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

Abstract

A method of treating cancer comprising administering an anti-CC-chemokine receptor 4 (CCR4) antibody and an anti-programmed death-1 (PD-1) antibody to a subject is provided. Also provided is a composition or kit for use in treating a cancer 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, the method comprising administering an anti-CCR4 antibody and an anti-PD-1 antibody to the individual. The present invention further provides a pharmaceutical composition for treating cancer in an individual in need, the pharmaceutical composition comprising an anti-CCR4 antibody and an anti-PD-1 antibody.

CC chemokine receptor 4 (CCR4) is known as the lymphocyte chemokine receptor for two chemokines, the two chemokines are the thymus and activation-regulated chemokine (TARC) (also known as CCL17) And macrophage-derived chemokine (MDC) (also known as CCL22). In addition, 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 ( PTCL). Recently, most promising anti-CCR4 humanized antibodies, mogulizumab (mogamulizumab), have been approved by the Ministry of Health, Labour and Welfare in Japan (MHLW) to obtain a marketing license to treat CCR4 Positive adult T cell leukemia lymphoma (ATL) (Non-Patent Document 1) and CCR4 ⁺ relapsed / 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 receptors (KIR) have become available to trigger antitumor 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 (specifically 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 the second ligand of PD-1, which has inhibitory activity on T cells similar to PD-L1. In contrast, CTLA-4 is specifically expressed on activated CD4 ⁺ T cells, has a structure similar to CD28 and binds CD80 / CD86 (B7-1, B7-2) to antigen presenting cells (APC) , Such as on dendritic cells to regulate T cell activity. Therapeutic antibodies used to treat different cancers have been approved and / or have been developed for multiple immune checkpoint molecules. In the United States, an anti-PD-1 human IgG4 antibody that blocks PD-1 activity, nivolumab (previously 5C4, BMS-936558, MDX-1106, or ONO-4538) has been approved (Patent Literature 1 and Non-Patent Reference 3) Then ipilimumab (ipilimumab) and if the BRAF V600 mutation is positive, the BRAF inhibitor is 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 to be administered 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 at 2 mg / kg every three weeks. In addition, another anti-PD-1 antibody has been approved in the United States, pembrolizumab (previously designated lambrolizumab or MK-3475), followed by ipilimumab and rubraf If the V600 mutation is positive, the BRAF inhibitor is used to treat patients with unresectable or metastatic melanoma and progressive disease. Other checkpoint inhibitor antibodies under development include anti-CTLA-4 antibodies (e.g., ipalimumab and tremelimumab, the active ingredients of YERVOY (registered trademark)), anti-PD-1 antibodies (e.g., MEDI0608), Anti-PD-L1 antibodies (eg, MEDI4736, MPDL3280A, and MSB0010718C) and PD-L2Ig (eg, AMP-224). [ Citation List ] [ Patent Literature ] PTL1: US Patent No. 8,008,449 [ Non-Patent Literature ] 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 present invention provides a method for treating cancer in an individual in need, the method comprising administering an anti-PD-1 antibody in combination with an anti-CCR4 antibody to the individual. In one embodiment, the present invention includes a method of treating cancer in an individual, the method comprising binding 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 ") and an antibody or antigen-binding portion that specifically binds to human programmed death-1 (PD-1) (" anti-PD-1 antibody or antigen-binding portion ") are administered to an individual. In another embodiment, the invention includes a method of reducing the size of a tumor in an individual with cancer by at least about 1%, 5%, 10%, 15%, 20%, or 30%, the method comprising The CCR4 antibody or its antigen-binding portion and the anti-PD-1 antibody or its antigen-binding portion 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 used in the method is selected from the group consisting of: (i) an antibody or antigen-binding portion that binds to the same epitope as the antibody, which includes: comprising The heavy chain variable region ("VH") complementarity determining region (CDR) 1, the sequence set forth in SEQ ID NO: 1, the VH CDR2 containing the sequence set forth in SEQ ID NO: 2, and the SEQ ID NO: One or more of the VH CDR3 of the sequence set forth in 3, and the light chain variable region ("VL") CDR1 containing the sequence set forth in SEQ ID NO: 4, including the set forth in SEQ ID NO: 5 VL CDR2 of the sequence and one or more of the VL CDR3 containing 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: 1 VH CDR1 of the sequence, VH CDR2 of the sequence set forth in SEQ ID NO: 2, VH CDR3 of the sequence set forth in SEQ ID NO: 3, VL CDR1 of the sequence set forth in SEQ ID NO: 4 VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (iii) antibody or anti- The binding portion, comprising: VH comprising the sequence set forth in SEQ ID NO: 7 and VL comprising the sequence set forth in SEQ ID NO: 8; (iv) antibody, comprising: comprising the set forth in SEQ ID NO: 9 The heavy chain of the sequence described and the light chain comprising the sequence set forth in SEQ ID NO: 10; (v) the antibody or antigen-binding portion thereof, which cross-competes with the antibody of (ii); and (vi) Mogley beads MAb or its antigen binding portion. 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 that binds to the same epitope as the antibody, which comprises: comprising SEQ ID One or more of VH CDR1 of the sequence set forth in NO: 11, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, and VH CDR3 containing the sequence set forth in SEQ ID NO: 13, and including One or more of VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and VL CDR3 containing the sequence set forth in SEQ ID NO: 16; (ii) Antibody or antigen-binding portion thereof, comprising: 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 SEQ ID NO: 13 VH CDR3 of the sequence described, VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 of the sequence set forth in SEQ ID NO: 15, and the sequence of SEQ ID NO: 16 VL CDR3; (iii) antibody or antigen-binding portion thereof, comprising: comprising SEQ ID NO: 17 VH of the sequence and VL comprising the sequence set forth in SEQ ID NO: 18; (iv) Antibody comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising the set forth in SEQ ID NO: 20 The light chain of the sequence; (v) the antibody or its antigen-binding portion, cross-competing with the antibody of (ii); (vi) nivolumab or its antigen-binding portion; (vii) peclizumab or its antigen A binding portion; and (viii) MEDI0608 or an antigen binding portion thereof. In certain embodiments, the cancer that can be treated by the method of the present invention is selected from the group consisting of melanoma cancer, liver cancer, hepatocellular cell carcinoma (hepatocellular cell carcinoma), cholangiocarcinoma, kidney 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, 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 Chronic or acute leukemia of children with leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal pelvis cancer, central nervous system (CNS) swelling Neoplasms, primary CNS lymphoma, tumor angiogenesis, glioblastoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma, Kaposi's sarcoma ( Kaposi's sarcoma), epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, including environment-induced cancers 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 yet other embodiments, the cancer is progressive, metastatic, and / or unresectable cancer. In some embodiments, the anti-CCR4 antibody is administered at 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 and then 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, and then administered 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 the average Dosage adjustment. 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 at 2.0 mg / kg every two weeks or at 3.0 mg / kg once every two weeks, or at 240 mg / body as a flat dose every two weeks Give once. In some embodiments, 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 concurrently 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) decreased PD-1 positive T cells, (v) increased tumor infiltrating lymphocytes (TIL), and (vi) any combination thereof. In certain other embodiments, the methods further include additional anti-cancer agents. In a particular embodiment, one or more of the tumors exhibit PD-L1, PD-L2, CCR4, or any combination thereof. In certain embodiments, the present invention also includes a kit for treating individuals suffering from cancer, the kit comprising: (a) a dose ranging from 0.1 to 10 mg / kg body weight that specifically binds to PD -1 antibody or antigen-binding portion thereof ("anti-PD-1 antibody or antigen-binding portion"); (b) an antibody or its specific binding to CCR4 at a dose in the range of 0.1 to 10 mg / kg body weight Antigen binding portion ("anti-CCR4 antibody or antigen binding portion thereof"); and (c) instructions for using anti-PD-1 antibody and anti-CCR4 antibody in these methods. In other embodiments, the invention includes a pharmaceutical composition for treating cancer, the pharmaceutical composition comprising (a) an antibody or antigen-binding portion thereof that specifically binds to PD-1 and inhibits PD-1 activity ("Anti PD-1 antibody or antigen-binding portion ") and an antibody or antigen-binding portion that specifically binds to CCR4 and inhibits CCR4 (" anti-CCR4 antibody or antigen-binding portion ").

Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present invention belongs. The following references provide the skilled person with a general definition of multiple terms used in the present invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd Edition 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, unless otherwise specified, the following terms have the meaning attributed to them below. "Dosing" refers to using any of a variety of methods and delivery systems known to those skilled in the art to physically introduce a composition containing a therapeutic agent to an individual. The administration route of the anti-PD-1 antibody includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal cord, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase "non-intestinal administration" means the mode of administration other than enteral and local administration, usually by injection, and includes (but is not limited to) intravenous, intramuscular, intraarterial , Intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural And intrasternal injection and infusion, and electroporation in vivo. In some embodiments, the agent is administered orally via a non-parenteral route, in some embodiments. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, transvaginal, transrectal, sublingual or topical. The administration can also be performed once, plural times, and / or over one or more extended time periods, for example. As used herein, "adverse event" (AE) is any adverse and generally undesirable or undesirable sign (including abnormal laboratory findings), symptoms, or disease associated with the use of medical treatment. For example, adverse events can be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment. The medical treatment may have one or more related AEs and each AE may have the same or different severity. Reference to methods that can "modify adverse events" means treatments that reduce the incidence and / or severity of one or more AEs. "Isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to PD-1 does not substantially contain specific binding to other than PD-1 Antigen antibody). However, isolated antibodies that specifically bind to PD-1 can cross-react with other antigens, such as PD-1 molecules from different species. In addition, the isolated antibody may be substantially free of other cellular materials and / or chemicals. "Anti-antigen" anti-system refers to an antibody that specifically binds to an antigen. For example, anti-PD-1 antibodies specifically bind to PD-1 and anti-CTLA-4 antibodies specifically bind to CTLA-4. The "antigen-binding portion" (also called "antigen-binding fragment") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the entire antibody. In the present invention, "comprises / comprising", "containing" and "having" and the like may have the meaning attributed to them in the US Patent Law and may mean "includes / including" and Similar to it; "consisting essentially of" or "essentially consisting of" also have the meaning attributed to the US Patent Law and the term is open-ended, as long as the basic or novel features cited are not greater than those cited Exist and change, but excluding the prior art embodiments, the existence of content greater than the cited content is allowed. "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 part of the body via the lymphatic system or blood flow. After the cancer has metastasized, the distant tumor can be said to be "derived from" the original, pre-metastatic tumor. Since distal tumors are derived from pre-metastatic tumors, "derived from" tumors may also include pre-metastatic tumors. The term "immunotherapy" refers to the treatment of individuals suffering from disease or at risk of infection or suffering from disease recurrence by methods that include inducing, enhancing, inhibiting or otherwise modifying the immune response. "Treatment" or "therapy" of an individual refers to any type of intervention or treatment performed on the individual, or administration of an active agent to the individual, with the goal of reversing, relieving, improving, inhibiting, alleviating or preventing symptoms, complications, or disease The onset, progression, development, severity, or recurrence of symptoms or biochemical markers associated with the disease. The "therapeutically effective amount", "effective amount", "effective dose" or "therapeutically effective dose" of a drug or therapeutic agent is when used alone or in combination with another therapeutic agent to protect the individual from the onset of the disease or promote the disease A reduction in the severity of symptoms, an increase in the frequency