificial sequence; Nivolumab_VH CDR1 SEQ ID NO. 12: Description of artificial sequence; Nivolumab_VH CDR2 SEQ ID NO. 13: Description of artificial sequence; Nivolumab_VH CDR3 SEQ ID NO. 14: Description of artificial sequence; Nivolumab_VL CDR1 SEQ ID NO. 15: Description of artificial sequence; Nivolumab_VL CDR2 SEQ ID NO. 16: Description of artificial sequence; Nivolumab_VL CDR3 SEQ ID NO. 17: Description of artificial sequence; Nivolumab_VH SEQ ID NO. 18: Description of artificial sequence; Nivolumab_VL SEQ ID NO.19: Description of artificial sequence ; Nivolumab_H SEQ ID NO. 20: description of the artificial sequence; Nivolumab_L SEQ ID NO. 21: description of the artificial sequence; human CCR4 cd nucleotide and amino acid sequence SEQ ID NO. 22: description of the artificial sequence; synthetic construction CCR4 Amino acid sequence SEQ ID NO. 23: Description of artificial sequence; PD-1 cd human PD-1 nucleotide and amino acid sequence SEQ ID NO. 24: Description of artificial sequence; synthetic construction of human PD-1 amine group Acid sequence

[Fig. 1] Fig. 1 is a schematic diagram showing the administration schedule of an anti-CCR4 antibody (for example, moglizumab) and an anti-PD-1 antibody (for example, navobizumab). Fig. 2 shows the results of clinical efficacy of combination therapy with anti-CCR4 antibody (moglixuzumab) and anti-PD-1 antibody (nabuzumab) in hepatocellular carcinoma patients. Figure 2 indicates a spider plot for each cancer patient. The vertical axis indicates the "tumor contraction rate (%) of the target region" before the combination therapy and the horizontal axis indicates the number of weeks after the start of treatment. The "+" sign indicates the first appearance of a new type of lesion. [Fig. 3] Fig. 3 shows the results of clinical treatment of a combination therapy of an anti-CCR4 antibody (moglinizumab) and an anti-PD-1 antibody (nabuzumab) in a patient with pancreatic cancer. Figure 3 shows a spider map of each cancer patient. The vertical axis indicates the "tumor contraction rate (%) of the target region" before the combination therapy and the horizontal axis indicates the number of weeks after the start of treatment. The "+" sign indicates the first appearance of a new type of lesion. [Fig. 4] Fig. 4 shows criteria for dose discovery and amplification. DLT is an abbreviation for dose limiting toxicity.

Claims (35)

  1. A method for treating cancer in an individual in need thereof, which comprises binding an antibody or antigen-binding portion thereof ("anti-CCR4 antibody or antigen-binding portion thereof") specifically binding to human CC chemokine receptor 4 (CCR4) and An antibody or antigen-binding portion thereof ("anti-PD-1 antibody or antigen-binding portion thereof") that specifically binds to human programmed death-1 (PD-1) is administered to an individual.
  2. A method of reducing the size of a tumor in an individual having cancer by at least about 1%, 5%, 10%, 15%, 20% or 30%, the method comprising the anti-CCR4 antibody or antigen binding portion thereof and anti-PD The -1 antibody or antigen binding portion thereof is administered to the individual.
  3. The method of claim 1 or 2, wherein the anti-CCR4 antibody is a chimeric antibody, a humanized antibody or a human antibody.
  4. The method of any one of claims 1 to 3, wherein the anti-CCR4 antibody or antigen-binding portion thereof is selected from the group consisting of: (i) an antibody or antigen-binding portion thereof that binds to the same epitope as the antibody, It comprises: a heavy chain variable region ("VH") complementarity determining region (CDR) comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and comprising One or more of the VH CDR3s of the sequence set forth in SEQ ID NO: 3, and the light chain variable region ("VL") CDR1 comprising the sequence set forth in SEQ ID NO: 4, comprising SEQ ID NO: a VL CDR2 of the sequence set forth in 5 and one or more of the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) an antibody or antigen binding portion thereof comprising: SEQ ID NO: 1 The VH CDR1 of the sequence set forth in the sequence, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, comprising the sequence set forth in SEQ ID NO: VL CDR1, VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (iii) antibody Or an antigen binding portion thereof, comprising: a VH comprising the sequence set forth in SEQ ID NO: 7 and a VL comprising the sequence set forth in SEQ ID NO: 8; (iv) an antibody comprising: comprising SEQ ID NO: a heavy chain of the sequence set forth in 9 and a light chain comprising the sequence set forth in SEQ ID NO: 10; (v) an antibody or antigen binding portion thereof, which competes with (ii) the antibody; and (vi) Glimizumab (mogamulizumab) or an antigen binding portion thereof.