and duration of periods without disease symptoms, evidence of the regression of the disease, or any amount of medicine that prevents injury or disability due to the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using various methods known to those skilled in the art, such as evaluation in human individuals during clinical trials, evaluation in animal model systems that predict efficacy in humans, or by In the external analysis method, the activity of the analysis reagent is evaluated. In one embodiment, the antibodies or combinations of antibodies described herein promote cancer regression or prevent other tumor growth in the individual. In certain embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means that an effective amount of the drug is administered alone or in combination with an anti-tumor agent, resulting in tumor growth or size reduction, tumor necrosis, reduction in the severity of at least one disease symptom, frequency of time period without disease symptom and Increase the duration, or prevent injury or disability due to illness and illness. In addition, the terms "effective" and "utility" regarding treatment include both pharmacological utility and physiological safety. Pharmacological utility refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the degree of toxicity due to the administration of drugs, or other adverse physiological effects (adverse effects) on the level of cells, organs and / or organisms. For example, for the treatment of tumors, a therapeutically effective amount of an antibody or combination thereof can inhibit cell growth or tumor growth by at least about 100% relative to an untreated individual or in certain embodiments, relative to a patient treated with standard care therapy 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 these final measures of therapeutic effectiveness, the evaluation of immunotherapy drugs must also take into account "immune-related" response patterns. "Immune-related" response patterns refer to the clinical response patterns commonly observed in cancer patients treated with immunotherapeutic agents. These immunotherapeutic agents produce resistance by inducing cancer-specific immune responses or by modifying the native immune process Tumor effect. This response pattern is characterized by beneficial therapeutic effects after the initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutics and will be synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease. A therapeutically effective amount of a drug includes a "prophylactically effective amount", which is when administered alone or in combination with an antineoplastic agent to individuals at risk of developing cancer (eg, individuals with precancerous conditions) or individuals suffering from cancer relapse , Any amount of drugs that inhibit the development or recurrence of cancer. In certain embodiments, the prophylactically effective amount completely prevents the development or recurrence of cancer. "Suppressing" the development or recurrence of cancer means reducing the possibility of the development or recurrence of cancer or completely preventing the development or recurrence of cancer. It should be understood that the use of substitutes (eg, "or") means one of the substitutes, both, or any combination thereof. As used herein, it should be understood that the indefinite article "a (an)" refers to "one or more" of any cited or enumerated component. The term "about" or "substantially encompass" refers to a value or composition that is within an acceptable error range of the value or composition as determined by those of ordinary skill in the art, which will depend in part on how to measure or The judgment value or composition is the limitation of the measurement system. For example, "about" or "substantially encompass" may mean within 1 or more than 1 standard deviation according to practice in the art. Alternatively, "about" or "substantially encompass" may mean a range of at most 10% (ie, + 10% to -10%). For example, about 3 mg may include any value between 2.7 mg and 3.3 mg (for 10%). In addition, especially in terms of biological systems or methods, these terms may mean at most an order of magnitude or at most 5 times the value. When a specific value or composition is provided in the scope of this application and patent application, unless otherwise stated, the meaning of "about" or "substantially included" shall be assumed to be within the acceptable error range of the specific value or composition . As used herein, the term "about once a week" means a rough numerical value, and "about once a week" may include every six days to every eight days. Therefore, the frequency of "once a week" administration can be every six days, every seven days, or every eight days. As described herein, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range and, where appropriate, its fraction (such as tenths of 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 herein and are meant to include SEQ ID NO: 22 Amino acid sequence or a functional fragment of the polypeptide; including the GenBank deposit number NP_005499.1 amino acid sequence of the polypeptide, included in the amino acid sequence represented by SEQ ID NO: 22 or NP_005499.1 deletion, substitution 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, at least about 90% homology with the amino acid sequence represented by SEQ ID NO: 22 Homology, at least about 93% homology, and at least about 95%, about 96%, about 97%, about 98%, or about 99%, higher homology amino acid sequences and CCR4 activity polypeptides; and including Related polypeptides of SNP variants and the like. Related polypeptides include SNP variants, splice variants, fragments, substitutes, deletions, and insertions, which preserve CCR4 activity and / or function. In addition, the CCR4 polypeptide includes a polypeptide encoded by the nucleotide sequence of SEQ ID NO: 21 or GenBank accession number NM_005508.4. In some embodiments, the gene encoding CCR4 includes nucleotides having one or more nucleotide deletions, substitutions, or additions in the nucleotide sequence of SEQ ID NO: 21 or GenBank accession number NM_005508.4 sequence. In other embodiments, the CCR4 gene encodes a polypeptide having CCR4 function and contains at least about 60% or higher homology with the nucleotide sequence of SEQ ID NO: 21 or GenBank accession number NM_005508.4, in some embodiments Nucleotide sequences that are at least about 80% or higher in homology, and in other embodiments at least about 95%, about 96%, about 97%, about 98%, or about 99%, higher homology. In some embodiments, the CCR4 gene encodes a polypeptide having the function of CCR4 and includes a nucleotide sequence that hybridizes to the nucleotide sequence of SEQ ID NO: 21 or GenBank accession number NM_005508.4 under stringent conditions. As used herein, the term "CCR4 nucleic acid molecule" refers to a polynucleotide that encodes a CCR4 polypeptide. Exemplary CCR4 nucleic acid molecules are provided in SEQ ID NO: 21 or GenBank accession number NM_005508.4. Gene polymorphism is often identified in the nucleotide sequence of genes encoding proteins in eukaryotes. The CCR4 gene used in the present invention also includes genes that generate minor modifications in the nucleotide sequence by this polymorphism, as the genes used in the present invention. CCR4 is a G protein coupled seven transmembrane receptor cloned from human immature basophil 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 the amino acid sequence from position 1 to 39, position 99 to 111, position 176 to 206, and position 268 to 284, and the intracellular region is in the amino acid sequence (GenBank accession number NP_005499.1) These are positions 68 to 77, positions 134 to 150, positions 227 to 242, and positions 309 to 360. CCR4 can specifically bind to different molecules, including (but not limited to) TARC (thymus and activation regulating chemokines) produced by thymocytes (J. Biol. Chem., 271, 21514, 1996) and separated from macrophages MDC (macrophage-derived chemokine) (J. Exp. Med., 185, 1595, 1997), also known as STCP-1 (stimulated T cell chemokine-1) (J. Biol. Chem ., 272,25229,1997). TARC and MDC are also called CCL17 and CCL22, respectively. One or more functions of CCR4 include its ability to bind to TARC and / or MDC. Other functions of CCR4 in the present invention include the expression of Ca on CCR4 cells depending on the expression of CCR4 ligands (such as CCL17 and / or CCL22)^{2 +} Inflow and express the cell migration function of CCR4 cells. The terms "programmed cell death-1", "PD-1", "PD-1 polypeptide" or "CD279" are used interchangeably herein and mean having at least one function of PD-1 activity (eg, by PD The -1 pathway activates T cells and / or binds to PD-L1 or PD-L2) polypeptides or fragments 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 deposit 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 of activity. In some embodiments, PD-1 also includes SNP variants, splice variants, fragments, substitutes, 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 number NM_005018.2. The PD-1 gene also includes genes containing DNA that contains nucleosides with one or more nucleotide deletions, substitutions, or additions in the nucleotide sequence of SEQ ID NO: 23 or GenBank accession number NM_005018.2 Acid sequence. In some embodiments, PD-1 has a nucleotide sequence at least about 60%, about 70%, about 80%, about 90%, about 95%, having a nucleotide sequence with SEQ ID NO: 23 or GenBank accession number NM_005018.2, Approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100% identical nucleotide sequence codes 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 hybridized with SEQ ID NO: 23 or the nucleotide sequence of GenBank accession number NM_005018.2 under stringent conditions and has the function of a PD-1 polypeptide . The term "PD-1 nucleic acid molecule" refers to a polynucleotide that encodes a PD-1 polypeptide. Exemplary PD-1 nucleic acid molecules are provided in SEQ ID NO: 23 or GenBank accession number NM_005018.2. Gene polymorphism is often identified in the nucleotide sequence of genes encoding proteins in eukaryotes. The PD-1 gene used in the present invention also includes genes that generate minor modifications in the nucleotide sequence by this polymorphism, as the genes used in the present invention. PD-1 was cloned as 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 ITSM motifs (exchange motifs based on immunoreceptor tyrosine) and ITIM motifs (inhibitory motifs based on immune receptor tyrosine) that can be suppression domains of immune responses. Since mice lacking PD-1 develop lupus-like autoimmune diseases such as glomerulonephritis and arthritis and diseases similar to dilated cardiomyopathy, PD-1 appears to be a negative regulator of immune response. The other PD-1 ligand, PD-L1, is known as a ligand for PD-1 and a type I transmembrane protein that acts as an inhibitor ligand for T cell proliferation by binding to PD-1. It has immunoglobulin class V domain, class C domain and cytoplasmic tail region. PD-L1 is known to be expressed on antigen-presenting cells and some cancer cells. "Anti-CCR4 antibody" refers to an antibody that selectively binds to human CCR4 polypeptide. Exemplary anti-CCR4 antibodies are provided herein, for example, anti-CCR4 antibodies consisting of amino acid residues 2 to 29 of SEQ ID NO: 22 bound to an epitope. In one embodiment, the anti-CCR4 antibody is moglizumab (POTELIGEO (registered trademark)). In another embodiment, the anti-CCR4 antibody reduces, inhibits, or prevents one or more functions of CCR4. In other embodiments, anti-CCR4 antibodies cross-compete with moglizumab. "Anti-PD-1 antibody" refers to an antibody that selectively binds to PD-1 polypeptide. Exemplary anti-PD-1 antibodies are described in, for example, US Patent No. 8,008,449, which is incorporated herein by reference. In one embodiment, the anti-PD-1 antibody is nivolumab (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 nivolumab. As used in this disclosure, the term "antibody" refers to immunoglobulins or fragments or derivatives thereof, and encompasses any polypeptide that includes 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 antibodies. Unless otherwise modified by the term "intact", like "intact antibody", for the purposes of this disclosure, the term "antibody" also includes preservation of antigen-binding function (ie, the ability to specifically bind CCR4 or PD-1) Antibody fragments (or antigen-binding fragments), such as Fab, F (ab ')₂ , Fv, single chain Fv (scFv), Fd, dAb and other antibody fragments. Generally, such fragments will contain an antigen binding domain (or portion). Antibody molecules are formed from polypeptides called heavy chains (hereinafter referred to as H chains) and light chains (hereinafter referred to as L chains). In addition, the H chain is composed of the H chain variable region (also called V_H Or VH) and the H chain constant region (also called CH), and the L chain is composed of the L chain variable region (also called V_L Or VL) and L chain constant region (also called CL). Regarding CH, α, δ, ε, γ, and mu chains are known for each sub-category. Regarding CL, λ and κ are known. IgG antibodies have two heavy chains and two light chains, and form two antigen binding sites composed of VH and VL. Therefore, IgG antibodies are bivalent antibodies. The terms "antibody fragment", "antigen-binding domain", "antigen-binding fragment", "antigen-binding portion" and "binding fragment" refer to a portion of an antibody molecule that contains amino acids responsible for specific binding between an antibody and an antigen . For example, when the antigen is large, the antigen-binding domain may only bind to a part of the antigen. The part of the antigen molecule responsible for the specific interaction with the antigen binding domain is called the "antigenic determinant" or "antigenic determinant". The antigen binding domain usually contains the antibody light chain variable region (V_L Or VL) and antibody heavy chain variable region (V_H Or VH). However, it is not necessary to include both. For example, Fd antibody fragments consist of only V_H The domain is composed, but still retains a certain antigen binding function of the intact antibody. The term "complementarity determining region" or "CDR" refers to the essential part of the antigen-binding function of the antibody contained in the variable region of the antibody. There are three CDRs 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 technology or by enzymatic 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 antibodies other than "bispecific" or "bifunctional" antibodies are identical. Degradation of antibodies by enzymes (papain) produces two identical antigen-binding fragments, also known as "Fab" fragments and "Fc" fragments. These two antigen-binding fragments have no antigen-binding activity but have crystallization ability. F (ab ') is produced by breaking down antibodies by pepsin₂ A fragment in which the two arms of an antibody molecule remain linked and contain two antigen binding sites. F (ab ')₂ The fragments can be cross-linked with the antigen. As used herein, "Fv" refers to the smallest fragment of an antibody that retains both the antigen recognition site and the antigen binding site. As used herein, "Fab" refers to a fragment of an antibody that includes the constant domain of the light chain and the CH1 domain of the heavy chain. The term "mAb" refers to a monoclonal antibody. Antibodies that can be used 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 unconventional antibodies. The domain refers to the functional structural unit of each polypeptide constituting the antibody molecule. In addition, Fc that can be used in the present invention refers to the partial sequence and partial structure of the H chain constant region formed by the hinge domain, CH2 domain, and CH3 domain. In addition, CH is formed by the CH1 domain, hinge domain, CH2 domain, and CH3 domain from the N-terminal. The CH1 domain, hinge domain, CH2 domain, CH3 domain and Fc region in the present invention can be identified by multiple amino acid residues from the N-terminal according to the EU index [Kabat et al., Sequences of Proteins of Immunological Interest, US Dept .Health and Human Services (1991)]. Multiple amino acid residues are indicated by Kabat et al. By the EU index and in the present invention, the first multiple amino acid residues indicate the original or parent residue of the polypeptide and the last multiple amino acid residues indicate the polypeptide Replace or replace amino acid residues. 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 identified by positions 231 to 231 from the EU index The amino acid sequence of 340 is identified, and CH3 is identified by the amino acid sequence from positions 341 to 447 of the EU index. As used herein, the term "recombinant antibody" refers to antibodies produced by recombinant technology and monoclonal antibodies obtained from fusion tumors. Recombinant antibodies include chimeric antibodies prepared by combining a human antibody constant region and a non-human antibody variable region, and a framework by combining CDRs of the H chain and L chain of a non-human antibody variable region into a human antibody variable region Humanized antibodies (or CDR grafted antibodies) prepared in the region (hereinafter abbreviated as FR), and human antibodies prepared by using animals producing human antibodies 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 obtaining cDNAs encoding VH and VL from monoclonal antibody-derived fusion tumors derived from non-human animals, and inserting these cDNAs into animals with DNA encoding human antibody CH and CL The expression vector of the cell is used to construct a human chimeric antibody expression vector, and then the vector is introduced into animal cells to generate the antibody. The term "humanized antibody" refers to an antibody in which the amino acid sequence of the CDR of the VH and VL of the non-human animal antibody has been grafted into the corresponding CDR of the VH and VL of the human antibody. Except for the CDRs of VH and VL, this region is called FR. Humanized antibodies can be produced by: (i) constructing an amino acid consisting of the amino acid sequence of the CDR of the VH of the non-human antibody and the amino acid sequence of the framework region (FR) of the VH of any human antibody CDNA encoding the sequence and cDNA encoding the amino acid sequence of the VL composed 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 the VL of any human antibody; (ii) Respectively inserting these cDNAs into animal cell expression vectors with DNA encoding human antibody CH and CL to construct a humanized antibody expression vector; and (iii) introducing this vector into animal cells to express the antibody. As used herein, the term "human antibody" refers to an antibody having a variable region, where both the framework region and the CDR region are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibody of the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (for example, mutations induced by random or site-specific mutations in vitro or introduced by somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which 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, colonization of immortalized human peripheral blood lymphocytes or human antibody-producing transgenic animals prepared according to technological improvements in recent genetic engineering, cell engineering, and R & D engineering. Human antibodies can be obtained by immunizing mice with human immunoglobulin genes (Tomizuka K et al., Proc Natl Acad Sci USA. 97,722-7,2000) with the desired antigen. In addition, by using phage display libraries formed by the amplification of antibody genes from human B cells to select human antibodies with the desired binding activity, it is possible to obtain human antibodies without immunization (Winter G et al., Annu Rev Immunol. 12: 433-55. 1994). In addition, by using the Epstein-Barr (EB) virus to immortalize human B cells to prepare 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 that causes antibody fragments such as Fab and scFv to appear on its surface by inserting antibody genes prepared from human B cells into the genes of phage. By using the binding activity relative to the fixed antigen substrate as an index, it is possible to recover from this library phages that exhibit antibody fragments with the desired antigen binding activity. Antibody fragments can also be converted into human antibody molecules composed of two complete H chains and two complete L chains by genetic modification techniques. Transgenic animals that produce human antibodies refer to animals obtained by integrating human antibody genes into the chromosomes of host animals. Specifically, human antibody genes are introduced into mouse ES cells. The ES cells were then transferred to the early embryos of another mouse. Transgenic animals that produce human antibodies can be produced from the embryo. To produce human antibodies from transgenic animals that produce human antibodies, human antibody-producing fusion tumors are obtained by the normal fusion tumor preparation method. After culturing fusion tumors obtained from mammals other than humans, human antibodies can be produced and expressed in the culture. Specifically, antibodies suitable for the present disclosure may include non-human animal antibodies, humanized antibodies, and VH and VL of human antibodies produced by fusion of tumors or antibody-producing cells by any method known in the art Amino acid sequence. The amino acid sequence of CL in the antibody of the present invention may be any of the amino acid sequence of a human antibody or the amino acid sequence of a non-human animal antibody. In certain embodiments, the amino acid sequence of Cκ or Cλ of human antibodies is used. The CH in the antibody of the present invention may be any of immunoglobulins. In certain embodiments, any one of γ1 (IgG1), γ2 (IgG2), and γ4 (IgG4) and variants thereof may be suitable for the antibody in the present invention. The term "effector function" as used in the present invention refers to the cytotoxic activity induced by antibodies, including antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (ADCC) by effector cells, such as natural killer (NK) cells ( CDC), antibody dependent phagocytosis (ADP), or any combination thereof. The effector function of antibodies can be adjusted by known methods. For example, it is known in the art that ADCC activity can be adjusted by controlling the amount of trehalose (also known as "nucleated trehalose"), which is reduced by a complex N-glycoside-linked sugar chain The α1-6 bond in the terminal binds to N-acetyl glucosamine (GlcNAc), the complex N-glycoside-linked sugar chain binds to the Fc region of the antibody according to the EU index (Kabat et al., Sequence of Proteins of immunological interests, 5th edition, 1991) asparagine (Asn) at position 297 (see WO2005 / 035586, WO2002 / 31140, WO00 / 61739), each of which is cited in full Is incorporated into this article. In addition, it is known in the art that ADCC and / or CDC can be adjusted, for example, by modifying amino acid residues in the Fc region of an antibody. The effector activity of an antibody can be enhanced or reduced by controlling the amount of nucleated trehalose in the complex N-glycoside-linked sugar chain bound to the Fc region of the antibody. To reduce the trehalose content of the complex N-glycoside-linked sugar chain bound to the Fc of the antibody, CHO cells lacking the α1,6-trehalosyltransferase gene (FUT8) can be used to express the antibody and An antibody that did not bind trehalose was obtained. Antibodies without trehalose have higher ADCC activity. To increase the trehalose content of the complex N-glycoside-linked sugar chain bound to the Fc of the antibody, trehalose can be obtained by expressing the antibody by using a host expressing the α1,6-trehalosyl transferase gene Of antibodies. Antibodies with trehalose have lower ADCC activity than antibodies without trehalose. In one embodiment, the anti-CCR4 antibody used in the present invention is an antibody having a trehalosylated N-glycoside-linked sugar chain bound to the Fc region of the antibody. In certain embodiments, the anti-CCR4 antibody used in the present invention is an antibody having a trehalosylated N-glycoside-linked sugar chain bound to the Fc region of the antibody. In some embodiments, about 50% or Bigger. In other embodiments, the antibody has a trehalosylation range of about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% or greater. In addition, by modifying amino acid residues in the Fc region of the antibody, ADCC activity or CDC activity can be increased or decreased. Amino acid residues in the Fc region are modified to increase or decrease the binding activity for FcγR, thereby controlling ADCC activity. 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 US2007 / 0148165. In addition, ADCC activity or CDC activity can be modified as described in the specifications of US6,737,056, US7,297,775, US7,317,091, WO2005 / 070963 and Oganesyan et al. (Biol. Crystal., 2008; 64; 700-704) Increase or decrease the amino acid residue. In some embodiments, the anti-PD-1 antibody has no effector function, and only neutralizes PD-1 function by PD-L1 or PD-L2 binding. In certain embodiments, anti-PD1 antibodies suitable for use in the present invention may be IgG2 or IgG4 subclasses that exhibit reduced effector function or no effector function. In one embodiment, the anti-PD-1 antibody used in the present invention may have an Fc variant with reduced effect function or no effect function. As used herein, the term "individual" includes any human or non-human animal. The term "non-human animals" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, and the like. Unless otherwise indicated, the terms "patient" or "individual" are used interchangeably herein. The term "leveling dose" or "leveling amount" used in relation to the composition of the present invention means the dose administered to the patient regardless of the patient's weight or body surface area (BSA). Therefore, the flattened dose is not provided as a mg / kg dose, but as an absolute amount of the agent (eg, anti-CCR4 antibody and / or anti-PD-1 antibody). For example, a person of 60 kg and a person of 100 kg will receive the same dose of the composition (eg 240 mg of anti-PD1 antibody and 80 mg of anti-CCR4 antibody). As mentioned herein, the term "body weight-based dose" means that the dose administered to the patient is calculated based on the weight of the patient. For example, when a patient with a weight of 60 kg 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 families of lymphocyte chemokine receptors that act as two chemokines, TARC (CCL17) and MDC (CCL22). CCR4 performance includes CD4⁺ CD4 of regulatory T cells (Treg)⁺ 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-state tumors have been demonstrated to express CCR4. Ca induced by CCR4 bound ligand^{2 +} Flow into CCR4⁺ On cells and induce cell proliferation or cell migration towards ligand secretory tissues. CD4⁺ Th2 cells are regulatory cells in humoral immunity. When Th2 cells promote antibody production to additional antigens by B cells, Th2 cells also inhibit Th1 cell function. Th2 cells act as helper T cells by producing immunosuppressive interleukins, such as interleukin (IL) -10, thereby suppressing cellular immunity. CD4, CD25, CTLA-4 and GITR (glucocorticoid-induced tumor necrosis factor receptor family related genes) are known Treg markers (Journal of Allergy and Clinical Immunology, 110: 693-701, 2002). In addition, FoxP3 (forkhead box protein 3) transcription factor is a major gene involved in the differentiation and functional performance 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 a group of T cells that inhibit the activation of autoreactive T cells and are responsible for immune self-tolerance, preventing the immune system from attacking self 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) -β via direct and / or indirect pathways, such as cell-cell interactions, to deplete T cell stimulation Sex chemokine and IL-2 to suppress immune stimulation. Exemplary cells expressing CCR4 targeted in the methods provided herein are selected from CCR4⁺ Immune cells and CCR4⁺ Cells in tumor cells. In certain embodiments, CCR4⁺ The cells are selected from the group consisting of: CCR4⁺ T cells, CCR4⁺ Th2 cells, CD4⁺ CD25⁺ CCR4⁺ T cells, CCR4⁺ Foxp3⁺ T cells, CD4⁺ CD25⁺ CCR4⁺ Foxp3⁺ T cells, CD4⁺ CD25⁺ CCR4⁺ CD127^low T cells and CD4⁺ CD25⁺ CD45RA^- CCR4⁺ Foxp3⁺ T cells (called effector Tregs) (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 