  5. The method of any one of claims 1 to 4, wherein the anti-PD-1 antibody is a chimeric antibody, a humanized antibody or a human antibody.
  6. The method of any one of claims 1 to 5, wherein the anti-PD-1 antibody or antigen-binding portion thereof is selected from the group consisting of: (i) an antibody or antigen binding thereof that binds to the same epitope as the antibody Partially comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: One or more, and a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL comprising the sequence set forth in SEQ ID NO: One or more of CDR3; (ii) an antibody or antigen binding portion thereof comprising: a VH CDR comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and comprising the SEQ ID a VL CDR3 of the sequence set forth in NO: 16; (iii) an antibody or antigen binding portion thereof comprising: comprising the SEQ ID a VH of the sequence set forth in NO: 17 and a VL comprising the sequence set forth in SEQ ID NO: 18; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising the SEQ ID NO: the light chain of the sequence set forth in 20; (v) an antibody that cross-competes with the antibody of (ii); (vi) nivolumab or its antigen-binding portion; (vii) a monoclonal antibody (pembrolizumab) or an antigen binding portion thereof; and (viii) MEDI0608 or an antigen binding portion thereof.
  7. The method of any one of claims 1 to 6, wherein the cancer is selected from the group consisting of melanoma cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer , bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, cervical cancer, endometrial cancer, rectal cancer, anal cancer, stomach cancer, Testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's Disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system Cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, including acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemia, solid state in children Tumor, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, angiogenic tumor, glue Blastoma, spinal tumor, brainstem neuroma, pituitary adenoma, mesothelioma, Kaposi's sarcoma, epidermoid cancer, squamous cell carcinoma, T-cell lymphoma, including induction by asbestos Their environment induces cancer, and any combination thereof.
  8. The method of any one of claims 1 to 6, wherein the cancer is lung cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, or any combination thereof.
  9. The method of claim 8, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer, the gastrointestinal cancer is esophageal cancer, gastric cancer or colorectal cancer, the liver cancer is hepatocellular carcinoma, and the pancreatic cancer is pancreatic cancer.
  10. The method of claim 9, wherein the non-small cell lung cancer is non-squamous non-small cell lung cancer or squamous non-small cell lung cancer.
  11. The method of any one of claims 1 to 6, wherein the cancer is melanoma.
  12. The method of any one of claims 1 to 11, wherein the cancer is a progressive, metastatic, and/or unresectable cancer.
  13. The method of any one of claims 1 to 12, wherein the anti-CCR4 antibody is administered at least about 0.1, 0.3, 0.5, 0.75, 1.0, 2.0 or 3.0 mg/kg.
  14. The method of any one of claims 1 to 13, wherein the anti-CCR4 antibody or antigen-binding portion thereof is administered at least once a week, at least once every two weeks, or at least once a week and then once every two weeks.
  15. The method of any one of claims 1 to 13, wherein the anti-CCR4 antibody or antigen-binding portion thereof is administered once a week for four weeks after the first administration, and then administered once every two weeks.
  16. The method of any one of claims 1 to 15, wherein the anti-PD-1 antibody or antigen-binding portion thereof is at least about 1 mg/kg, 2.0 mg/kg, 3.0 mg/kg, or 5 mg/kg or 240 mg / body is administered in a flat dose.
  17. The method of claim 16, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at least once a week, at least once every two weeks, or at least once every three weeks.
  18. The method of any one of claims 1 to 17, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered once every two weeks at 2.0 mg/kg.
  19. The method of any one of claims 1 to 17, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered once every two weeks at 3.0 mg/kg once every two weeks, or at a dose of at least 240 mg/body once every two weeks. Cast.
  20. The method of any one of claims 1 to 19, wherein the anti-CCR4 antibody or antigen-binding portion thereof and the anti-PD-1 antibody or antigen-binding portion thereof are administered to the individual in parallel or sequentially.
  21. The method of claim 20, wherein the anti-CCR4 antibody or antigen-binding portion thereof is administered before or after the anti-PD-1 antibody or antigen-binding portion thereof.