setting selected from: CD4⁺ CD25⁺ CCR4⁺ , CD25⁺ Foxp3⁺ , CCR4⁺ Foxp3⁺ , CD4⁺ CD25⁺ CCR4⁺ Foxp3⁺ , CD4⁺ CD25⁺ CCR4⁺ CD127^low And CD4⁺ CD25⁺ CD45RA^- CCR4⁺ Foxp3⁺ Can be illustrative.PD-1 T cell activation and deactivation in the human body are complexly regulated by multiple membrane proteins simultaneously. One of these membrane proteins, PD-1 was cloned as a type I membrane protein of 55 kDa (Ishida et al., EMBO J., 1992; 11; 3887-3895). PD-1 is expressed on multiple cell types activated T cells, regulatory T cells (Treg), activated B cells and natural killer (NK) cells and PD-1 is known to bind to its ligand, PD-L1 And PD-L2 to regulate T cell activation. The intracellular domain of PD-1 contains ITSM motifs and ITIM motifs that can be inhibitory domains of immune responses. PD-1 bound by PD-L1 induces inhibitory signals in T cells or other cells expressing PD-1, thereby blocking the activation, cell proliferation and / or inflammatory cells of T cells or other cells expressing PD-1 Interleukin releases or disables T cells. On the other hand, PD-L1 (human PD-L1 cDNA, AF233516) and PD-L2 (human PD-L2 NM_025239) are PD-1 ligands. PD-L1 is expressed on multiple 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 analysis such as flow cytometry, immunohistochemistry (IHC). "PD-1 positive" means at least about 0.1%, at least about 1%, at least about 5%, at least about 10%, or at least about 20% or more stained cells, tissues, and body fluids of a human individual. As used herein, "PD-L1 positive" or "PD-L2 positive" can be used interchangeably with "at least about 1% of PD-L1 and / or PD-L2 performance." In one embodiment, the PD-L1 performance and / or PD-L2 performance can be used by any method known in the art. In another embodiment, PD-L1 performance and / or PD-L2 performance is measured by automatic in situ hybridization (IHC). PD-L1 and / or PD-L2 positive tumors may therefore have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 1% as measured by automated IHC 30%, at least about 40%, or at least about 50% of tumor cells expressing PD-L1.anti- CCR4 antibody Anti-CCR4 antibodies suitable for the present invention can specifically bind to human CCR4. In one embodiment, the anti-CCR4 antibody can attenuate, inhibit, or prevent at least one function of the 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, induced by major natural killer (NK) cells Antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or antibody-dependent phagocytosis (ADP) by phagocytic cells such as macrophages or dendritic cells and / or neutralizing CCR4 coordination body. In one embodiment, the anti-CCR4 antibody used in this method binds to the extracellular region of the CCR4 molecule and exhibits ADCC activity. In another embodiment, the anti-CCR4 antibody binds to the epitope of amino acids 2 to 29 of the CCR4 protein (eg, amino acids 2 to 29 corresponding to SEQ ID NO: 22) and exhibits ADCC activity. In other embodiments, the anti-CCR4 antibody binds to the 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 cross-competes with an antibody comprising the following to bind to CCR4: VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, VH CDR2 comprising the sequence set forth in SEQ ID NO: 2 , A VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and a VL CDR2 containing the sequence set forth in SEQ ID NO: 5. : VL CDR3 of the sequence described in 6. In one embodiment, the anti-CCR4 antibody or antigen-binding portion thereof used in the present invention binds to the same epitope bound by an antibody or moglizumab comprising the following: comprising SEQ ID NO: 1 VH CDR1 of the sequence set forth, VH CDR2 of the sequence set forth in SEQ ID NO: 2, VH CDR3 of the sequence set forth in SEQ ID NO: 3, VL of the sequence set forth in SEQ ID NO: 4 CDR1, VL CDR2 containing the sequence set forth in SEQ ID NO: 5 and VL CDR3 containing the sequence set forth in SEQ ID NO: 6. In another embodiment, an anti-CCR4 antibody suitable for use in the present invention 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, and comprising SEQ ID One or more of the VH CDR3 of the sequence set forth in NO: 3, and the VL CDR1 containing the sequence set forth in SEQ ID NO: 4, the VL CDR2 containing the sequence set forth in SEQ ID NO: 5 and containing One or more of the VL CDR3 of the sequence 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 SEQ ID NO: 3 VH CDR3 of the sequence, VL CDR1 containing the sequence set forth in SEQ ID NO: 4, VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6 . 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, the 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 nucleated trehalose that does not bind to N-acetylglucosamine at position 297 of the Fc region. In a specific embodiment, the anti-CCR4 antibody is moglizumab (POTELIGEO (registered trademark)). In certain embodiments, the anti-CCR4 antibody used in the method or composition has a lower trehalosylation, detrehalosylation, or no trehalosylation of N-glycoside linkages bound to the Fc region of the antibody Sugar chain. Antibodies with lower trehalosylation, de-trehalosylation, or no trehalosylation may have higher ADCC activity than trehalosylated antibodies. Therefore, in one embodiment, the anti-CCR4 antibody used in the method or in the composition of the present invention can be produced by cells having low or no alpha 1,6-trehalosyltransferase (FUT8) activity. In another embodiment, the anti-CCR4 antibody used in the method or composition of the present invention is substantially free of nucleated trehalose, which is linked to the sugar chain by the N-glycoside linkage of Asn 297 in the Fc region The α1,6 bond is bound to N-acetylglucosamine. In certain embodiments, the method further comprises identifying CCR4 performance prior to administration of the anti-CCR4 antibody. In other embodiments, CCR4 infiltrating the tumor tissue of the patient and / or tissue effluents such as the abdomen and pleura can be monitored before, during, and / or after treatment⁺ T cell or CCR4⁺ Treg cell population, CCR4⁺ T cell or CCR4⁺ The degree of reduction / consumption of Treg. In addition, CCR4 performance 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 method of the present invention. In another embodiment, the anti-PD-1 antibody or antigen-binding portion thereof blocks, inhibits, prevents or neutralizes PD-1 expression on cells or PD-1 related tumor immune response function. The anti-PD-1 antibody used in the method of the present invention binds to PD-1 with higher specificity and affinity, blocks the binding of PD-L1, and / or suppresses the immunosuppressive effect of the PD-1 signaling pathway. In any of the treatment methods or composition uses disclosed herein, anti-PD-1 antibodies include antigen binding that binds to PD-1 and exhibits ligand-like binding inhibition and upregulates the functional properties of the immune system similar to whole antibodies Fragment. In some embodiments, the anti-PD-1 antibody of the invention comprises: VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and SEQ ID NO : One or more of the VH CDR3 of the sequence set forth in 13 and the VL CDR1 containing the sequence set forth in SEQ ID NO: 14, the VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and the VL CDR3 containing the sequence set forth in SEQ ID NO: 15 One or more of the VL CDR3 of the sequence set forth in ID NO: 16. In certain embodiments, the anti-PD-1 antibody comprises: VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and SEQ ID NO: The sequence VH CDR3 set forth in 13, the VL CDR 1 containing the sequence set forth in SEQ ID NO: 14, the VL CDR2 containing 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: VH comprising the sequence set forth in SEQ ID NO: 17 and 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 that has effect-reducing activity. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof competes with nivolumab to bind to human PD-1 and the anti-PD-1 antibody or antigen-binding fragment such as nivolumab binds to human The same antigenic determinant 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 human subjects, the monoclonal antibody is a humanized antibody. In other embodiments for treating human subjects, the antibody is a human antibody. In other embodiments, antibodies of the IgG1, 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 belonging to a human IgG1 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 contains the S228P mutation, which replaces the hinge with a proline residue normally found at the corresponding position in the IgG1 isotype antibody Serine residues in the region. This mutation present in nivolumab prevents the exchange of Fab arms with endogenous IgG4 antibodies, while maintaining a lower affinity for activation of 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. Humanized antibodies or human antibodies (HuMab) that specifically bind to PD-1 with higher affinity have been disclosed in US Patent No. 8,008,449 or 8,779,105. Other anti-PD-1 monoclonal antibodies have been described in, for example, US 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 US Patent No. 8,008,449 has been shown to exhibit one or more of the following characteristics: (a) combined with 1 × 10-⁷ M or less than 1 × 10^{- 7} K of M_D Human PD-1, as determined by surface plasmon resonance using the Biacore biosensor system; (b) is not substantially bound to human CD28, CTLA-4, or ICOS; (c) increases mixed lymph T cell proliferation in MLR analysis; (d) Increase interferon gamma production in MLR analysis; (e) Increase IL-2 secretion in MLR analysis; (f) Binding to human PD-1 and Crab-eating macaque PD-1; (g) inhibit PD-L1 and / or PD-L2 binding to PD-1; (h) stimulate antigen-specific memory response; (i) stimulate antibody response; and (j) inhibit activity Tumor cells grow in the body. Anti-PD-1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one of the aforementioned characteristics (in some embodiments, at least five). In some embodiments, the anti-PD-1 antibody is nivolumab. In one embodiment, the anti-PD-1 antibody is peclizumab. In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab (also known as "OPDIVO (registered trademark)"; previously specifically referred to as 5C4, BMS-936558, MDX-1106 or ONO-4538) is a selective protection against PD-1 ligands (PD-L1 and PD-L2) interaction, thereby blocking the all-human IgG4 (S228P) PD-1 immune checkpoint inhibitory antibody that down-regulates anti-tumor T cell function (US 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 Pelicuzumab. In a specific embodiment, the anti-PD-1 antibody is nivolumab. Palivizumab (also known as "KEYTRUDA (registered trademark)", ralizumab and MK-3475) is a human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) ) Of humanized single IgG4 antibody. Palivizumab is described in, for example, US Patent Nos. 8,354,509 and 8,900,587; see also http://www.cancer.gov/drugdictionary?cdrid=695789 (last visited: December 14, 2014). Palivizumab 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 same epitope as MEDI0608 (formerly AMP-514) which is a monoclonal antibody. In yet other embodiments, the anti-PD-1 antibody is MEDI0608. MEDI0608 is described in, for example, US Patent No. 8,609,089B2 or http://www.cancer.gov/drugdictionary?cdrid=756047 (last visited: December 14, 2014). Anti-PD-1 antibodies that can be used in the disclosed methods or disclosed compositions also include isolated antibodies that specifically bind to human PD-1 and cross-compete with nivolumab to bind to human PD-1 (see also , For example, US Patent Nos. 8,008,449 and 8,779,105; WO 2013/173223). The ability of antibodies to cross-compete to bind to an antigen may indicate that these antibodies bind to the same epitope of the antigen and sterically hinder the binding of other cross-competing antibodies to specific epitopes. By virtue of binding to the same epitope region of PD-1, these cross-competing antibodies are expected to have very similar functional properties to nivolumab. The cross-competitive antibody can be easily identified based on its ability to cross-compete with nivolumab in standard PD-1 binding analysis, such as Biacore analysis, ELISA assay, or flow cytometry (see, for example, WO 2013 / 173223). In certain embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO (registered trademark)). In other embodiments, the anti-PD-1 antibody is peclizumab (KEYTRUDA (registered trademark)). In other embodiments, the anti-PD-1 antibody is selected from human antibody 17D8, human antibody 2D3, human antibody 4H1, human antibody 4A11, human antibody 7D3, and human antibody 5F4 described in US 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 used in the method or composition that specifically binds to PD-1 and inhibits PD-1 activity (eg, binds to PD-L1 and / or PD-L2) It is suitable for the treatment of cancer, such as lung cancer (eg non-small cell lung cancer), esophageal cancer or gastric cancer. In one embodiment, the anti-PD-1 antibody used in the method or composition of the present invention includes: (i) an antibody that cross-competes with the antibody to bind to human PD-1, the antibody includes: comprising SEQ ID NO : One or more of the heavy chain CDR1 of the sequence set forth in 11, the heavy chain CDR2 of the sequence set forth in SEQ ID NO: 12, and the heavy chain CDR3 of the sequence set forth in SEQ ID NO: 13, And the light chain CDR1 comprising the sequence set forth in SEQ ID NO: 14, the light chain CDR2 comprising the sequence set forth in SEQ ID NO: 15, and the light chain CDR3 comprising the sequence set forth in SEQ ID NO: 16. One or more; (ii) an antibody that binds to the same epitope region as the epitope region in 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 containing the sequence set forth in SEQ ID NO: 13, the light chain CDR1 containing the sequence set forth in SEQ ID NO: 14, including SEQ ID NO : Light chain CDR2 of the sequence set forth in 15 and light chain CDR3 containing the sequence set forth in SEQ ID NO: 16; (iii) antibody, which Including: heavy chain CDR1 containing the sequence set forth in SEQ ID NO: 11, heavy chain CDR2 containing the sequence set forth in SEQ ID NO: 12, heavy chain CDR3 containing 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 containing the sequence set forth in SEQ ID NO: 16; ( iv) an antibody comprising: 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 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 a neutralizing or blocking activity on PD-1; that is, the anti-PD-1 antibody can block PD-1 activity through PD-L1 binding and inhibit T cell proliferation , Interleukin release and any combination thereof. In one embodiment, the anti-PD-1 antibodies ONO-4538, BMS-936558, nivolumab / OPDIVO (registered trademark) specifically bind to PD-1 and block PD-1 from binding to PD-L1 and PD -Exemplary anti-PD-1 antibody for L2. Nivolumab can alleviate PD-1 mediated inhibition of human T cell activation in vitro and inhibit tumor growth in xenograft models via T cell dependent mechanisms.( i ) anti- CCR4 Antibodies and ( ii ) anti- PD - 1 Antibody combination therapy The present invention relates to a method of treating cancer, the method comprising administering a CCR4 antagonist and a PD-1 antagonist, wherein the CCR4 antagonist comprises binding to CCR4, interfering with CCR4 or otherwise blocking the binding of CCR4 to its ligand ( For example, CCL17 and / or CCL22) any smaller or larger molecules (eg, anti-CCR4 antibodies), and the PD-1 antagonist includes binding to PD-1, interfering with PD-1, or otherwise blocking PD- 1 Any smaller or larger molecule (eg, anti-PD-1 antibody) that binds to its ligand (eg, PD-L1). In one embodiment, the invention includes 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 administration schedule of the method includes the administration schedule for cancer patients, including administration of anti-CCR4 antibody and anti-PD-1 antibody. In certain embodiments, the anti-CCR4 antibody and anti-PD-1 anti-system are administered in an effective amount to treat cancer. Also provided herein is a method of reducing the size of a tumor in an individual with 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 method of the present invention enhances anti-tumor efficacy compared to anti-CCR4 antibody or anti-PD-1 antibody monotherapy. 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. The combination methods of the present invention can suppress the anti-tumor immune response by reducing or depleting CCR4⁺ Treg cells can bring one or more beneficial effects on anti-tumor immunotherapy of cancer patients; therefore, anti-CCR4 antibodies counteract CCR4⁺ The immunosuppressive effect of Treg cells causes and enhances the anti-tumor immune response. At the same time, anti-PD-1 antibodies block or neutralize T cells, and PD-1 is a negative regulator of cytotoxic T cells that attack tumor cells in the tumor microenvironment; therefore, anti-PD-1 antibodies counteract negative signals against T cells And cause anti-tumor immune response. The dose of anti-CCR4 antibody used in this method includes any dose of about 0.1 mg / kg to about 10.0 mg / kg per administration. In one aspect, the dose of anti-CCR4 antibody used in the method includes 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. The dose of anti-PD-1 antibody used in the method includes any dose of about 1.0 mg / kg to about 10.0 mg / kg per administration. In one aspect, the dose of anti-PD-1 antibody used in the method includes 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 anti-PD-1 antibody is about 2.0 mg / kg. In a specific embodiment, the dose of anti-PD-1 antibody is about 3.0 mg / kg. In a specific embodiment, the dose of anti-PD-1 antibody is about 240 mg / body as a flat dose. In some embodiments, the dose of 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 some embodiments, the dose of anti-PD-1 antibody is 480 mg per body dose. The dosing cycle of antibodies used in this method includes any suitable dosing cycle for each antibody. The dosing cycle is defined as about once a week (Q1W), about once 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 this method includes once a week (Q1W) for four 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 once every two weeks (maintenance phase) after the first administration. The administration cycle of the anti-PD-1 antibody used in this method includes once every two weeks, once every three weeks, or once every four weeks. In another embodiment, the method of the invention includes a method of treating at least one cancer in an individual, the method comprising administering about 0.1 mg about once a week for 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, 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 combination of anti-PD-1 antibodies. In other embodiments, the method of the invention includes treating at least one cancer in an individual, the method comprising administering; (i) about once a week for four weeks after the first administration and then about 0.1 every about once every two weeks 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 Administer about 2.0 mg / kg of anti-PD-1 antibody combination at one time; (ii) about 0.1 mg / kg, about 0.3 mg / kg about once a week for four weeks 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 in combination with about 3.0 mg / kg of anti-PD-1 antibody administered about once every two weeks; (iii) 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 one dose, about once a week for four weeks and then about once every two weeks mg / kg or about 3.0 mg / kg of anti-CCR4 antibody, and at least about 100 mg / body, 120 mg / body, 140 mg / body, 160 mg / body, 180 mg / body, and 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 combination of anti-PD-1 antibodies; (iv) about one week after the first dose Anti-CCR4 antibody of 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 once for four weeks and then about every two weeks , And in combination with about 2.0 mg / kg of anti-PD-1 antibody administered about once every four weeks; (v) about 0.1 mg / kg about once a week for 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-c PD-1 antibody combination or (vi) about 0.1 mg / kg, about 0.3 mg / kg, about 0.75 mg / kg, about 1.0 after the first administration, about once a week for four weeks and then about once every four weeks 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 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 anti-PD-1 antibody combination. In one embodiment, the method of the present invention includes a method of treating at least one cancer in an individual, the method comprising administering about 0.1 mg / day about once a week for 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 once every two weeks With about 2.0 mg / kg or about 3.0 mg / kg, or about 240 mg / body as an adjusted dose of anti-PD-1 antibody, or about once every four weeks about 480 mg / body as an adjusted 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 VH CDR3 of the sequence set forth in SEQ ID NO: 3, VL CDR1 containing the sequence set forth in SEQ ID NO: 4, VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and containing 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: comprising SEQ ID NO: 11 VH CDR1 of the sequence set forth, VH CDR2 of the sequence set forth in SEQ ID NO: 12, VH CDR3 of the sequence set forth in SEQ ID NO: 13, of 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 present invention includes a method of treating a cancer patient, the method comprising about once a week for four weeks and then about once 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 2.0 mg / kg or about 3.0 mg / about every two weeks kg, or about 240 mg / body as an adjusted dose of anti-PD-1 antibody, or about every four weeks about 480 mg / body as an adjusted dose of anti-D-1 antibody combination, wherein the anti-CCR4 antibody binds to the antibody The same epitope, the antibody contains: VH CDR1 containing the sequence set forth in SEQ ID NO: 1, VH CDR2 containing the sequence set forth in SEQ ID NO: 2, including the set forth in SEQ ID NO: 3 VH CDR3 of the sequence, VL CDR including the sequence set forth in SEQ ID NO: 4, VL CDR2 including the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6, And where the anti-PD-1 antibody binds to the same epitope as the antibody, the antibody includes: comprising the sequence set forth in SEQ ID NO: 11 VH CDR1, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, VH CDR3 containing the sequence set forth in SEQ ID NO: 13, VL CDR1 containing the sequence set forth in SEQ ID NO: 14, including 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 present invention includes a method of treating a cancer patient, the method comprising about once a week for four weeks and then about once 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 2.0 mg / kg or about 3.0 mg administered about every two weeks / kg, or an anti-PD-1 antibody with an adjusted dose of about 240 mg / body, or an anti-PD-1 antibody combination with an adjusted dose of about 480 mg / body about once every four weeks, wherein the anti-CCR4 antibody Contains: VH CDR1 containing the sequence set forth in SEQ ID NO: 1, VH CDR2 containing the sequence set forth in SEQ ID NO: 2, VH CDR3 containing the sequence set forth in SEQ ID NO: 3, containing SEQ ID VL CDR1 of the sequence set forth in NO: 4, VL CDR2 containing the sequence set forth in SEQ ID NO: 5 and VL CDR3 containing the sequence set forth in SEQ ID NO: 6, and wherein the anti-PD-1 antibody Contains: VH CDR1 containing the sequence set forth in SEQ ID NO: 11, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, including the set forth in SEQ ID NO: 13 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 present invention includes a method of treating a cancer patient, the method comprising about once a week for four weeks and then about once 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 (moglizumab), and about once every two weeks 2.0 mg / kg, or about 3.0 mg / kg, or about 240 mg / body as a flat dose of anti-PD-1 antibody (nivolumab) or about every four weeks, about 480 mg / body as a flat agent A combination of anti-PD-1 antibodies (Nivolumab). In the methods or compositions described herein, antibody combinations can be administered to cancer patients in parallel (or simultaneously) or sequentially. The term "in 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 only or a mixture thereof, and both by intravenous line and / or infusion The bag is administered to the patient. The term "in order" means that one antibody is administered to cancer patients, and then the second antibody is administered to these cancer patients at a later time allowed after administration of the first antibody. In certain embodiments, the present disclosure includes a method of treating patients with HCC, wherein 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 Days, 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 combination therapy of anti-CCR4 antibody and anti-PD-1 antibody is higher than that of anti-CCR4 antibody monotherapy and / or anti-PD-1 antibody monotherapy (higher than 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 patients with HCC, wherein the overall survival period 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 (higher than 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 Month, at least about 3.5 years, at least about 4 years, at least about 4.5 years, or at least about 5 years).Used to treat cancer CCR4 Antibodies and anti PD - 1 Antibody Kit The present invention also includes a kit for treating individuals suffering from cancer, the kit comprising: (a) a dose ranging from about 0.1 mg / kg to about 10 mg / kg body weight that specifically binds to PD-1 and / Or an antibody or antigen-binding portion thereof that inhibits PD-1 activity ("anti-PD-1 antibody or antigen-binding portion"); (b) a dose ranging from about 0.1 mg / kg to about 10 mg / kg body weight An antibody or antigen-binding portion thereof that specifically binds to CCR4 and / or inhibits CCR4 activity ("anti-CCR4 antibody or antigen-binding portion thereof"); and (c) use an anti-PD-1 antibody in any method disclosed herein and Instructions for anti-CCR4 antibody. The kit usually includes a label and instruction manual indicating the intended use of the contents of the kit. The term label includes any written or recorded material supplied on or with the kit or otherwise accompanying the kit. 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 that binds to the same epitope as the antibody, which includes: comprising SEQ ID NO: 1 VH CDR1 of the sequence set forth in one or more of VH CDR2 including the sequence set forth in SEQ ID NO: 2 and VH CDR3 including the sequence set forth in SEQ ID NO: 3, and including SEQ ID NO : VL CDR1 of the sequence set forth in 4: one or more of VL CDR2 containing the sequence set forth in SEQ ID NO: 5 and VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (ii ) Antibody or antigen-binding portion thereof, 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, including the set forth in SEQ ID NO: 3 VH CDR3 of the sequence, VL CDR1 containing the sequence set forth in SEQ ID NO: 4, VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and VL containing the sequence set forth in SEQ ID NO: 6 CDR3; (iii) antibody or antigen-binding portion thereof, comprising: VH comprising the sequence set forth in SEQ ID NO: 7 and comprising SEQ VL of the sequence set forth in ID NO: 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 that cross-competes with the antibody of (ii); and (vi) moglizumab or its antigen-binding portion. 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 that binds to the same epitope as the antibody, which comprises: comprising SEQ ID One or more of VH CDR1 of the sequence set forth in NO: 11, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, and VH CDR3 containing the sequence set forth in SEQ ID NO: 13, and including One or more of VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and VL CDR3 containing the sequence set forth in SEQ ID NO: 16; (ii) Antibody or antigen-binding portion thereof, comprising: 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 SEQ ID NO: 13 VH CDR3 of the sequence described, VL CDR1 of the sequence set forth in SEQ ID NO: 14, VL CDR2 of the sequence set forth in SEQ ID NO: 15, and the sequence of SEQ ID NO: 16 VL CDR3; (iii) antibody or antigen-binding portion thereof, comprising: comprising the sequence set forth in SEQ ID NO: 17 VH and VL comprising the sequence set forth in SEQ ID NO: 18; (iv) Antibodies comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising the sequence set forth in SEQ ID NO: 20 The light chain of the sequence; (v) an antibody that cross-competes with the antibody of (ii); (vi) nivolumab or its antigen binding portion; (vii) peclizumab or its antigen binding portion; and (viii ) MEDI0608 or its antigen binding portion.Used to treat cancer CCR4 Antibodies and anti PD - 1 Antibody composition In one embodiment, the composition of the present invention comprises an anti-CCR4 antibody and an anti-PD-1 antibody for 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 four weeks and then about once every two weeks, 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 once every two weeks at 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 or about 480 mg / body as a flat dose of anti-PD-1 antibody combination every four weeks. In certain embodiments, the composition is prepared to be used as a flat dose of 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 about once every four weeks as a flat dose of anti-PD-1 antibody and about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg about once a week for four weeks and then about once 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 combination. 