  22. The method of any one of claims 1 to 21, wherein the administering results in one or more of the following effects: (i) reduced CCR4 + T cells, (ii) reduced regulatory T cells, (iii) enhanced PD-L1 expression in tumor tissues, (iv) reduced PD-1 positive T cells, and (v) increased tumor infiltrating lymphocytes (TIL).
  23. The method of any one of claims 1 to 22, further comprising administering an additional anticancer agent.
  24. The method of claim 23, wherein one or more of the tumors exhibit PD-L1, PD-L2, CCR4, or any combination thereof.
  25. A method of treating one or more cancers selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method comprising one week after the first administration One week, 0.1, 0.3, 0.5, 0.75, 1.0, 2.0, or 3.0 mg/kg of moglizumab and 2.0 or 3.0 mg/kg of numbumab every two or three weeks, or 240 mg/body of naluzumab is administered as a flat dose combination to individuals with this (these) cancer.
  26. A method of treating one or more cancers selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method comprising one week after the first administration One week, 0.1, 0.3, 0.5, 0.75, 1.0, 2.0, or 3.0 mg/kg of moglizumab, with 2.0 mg/kg of numbumab once every two weeks, or 240 mg/body The navozumab is administered as a flat dose combination to an individual having the (these) cancer.
  27. A method of treating one or more cancers selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method comprising one week after the first administration One week, 0.1, 0.3, 0.5, 0.75, 1.0, 2.0, or 3.0 mg/kg of moglizumab, with 3.0 mg/kg of numbumab once every two weeks, or 240 mg/body The navozumab is administered as a flat dose combination to an individual having the (these) cancer.
  28. A kit for treating an individual suffering from cancer, the kit comprising: (a) a dose of 0.1 to 10 mg/kg of body weight specifically binding to an antibody or antigen binding portion thereof of human PD-1 ( "anti-PD-1 antibody or antigen-binding portion thereof"); (b) an antibody that binds specifically to human CCR4 or an antigen-binding portion thereof at a dose ranging from 0.1 to 10 mg/kg body weight; ("anti-CCR4 antibody Or the antigen-binding portion thereof; and (c) the instructions for using the anti-PD-1 antibody and the anti-CCR4 antibody in the method of any one of claims 1 to 27.
  29. A kit for use in claim 28, wherein the anti-CCR4 antibody or antigen binding portion thereof is selected from the group consisting of: (i) an antibody or antigen binding portion thereof that binds to the same epitope as the antibody, comprising: comprising The heavy chain variable region ("VH") complementarity determining region (CDR) of the sequence set forth in SEQ ID NO: 1, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and comprising SEQ ID NO: 3 One or more of the VH CDR3s of the sequences set forth in the sequences, and the light chain variable region ("VL") CDR1 comprising the sequence set forth in SEQ ID NO: 4, comprising the set forth in SEQ ID NO: a VL CDR2 of the sequence and one or more of the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) an antibody or antigen binding portion thereof comprising: comprising the sequence set forth in SEQ ID NO: VH CDR1, VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, comprising VL CDR2 of the sequence set forth in SEQ ID NO: 5, and VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (iii) antibody or antigen binding thereof a portion comprising: a VH comprising the sequence set forth in SEQ ID NO: 7 and a VL comprising the sequence set forth in SEQ ID NO: 8; (iv) an antibody comprising: comprising the set forth in SEQ ID NO: a heavy chain of the sequence and a light chain comprising the sequence set forth in SEQ ID NO: 10; (v) an antibody or antigen binding portion thereof, which competes with (ii) the antibody; and (vi) mogliari Anti-antigen or its antigen binding moiety.
  30. A kit for use in claim 28 or 29, wherein the anti-PD-1 antibody or antigen-binding portion thereof is selected from the group consisting of: (i) an antibody or antigen-binding portion thereof that binds to the same epitope as the antibody, It comprises: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and one of the VH CDR3 comprising the sequence set forth in SEQ ID NO: Or more, and a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 16 (ii) an antibody or antigen-binding portion thereof comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, comprising The VH CDR3 of the sequence set forth in SEQ ID NO: 13, the VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, the VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and comprising SEQ ID NO: a VL CDR3 of the sequence set forth in 16; (iii) an antibody or antigen binding portion thereof comprising: comprising SEQ ID NO: a VH of the sequence set forth in 17 and a VL comprising the sequence set forth in SEQ ID NO: 18; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising SEQ ID NO a light chain of the sequence set forth in 20; (v) an antibody that cross-competes with the antibody of (ii); (vi) nalumuzumab or an antigen binding portion thereof; (vii) peizumab or an antigen thereof a binding moiety; and (viii) MEDI0608 or an antigen binding portion thereof.