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 four weeks and then about once every two weeks, About 1.0 mg / kg, about 2.0 mg / kg or about 3.0 mg / kg dose of anti-CCR4 antibody and about once every two weeks about 2.0 mg / kg or about 3.0 mg / kg or about 240 mg / body as a flat dose The anti-PD-1 antibody or about 480 mg / body about once every four weeks is administered as a flat-dose combination of anti-PD-1 antibodies. In other embodiments, the composition is prepared to be administered with an anti-PD-1 antibody 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 and about once a week An anti-CCR4 antibody combination is administered at a 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 that lasts for 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 (moglizumab) for about four times a week and then about once every two weeks 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 mg / kg or about 3.0 mg / kg and about once every two weeks at about 2.0 mg / kg or about 3.0 mg / The dose of kg or about 240 mg / body is a flat dose or about once every four weeks with a combination of about 480 mg / body as a flat dose of anti-PD-1 antibody (nivolumab) to treat cancer in the individual. In another embodiment, the composition comprises an anti-PD-1 antibody (nivolumab) at a dose of about 2.0 mg / kg or about 3.0 mg / kg or about 240 mg / body for about once every two weeks Equalized dose or about once every four weeks with about 480 mg / body as an adjusted dose and about once a week for four weeks and then about once every two weeks about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, Combination of anti-CCR4 antibody (moglizumab) at a dose of about 0.75 mg / kg, about 1.0 mg / kg, or about 3.0 mg / kg. In certain embodiments, the composition used in the present invention is prepared as a flat dose composition; for example, the flat dose of an anti-CCR4 antibody may 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 is in the range of about 1 mg to about 200 mg, about 2 mg to about 180 mg, about 3 mg to about 170 mg, or about 6 mg to about 160 mg. In another embodiment, the composition comprises an anti-CCR4 antibody in a dose ranging from about 6 mg to about 60 mg, about 10 mg to about 80 mg, or about 20 mg to about 70 mg. In other embodiments, the dose of 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 composition used in the present invention is administered in a flat dose, wherein the dose of 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 dose of the anti-PD-1 antibody 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 yet other embodiments, the dose of 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 includes any composition for use, including 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 Provided that the pharmaceutical formulation is generally prepared by mixing each antibody with one or more pharmaceutically acceptable carriers according to any well-known method in the pharmaceutical field. In addition, the antibodies used in the present invention are also provided in the form of pharmaceutical formulations, which are generally combined with one or more pharmaceutically acceptable carriers by any well-known method in the medical field Mix to prepare. In some embodiments, the anti-system of the invention is provided in the form of a sterile solution, wherein the antibody is dissolved in an aqueous vehicle such as water, or an aqueous solution of the salt, glycine, glucose or human albumin used. Pharmaceutically acceptable additives such as buffers or tonicity agents can also be added to prepare solutions more similar to physiological conditions and their examples, including sodium acetate, sodium chloride, sodium lactate, potassium chloride, sodium citrate or their analog. It can also be stored by freeze-drying and in actual use, it can be used by dissolving in an appropriate solvent. Regarding the administration route of the antibody used in the present invention or the composition of the present invention, in some 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. Excipients such as lactose, glucose, sucrose, mannitol, or the like can be used for capsules, lozenges, powders, granules 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 , Such as glycerin or its analogues are prepared as additives. Examples of formulations suitable for parenteral administration may include injectable formulations, suppositories, air spray or the like. For example, injectable formulations are prepared using carriers including saline solutions, glucose solutions, or mixtures thereof. Suppositories are prepared using carriers such as cocoa butter, hydrogenated fat, carboxylic acid or the like. The air spray is prepared using, for example, a carrier that does not stimulate the antibody itself and the mucosa of the mouth and respiratory tract to be administered to a person, and disperses the antibody into fine particles so that it is easily absorbed. Specific examples of carriers include lactose, glycerin, or the like. Depending on the characteristics of the antibody and carrier used, aerosols, dry powders or the like can be prepared. In addition, even in parenteral preparations, components exemplified as additives in oral preparations may be added. In one embodiment, cancer patients in the present invention include any cancer patients that can be effectively treated by the composition or method of the present invention. For example, in an embodiment of the present invention, the cancer patient is at least one cancer patient with cancer selected from lung cancer, gastrointestinal cancer, gastric cancer (or gastric cancer), colon cancer, colorectal cancer, esophageal cancer, pancreas Cancer, liver cancer, kidney cancer, ovarian cancer, breast cancer, head and neck cancer, skin cancer, melanoma, and hematopoietic cancers including leukemia and lymphoma. In another embodiment, the cancer in the present invention includes any stage of cancer, primary / metastatic cancer, locally advanced / 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 lung cancer including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, and large cell Carcinoma, adenosquamous carcinoma, carcinoma with pleomorphic sarcomatoid or sarcoma elements, cartinoid tumor and classified salivary adenocarcinoma (carcinomas of salivary-gland type), gastric cancer, liver cancer, hepatocytes 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 duct cancer, pancreatic head cancer, pancreatic body cancer, pancreatic tail cancer, and any combination thereof. In another embodiment, the patient has head and neck cancer selected from the group consisting of oral cancer, pharyngeal cancer, larynx cancer, neck cancer, salivary gland cancer, and any combination thereof. In the present invention, cancer patients can be diagnosed before administering the combination therapy. In one embodiment, the diagnostic method may be by methods known in the background art, such as X-ray graphics, computed tomography (CT), positron emission tomography CT (PET-CT), magnetic nuclear resonance imaging (MRI) And / or perform one or several biomarkers in the patient's plasma, serum, peripheral blood, and tumor tissue for analysis and execution. In addition, cancer progression, disease stage, and / or response to treatment can be analyzed by known methods and parameters in combination with the aforementioned imaging and biomarkers. For example, tumor metabolism with regard to glucose consumption is usually spent on FDG-PET based on the upregulated radioisotope labeling glucose, such as¹⁸ F fluorodeoxyglucose (FDG) was analyzed as cancer tissue. FDG is highly accumulated in cancer tissues because cancer cells metabolize glucose highly and require a greater amount of glucose than normal tissues. In addition, analysis of cell populations in peripheral blood lymphocytes (PBL), pleural effusion lymphocytes (LPE), and / or tumor-infiltrating lymphocytes (TIL) can be used to assess tissues in each patient and / or the entire body Immune response status. 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. Performance CD4 detected⁺ CD25⁺ , CD8⁺ CD25⁺ , PD-1⁺ And / or CTLA-4⁺ Activated T cells, express CD4⁺ CD25⁺ CCR4⁺ , CD25⁺ Foxp3⁺ , CCR4⁺ Foxp3^high , CD4⁺ CCR4⁺ Foxp3⁺ Or CD4⁺ CD25⁺ CD45RA^- CCR4⁺ Foxp3⁺ Treg cells, and when the activated T cells in the patient increase and / or the Treg cells decrease, it is considered that the immune response in the patient is enhanced. In one analysis, CD4, CD8, CD25, CD45RA, CD45RO, CCR4, CD127, PD-1, PD-L1 (B7-H1, CD274), PD can be analyzed before and / or after administration of the combination therapy -T cells, effector Treg, depletion recognized by the performance of L2, CTLA-4 (CD152), IFN-γ, IL-2, IL-4, IL-12 and / or Foxp3, or peripheral / microenvironment cytokines T cells, activated T cells, effector T cells, non-allergic T cells, or bone marrow-derived suppressor cells (MSDC). In some embodiments, the combination therapy of anti-CCR4 antibody and anti-PD-1 antibody can reduce Treg cells and / or increase activated T cells in the peripheral blood, pleural effluent, and / or tumor tissue of the patient. Therefore, the combination of antibodies can enhance the immune response to cancer cells in the patient. In addition, in one embodiment, the method further includes analyzing or measuring the PD-L1, PD-L2, or CCR4 performance level on the tumor cells prior to administration to determine whether the patient is suitable for the combination therapy. In another embodiment, the PD-L1 or PD-L2 manifestation in the patient can be regarded as a sign that the patient is suitable for the combination therapy of the present invention. In addition, the indoleamine 2,3-dioxase (IDO) activity in the patient's plasma sample can be analyzed in the present invention. It is known in the art that IDO manifested in various organs, such as lung, small intestine, and placenta, is related to the induction of Treg differentiation, which will cause immune tolerance. In addition, the molecule is highly expressed on multiple cancer cells, suppresses the immune response and induces immune tolerance of the cancer cells. Therefore, the analysis of IDO activity can detect the immune response status. IDO activity is usually detected by analyzing changes in the content of tryptophan, kynurenine, and kynurenine metabolites. When the IDO activity of the patient is increased, tryptophan, kynurenine, and kynurenine metabolites also increase, thereby resulting in a reduction in the patient's immune response. In other embodiments, the combination therapy of anti-CCR4 antibody and anti-PD-1 antibody increases the number of Treg cells in the patient and / or reduces IDO activity in the patient. The clinical medical evaluation of treatment will usually be assessed by the solid tumor response assessment criteria (RECIST) version 1.1 criteria and by the immune-related response criteria (irRC) (Wolchok et al., Clin. Cancer Res .; 2009, 15: 7412-7420 ).Examples 1 Stages of combination therapy with moglizumab and nivolumab in individuals with advanced solid tumors 1 the study 1. Research Overview This study is a combination of anti-CCR4 antibody moglizumab and anti-PD-1 antibody nivolumab in adult individuals with locally advanced or metastatic solid tumors diagnosed with histology or cytology. Two-part, multicenter, stage 1, open-label, and dose-escalation group expansion study. Study group: Locally advanced or metastatic solid tumor diagnosed by histology or cytology. Dose escalation stage: Individuals with locally advanced or metastatic solid tumors diagnosed with histology or cytology will be registered. Group expansion stage: Registration of 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) Cancer). 2. Research objectives: Main objective: The main objective is to characterize the safety and tolerability of the combination of moglizumab and nivolumab in individuals with locally advanced or metastatic solid tumors and to determine the combination Maximum tolerated dose (MTD) or fixed dose is recommended. Secondary objective: The first objective is to evaluate the combined resistance of moglizumab and nivolumab in individuals with locally advanced or metastatic solid tumors based on the solid tumor response assessment criteria (RECIST version 1.1) Tumor activity. The best overall response rate (BOR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) will be evaluated for antitumor activity. The second key objective was to characterize the pharmacokinetic (PK) properties of moglizumab and nivolumab in the combined course of moglizumab and nivolumab. Another major goal was to assess the immunogenicity of moglizumab and nivolumab. 3. Selection criteria: Including individuals who have voluntarily signed the informed consent form approved by the Institutional Review Board in accordance with the guiding principles of the regulatory body and dated. Written informed consent must be obtained before performing any research-related steps. The inclusion criteria include the following:-Individuals who are 20 years of age or older with informed consent. -Individuals with assessable lesions according to RECIST version 1.1 guidelines. -Individuals with life expectancy> 12 weeks. -Individuals with ECOG performance status (performance status) 0 to 1.Dose escalation phase : The individual may have been histologically or cytologically diagnosed as locally advanced or metastatic solid tumor (excluding primary CNS or hematological malignant disease).Group expansion stage : The individual 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 uncontrollable and apparently current (inter-current) disease. Exclusion criteria further include individuals with known CNS metastases and / or meningeal metastases. Individuals with asymptomatic brain metastases that have been treated are considered stable, and may include individuals who have not received corticosteroids or anticonvulsants for at least 28 days prior to Day 1 of Cycle 1. Exclude anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody or specifically targeted T cell co-stimulation or inspection Individuals who are treated with any other antibody or drug. Exclude individuals who have previously been treated with moglizumab. Individuals with any previous grade 3 or greater immune-related adverse events (irAE) who simultaneously received any previous immunotherapy agent or any undetermined irAE were excluded. Exclude individuals with a history of severe allergic reactions to drugs. Exclude individuals who have received live attenuated vaccinia within 28 days before the first day of the first cycle. Exclude individuals with a history of organ transplantation or allogeneic bone marrow transplantation. Excludes having received chemotherapy, immunotherapy, biological or hormonal therapy, another research drug, radiation or major surgery for cancer treatment (for nitrosourea or Individuals of mitomycin C). Individuals with any undetermined toxicity level 1 or less (as defined by CTCAE version 4.03) based on previous anti-cancer therapies are excluded. Exclude individuals with irreversible toxicity, which may be exacerbated by unreasonable expectations of research products that may be included in the discretion of the principal or associate researcher. Exclude individuals who have received systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first day of the first cycle. However, treatment with local immunosuppressive drugs may be included in the discretion of the principal or associate researcher. individual. Exclude those who require systemic steroids or immunosuppressants with known active autoimmune diseases or syndromes (eg, rheumatoid arthritis, uveitis, systemic lupus erythematosus, Wegener's granulomatosis) Or sarcomatoid). Based on this study, individuals with a history of leukoplakia, baldness, or autoimmune disease or syndrome who do not require systemic steroids or immunosuppressants for 3 years prior to written informed consent will 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, it may include individuals with a history of chronic GI disease who have not required any therapy for 3 years prior to written informed consent. Prior to human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), hepatitis B surface antigen, and hepatitis C virus antibodies with congenital or acquired immunodeficiency and having tuberculosis or testing Individuals with a clinical diagnosis of a known medical history. Exclude individuals with other traumatic malignant tumors within 5 years before the first day of the first cycle. However, individuals with non-invasive malignant tumors that have been cured surgically, such as carcinoma in situ of the cervix, non-melanoma carcinoma of the skin, or carcinoma in situ of the breast duct of the breast, can be registered. Exclude individuals who have registered another clinical study unless the other clinical study is an observational (non-intervention) clinical study or a follow-up phase of an intervention study. Exclude individuals with any condition that would interfere with the evaluation of research products or the interpretation of individual safety or research results in the opinion of the researcher and / or sponsor. 5. Research designDose escalation phase : The dose escalation phase is a parallel 3 + 3 design that will identify the MTD of the combination course or recommend a fixed dose. MTD is defined as a lower dose level of the studied moglizumab and nivolumab, of which more than 2 individuals in the 6 group of individuals undergoing dose-limiting toxicity (DLT); In this case, the recommended fixed dose for the group expansion phase will be determined according to the dose level in the MTD or group 2. During the dose escalation phase, approximately 3 to 18 individuals will be registered (3 to 6 individuals in each of up to 3 groups). Dose levels and schedules are described below. See also Figure 1. [Table 1]table 1 . Moglizumab and nivolumab in the dose-escalation phase Group expansion stage : The group expansion phase will further explore the safety, PK, PD and antitumor activity of each combination in up to 6 tumor types. At this stage, approximately 90 individuals will be registered with locally advanced or metastatic solid tumors, including (but not limited to) NSCLC, SCLC, GC, hepatocellular carcinoma, pancreatic cancer, and esophageal cancer; A tumor type can be considered to be guaranteed by observations at the dose escalation stage to assess other safety.Combination therapy : During the dose escalation phase and the group expansion phase, the individual will receive a combination of moglizumab and nivolumab. Individuals will receive nivolumab 3.0 mg / kg on day 1 and day 15 as an intravenous (IV) infusion lasting at least 1 hour. Individuals will also receive 0.1, 0.3, or 1.0 as an IV infusion over a period of at least 1 hour on Day 1, Day 8, Day 15, and Day 22 of the first cycle and Day 1 and Day 15 of subsequent cycles mg / kg of moglizumab. The combination course will be repeated on the 29th day. On days 1 and 15 of each cycle, after completion of nivolumab administration and 1 hour of observation, moglizumab will be administered. The individual will receive combination therapy until the disease progresses or dies.Safety and efficacy evaluation : All individuals will monitor safety on the 1st, 8th, 15th, and 22nd days of the 1st cycle period according to the event schedule; in subsequent cycles, on the 1st and 15th days every 2 weeks Perform safety assessment. The disease assessment by computed tomography (CT) or magnetic resonance imaging (MRI) will continue every 4 weeks for the first 2 cycles, every 8 weeks for the next 12 cycles, and then every 12 weeks after screening Perform until disease progression or death. Disease progression will be limited according to RECIST version 1.1 guidelines. [Table 2]table 2 . Research drug 6. Efficacy and safety variablesPrimary endpoint safety .Secondary endpoint efficacy : The following efficacy parameters will be used:-Best overall response (BOR) evaluated using RECIST version 1.1. -Time to response (TTR): days from the first day of the first cycle to the first assessment date of CR / PR diagnosis-Duration of response (DOR): from the first assessment date of CR / PR diagnosis to death or Days of PD (regardless of which earlier) date-progression-free survival (PFS): days from day 1 of cycle 1 to death or PD (regardless of earlier) date-total survival (OS): from 1st The number of days from the first day of the cycle to the date of deathStatistical Analysis : The following analysis set will be used for research:-Safety analysis set: includes all individuals who receive at least one dose (even a partial dose) of study drug. Full Analysis Set (FAS): Includes all individuals who receive at least one dose (even a partial dose) of study drug and have at least one available post-dose efficacy data. Adverse events will be listed by body system, severity and treatment proportion. Similar representations on serious adverse events, AEs leading to study discontinuation 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 evaluated. ORR will be calculated as the proportion of individuals who are responders, that is, complete response (CR) and partial response (PR); 95% accurate confidence interval for 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 in this clinical trial, as of September 7, 2016, 4 PRs, 6 SDs, and 3 PDs were observed in 15 patients with hepatocellular carcinoma (HCC). On the other hand, as of September 7, 2016, 1 PR, 5 SD, and 9 PD were observed in 15 patients with pancreatic cancer (PA). 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 cut-off date is August 31, 2017), 4 PRs and 6 SDs 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%) (Figure 3). For patients with HCC and PA, the intermediate progression-free survival period 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 intermediate overall survival period was 343.0, respectively Days (95% CI, 123.0 to inestimable) and 198.0 days (95% CI, 107.0 to 328.0). No dose limiting toxicity was observed during the dose escalation phase. Grade 3 to 4 drug-related adverse events (AE) occurred in 25.0% of the dose escalation stage and group expansion. No level 5 related AEs were seen. The most commonly associated AEs were skin rash (36.5%), skin papules (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).Examples 2 Open-labeled multicenter stage of moglizumab combined with nivolumab in individuals with locally advanced or metastatic solid tumors 1 / 2 the study 1. Research Overview This study is a multicenter anti-CCR4 antibody, such as moglizumab and anti-PD-1 antibody, such as nivolumab combination therapy in adult individuals with locally advanced or metastatic solid tumors A phase 1/2 open-labeled group expansion study of the discovered dose. Phase 1 will identify the MTD of the combination therapy of moglizumab and nivolumab individuals or the highest regimen-defined dose in the absence of excess 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 combined treatment course. Phase 2 will register up to 184 individuals (21 to 36 individuals / tumor type) with locally advanced or metastatic disease of the following tumor types: squamous cell non-small cell lung cancer (NSCLC); no program 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) higher colorectal cancer (CRC) ; Ovarian cancer; Hepatocellular carcinoma (HCC) and pancreatic cancer (PA). 2. Research objectives The main objective is to characterize the safety and tolerability of the combination therapy of moglizumab and nivolumab in individuals with locally advanced or metastatic solid tumors and to determine the combination therapy MTD or the highest regimen limit dose in the absence of MTD. Secondary objective The secondary objective was to evaluate the antitumor activity of the combination of moglizumab and nivolumab based on RECIST version 1.1. Antitumor activity will be assessed as overall response rate (ORR), TTR, DOR, PFS and OS. Exploring objectives Exploring objectives are:-to analyze the serum concentrations of moglizumab and nivolumab when the combination is administered;-to evaluate the immunogenicity of moglizumab and nivolumab when the combination is administered ;-Evaluate the pharmacodynamic (PD) properties of the combination of moglizumab and nivolumab and determine which biomarker may be related to safety and / or antitumor activity;-based on immune-related RECIST (irRECIST ) Version 1.1 evaluates the ORR of the combination of moglizumab and nivolumab. 3. Selection criteria Individuals must meet each of the following selection criteria during the screening phase to be eligible to participate in the study. In addition, individuals participating in stage 2 must meet all inclusion criteria and do not have one of the exclusion criteria for the relevant tumor type. Individuals -18 years old or older;-Individuals with solid tumors diagnosed histologically or cytologically;-Individuals with locally advanced or metastatic solid tumors;-Has developed or has not responded to any standard treatment regimen Individuals who tolerate or reject standard treatment, or do not have appropriate standard therapy for them;-Individuals with guidelines for assessable lesions / RECIST version 1.1;-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ( PS) individual;-If the individual is a woman who may be pregnant or a man who has sexual activity with a woman who may be pregnant, agree to participate in the study period since the signing of the ICF; and for women after the final dose of the research medical product (IMP) 23 weeks or for men who used adequate contraception 31 weeks after the last dose of IMP;-individuals with adequate blood, kidney, liver, and respiratory function limitations;-willing to undergo tumor biopsy during the screening phase, or if the tumor is not Access for biopsy, the archived tumor material must be available for submission to the individual; and-according to the guidelines of the regulatory agency, the voluntary approval of the agency review committee approval Consent and indicate the date of the individual. 