  31. A pharmaceutical composition for treating cancer comprising (a) an antibody or antigen-binding portion thereof ("anti-PD-1 antibody or antigen-binding portion thereof") which specifically binds to human PD-1 and specifically binds to human An antibody to CCR4 or an antigen binding portion thereof (anti-CCR4 antibody or antigen binding portion thereof).
  32. The pharmaceutical composition for use in claim 31, wherein the anti-CCR4 antibody or antigen-binding portion thereof is selected from the group consisting of: (i) an antibody or antigen-binding portion thereof that binds to the same epitope as the antibody, comprising: A heavy chain variable region ("VH") complementarity determining region (CDR) comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and comprising SEQ ID NO: One or more of the VH CDR3s of the sequences set forth in 3, and the light chain variable region ("VL") CDR1 comprising the sequence set forth in SEQ ID NO: 4, comprising the set forth in SEQ ID NO: a sequence of VL CDR2 and one or more of a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) an antibody or antigen binding portion thereof, comprising: comprising the set forth in SEQ ID NO: The VH CDR1 of the sequence, the VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, the VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, the VL CDR1 comprising the sequence set forth in SEQ ID NO: a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (iii) an antibody or an antibody thereof a pro-binding portion comprising: a VH comprising the sequence set forth in SEQ ID NO: 7 and a VL comprising the sequence set forth in SEQ ID NO: 8; (iv) an antibody comprising: comprising SEQ ID NO: 9 a heavy chain of the sequence set forth and a light chain comprising the sequence set forth in SEQ ID NO: 10; (v) an antibody or antigen binding portion thereof, which competes with (ii) the antibody; and (vi) Mogley Bep monoclonal antibody or an antigen binding portion thereof.
  33. The pharmaceutical composition for use in claim 31 or 32, wherein the anti-PD-1 antibody or antigen-binding portion thereof is selected from the group consisting of: (i) an antibody or antigen-binding portion thereof that binds to the same epitope as the antibody , comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: One or more, and a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: (ii) an antibody or antigen-binding portion thereof comprising: a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and comprising SEQ ID NO : VL CDR3 of the sequence set forth in 16:; (iii) an antibody or antigen binding portion thereof, comprising: comprising S EQ ID NO: a VH of the sequence set forth in 17 and a VL comprising the sequence set forth in SEQ ID NO: 18; (iv) an antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and a light chain comprising the sequence set forth in SEQ ID NO: 20; (v) an antibody or antigen binding portion thereof, which competes with (ii) the antibody; (vi) nalumab or an antigen binding portion thereof; (vii a platizumab or an antigen binding portion thereof; and (viii) MEDI0608 or an antigen binding portion thereof.
  34. A pharmaceutical composition for use in the treatment of cancer, as claimed in any one of claims 31 to 33.
  35. The pharmaceutical composition according to claim 34, wherein the cancer is selected from the group consisting of melanoma cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer , pancreatic cancer, skin cancer, cancer of the head or neck, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, cervical cancer, endometrial cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, Uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid gland Cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, including acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic or acute leukemia of chronic lymphocytic leukemia, solid tumor of children, lymphoblastic lymphoma , bladder cancer, kidney or urinary tract cancer, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, angiogenic tumor, glioblastoma , spinal axis tumors, brain stem neuromas, pituitary adenomas, mesothelioma, Kapo's sarcoma, epidermoid cancer, squamous cell carcinoma, T-cell lymphoma, including environmentally induced cancer induced by asbestos, And any combination thereof.
TW106142006A 2016-11-30 2017-11-30 Method of treating cancer using anti-ccr4 antibody and anti-pd-1 antibody TW201825119A (en)

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CA2369292C (en) 1999-04-09 2010-09-21 Kyowa Hakko Kogyo Co. Ltd. Method of modulating the activity of functional immune molecules
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CA2953239A1 (en) 2000-10-06 2002-04-18 Kyowa Hakko Kirin Co., Ltd. Antibody composition-producing cell
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