4. Exclusion criteria If any of the following exclusion criteria is met during the screening phase, the individual will not be eligible to participate in this study. In addition, individuals participating in stage 2 must meet all inclusion criteria and do not have one of the specific exclusion criteria for the relevant tumor type. -Female individuals who are pregnant or breastfeeding or any individuals who expect to become pregnant or have children during this study period;-Individuals with uncontrollable and obvious current disease. -Individuals with a mental illness / social situation that will limit compliance with research requirements in the researcher ’s perspective;-Individuals with a history of primary CNS tumors or known CNS cancer metastases and / or CNS cancer metastases and / or cancerous meningitis ; Exception: if the CNS cancer metastasis is adequately treated, the individual is eligible and has returned to baseline (except for residual conditions or symptoms related to CNS treatment) at least 4 weeks before registration. In addition, individuals must stop corticosteroids for 4 weeks before registration. -Received prior therapy for cancer before day 1 of cycle 1 or for nitrosourea or mitomycin C within 28 or 42 days, or tamoxifen for 14 days ) Individuals undergoing major surgery;-Individuals who have received radiation therapy or radiosurgery within 14 days before the first day of the first cycle;-Have been pre-treated with anti-PD-1, anti-PD-L1, anti-PD-L2, Individuals treated with anti-CD137 or anti-CTLA-4 antibodies or any other antibodies or drugs that specifically target T cell co-stimulation or checkpoint pathways;-Individuals who have previously been treated with moglizumab;-Patients with a history of allergies or Individuals with allergy to the study drug component;-Individuals who have received live attenuated vaccinia within 28 days before the first day of the first cycle;-Individuals with a history of organ transplantation or allogeneic bone marrow transplantation;-Individuals with previous cancer resistance Any individual with unresolved toxicity of> 1 level of therapy;-Individuals who have used immunosuppressive drugs within 14 days before the first day of the first cycle. -Individuals with known active autoimmune diseases or a history of autoimmune diseases that may affect the function of living organs or require immunosuppressive therapy including systemic corticosteroids;-have toxic epidermal necrolysis or Stevens Johnson syndrome (Stevens) -Individuals with a history of Johnson syndrome;-Individuals with a history of inflammatory bowel disease, Crohn's disease, ulcerative colitis or Wegener's granulomatosis;-Primary or acquired immunodeficiency or human immunodeficiency virus ( HIV) with a known medical history or a known acquired immunodeficiency syndrome; -Except for individuals with hepatocellular carcinoma, for hepatitis B surface antigen (HBVsAg) or hepatitis C RNA tests that indicate acute or chronic infection Individuals who are positive;-Individuals with another active malignant tumor that requires simultaneous intervention;-Individuals receiving any other investigational medicinal agents;-Have the ability to interfere with IMP's assessment or individual safety from the perspective of the researcher and / or sponsor Or an individual with another symptom that explains the results of the study; and-an individual with a history of pneumonia or interstitial lung disease. 5. Study design Phase 1: Dose discovery The Phase 1 dose discovery study has a 3 + 3 design that will identify the MTD or the highest regimen-defined dose in the absence of exceeding the MTD for this combination course. Phase 1 studies will register up to 12 individuals (3 to 6 individuals / group). Plan the initial dose level and optional dose level. The dose level and schedule are described in Table 3. MTD is defined as a dose level that is lower than the dose level of the group in which one third or more individuals experience DLT. The recommended dosage regimen for stage 2 is the MTD or highest dose level tested. [table 3]table 3 . dose level * If> 1 individual experiences DLT at dose level 1, this dose level can be registered. The guidelines for dose discovery are summarized in Figure 4. Stage 2: Expansion group To further characterize the safety, tolerability and anti-tumor activity of the combination, up to 184 individuals (21 to 36 individuals / Tumor type): Squamous cell non-small cell lung cancer (NSCLC); non-squamous cell NSCLC that does not show programmed cell death ligand 1 (PD-L1); squamous cell carcinoma of the head and neck (SCCHN); Non-microsatellite instability (non-MSI) is higher in colorectal cancer (CRC); ovarian cancer; hepatocellular carcinoma (HCC); and pancreatic cancer (PA). The individual will be treated with the highest dose of the combined course of treatment deemed to be tolerable in Phase 1. The monitoring will be used to monitor the safety and tolerability of the dosing course in each expansion group. Therapeutic Research Medicines (IMP) of the individual The following IMPs will be used in this study:-Moglizumab: on the first, eighth, fifteenth and twenty-second day of the first cycle and then on each subsequent 28 On day 1 and day 15 of the daily cycle, 0.3 or 1.0 mg / kg is administered as an intravenous infusion over a period of at least 1 hour. -Nivolumab: 240 mg of nivolumab was administered as an intravenous infusion over 1 and 15 days of each 28-day cycle for at least 30 minutes. Duration of treatment Individuals can receive combination therapy from day 1 of cycle 1 for up to 96 weeks. Individuals who discontinue treatment and have no disease progression and experience disease progression within 12 months of the last dose of IMP can receive an additional IMP for up to 48 weeks, provided that these individuals have not received other systemic therapies for their cancer. Safety and efficacy evaluation The individual's 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 clear disease progression or death. Tumor biopsies will be required during the screening phase (except for individuals with archived tumor tissue) and week 10 (unless the tumor is not accessible for biopsy). 6. Efficacy and safety variables Main endpoints Safety and tolerability will be assessed by evaluating changes in AE and physical test findings, vital sign measurements, 12-lead ECG readings, and clinical laboratory evaluations. The secondary end point will use the following efficacy parameters:-Best overall response (BOR) evaluated using RECIST version 1.1;-Time to response (TTR): From day 1 of cycle 1 to CR / PR diagnosis using RECIST version 1.1 Days of the first assessment date-duration of response (DOR): the number of days from the first assessment date of CR / PR diagnosed using RECIST version 1.1 to the date of 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; -Overall Survival (OS): The statistical method and planning analysis of the number of days from the first day of the first cycle to the date of death Consists of data list and summary display. Demographic and other baseline characteristics information will be summarized for safety analysis and efficacy analysis sets. Adverse events will be listed by body system, severity and treatment proportion. Similar presentations will be provided regarding SAE, AE that caused IMP to stop, and AE that caused death. The 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 evaluated. ORR will be calculated as the proportion of individuals who are responders, that is, complete response (CR) and partial response (PR); 95% accurate confidence interval for ORR will be calculated. The ORR will be used to derive the ORR using both the RECIST version 1.1 and the irRECIST version 1.1 in the expansion group based on the combination therapy. These individuals include all individuals who received the combination therapy on Day 1 of Cycle 1. 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 out of 10 HCC patients had undiagnosed PR, 2 out of 21 ovarian cancer patients were diagnosed with CR and 2 were diagnosed PR; and PR was confirmed in 1 of 29 CRC patients. As of October 23, 2017, 1 undiagnosed PR and 1 confirmed PR among 10 HCC patients; 2 confirmed CR, 2 confirmed PR, and 1 undiagnosed PR among 21 ovarian cancer patients; 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, the combination of anti-CCR4 antibody and anti-PD-1 antibody was found to be effective for certain types of cancer patients including at least HCC, ovarian cancer and CRC patients.Examples 3 Flow Cytometry Analysis of Immune Cell Subgroups in the Peripheral Blood of Individuals Methods In the Phase 1 study described in Example 1, immune cell subsets were measured by FCM. Before treatment, on the first day of the second cycle of treatment or on the end of treatment and on the first day of the third cycle, collect peripheral blood and TIL before and after treatment (from the 15th day of the second cycle of the treatment to the first day of the third cycle Or end of treatment) Separated from the newly prepared tumor biopsy sample. The analysis of the effect Treg was performed by the performance of CD4, Foxp3 and CD45RA according to the method described in Immunity, 2009, 30 (6) 899-911. Use FlowJo version 7.6.5 to analyze the data. At the same time, the percentage of each group in the peripheral blood is corrected by the number of lymphocytes. Results Through preliminary analysis of peripheral blood, the effect of Treg (CD3) on day 1 of cycle 2 (including the end of treatment) and day 1 of cycle 3 was observed⁺ CD4⁺ CD45RA-Foxp3^high ) Has no relation to the best overall response. Compared to those in non-responders, activated T cells (CD3) on day 1 of cycle 3 were also observed in responders⁺ CD4⁺ ICOS⁺ T cells) increased. By preliminary analysis of 11 pairs of TIL before and after treatment, the effect of TIL in TIL (CD3⁺ CD4⁺ CD45RA-Foxp3^high ) With total CD3⁺ The proportion of T cells has a tendency to decrease independently of clinical response after treatment. Compared to Treg, CD3 in TIL⁺ CD8⁺ T cells and total CD3⁺ The proportion of T cells has an overall increasing trend after treatment. CD3 in TIL⁺ CD8⁺ T cells / effector Treg also showed an increasing trend after treatment. In addition, by evaluating the levels of chemokines (MIG and IP-10) in the peripheral blood after treatment, it was found that the increasing trend was not related to the best overall response. Throughout this application, various publications refer to the name and date of the author in parentheses, or refer to the patent number or patent publication number. The disclosures of these publications are hereby incorporated by reference in their entirety in order to more fully describe the present invention as described and claimed herein, such as the current advanced technology known to those skilled in the art . However, the citation of references herein should not be taken as an admission that such references are prior art to the present invention. This application claims the US Provisional Application Serial No. 62 / 428,468 filed on November 30, 2016 and 2017 9 The US Provisional Application Serial No. 62 / 554,486, filed on May 5, is entitled to the entire contents of these two documents and is incorporated herein by reference.No text sequence list 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.4 : 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: artificial sequence description; KW-0761_VL SEQ ID NO. 9: artificial sequence description; KW-0761_H SEQ ID NO. 10: artificial sequence description; KW-0761_L SEQ ID NO. 11: artificial sequence description; Nivolumab_VH CDR1 SEQ ID NO. 12: artificial sequence description; Nivolumab_VH CDR2 SEQ ID NO. 13: artificial sequence description; Nivolumab_VH CDR3 SEQ ID NO. 14: artificial sequence description; 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: artificial sequence description; Nivolumab_L SEQ ID NO.21: artificial sequence description; human CCR4 cd nucleotide and amino acid sequence SEQ ID NO.22: artificial sequence description; 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; synthesis of human PD-1 amino group Acid sequence

[FIG. 1] FIG. 1 shows a schematic diagram showing the schedule of administration of anti-CCR4 antibody (eg, moglizumab) and anti-PD-1 antibody (eg, nivolumab). [FIG. 2] FIG. 2 shows the results of the clinical efficacy of the combination therapy of anti-CCR4 antibody (moglizumab) and anti-PD-1 antibody (nivolumab) in patients with hepatocellular carcinoma. Figure 2 indicates the spider plot of each cancer patient. The vertical axis indicates the "tumor contraction rate (%) of the target area" compared to 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 lesion. [FIG. 3] FIG. 3 shows the results of the clinical efficacy of combination therapy of anti-CCR4 antibody (moglizumab) and anti-PD-1 antibody (nivolumab) in patients with pancreatic cancer. Figure 3 indicates the spider web of each cancer patient. The vertical axis indicates the "tumor contraction rate (%) of the target area" compared to 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 lesion. [Figure 4] Figure 4 shows the criteria for dose discovery and amplification. DLT is an abbreviation for dose-limiting toxicity.

Claims (35)

A method of treating cancer in an individual in need thereof, the method comprising binding an antibody or antigen-binding portion thereof specifically to human CC chemokine receptor 4 (CCR4) ("anti-CCR4 antibody or antigen-binding portion thereof") and An antibody or antigen-binding portion thereof that specifically binds to PD-1 ("anti-PD-1 antibody or antigen-binding portion") is administered to an individual. A method for reducing the size of a tumor in an individual with cancer by at least about 1%, 5%, 10%, 15%, 20%, or 30%, the method comprising combining an anti-CCR4 antibody or antigen-binding portion thereof and anti-PD -1 The antibody or antigen-binding portion thereof is administered to the individual. The method of claim 1 or 2, wherein the anti-CCR4 antibody is a chimeric antibody, a humanized antibody, or a human antibody. The method according to 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 includes: 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 CDR3 of the sequence set forth in SEQ ID NO: 3, and the light chain variable region ("VL") CDR1 including the sequence set forth in SEQ ID NO: 4, including SEQ ID NO: One or more of the VL CDR2 of the sequence set forth in 5 and the VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (ii) an antibody or antigen-binding portion thereof, comprising: comprising SEQ ID NO: 1 VH CDR1 of the sequence set forth in V1, VH CDR2 including the sequence set forth in SEQ ID NO: 2, VH CDR3 containing the sequence set forth in SEQ ID NO: 3, including the sequence set forth in SEQ ID NO: 4 VL CDR1, VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (iii) antibody Or an antigen binding portion thereof, comprising: VH comprising the sequence set forth in SEQ ID NO: 7 and VL comprising the sequence set forth in SEQ ID NO: 8; (iv) antibody comprising: comprising SEQ ID NO: The heavy chain of the sequence set forth in 9 and the light chain containing the sequence set forth in SEQ ID NO: 10; (v) the antibody or antigen-binding portion thereof, which competes with the antibody of (ii); and (vi) Mo Glimizumab (mogamulizumab) or its antigen binding portion. The method according to any one of claims 1 to 4, wherein the anti-PD-1 antibody is a chimeric antibody, a humanized antibody, or a human antibody. The method according to 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 which binds to the same epitope as the antibody Part, which includes: VH CDR1 containing the sequence set forth in SEQ ID NO: 11, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, and VH CDR3 containing the sequence set forth in SEQ ID NO: 13. One or more of, and VL CDR1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and VL containing the sequence set forth in SEQ ID NO: 16. One or more of CDR3; (ii) an antibody or antigen-binding portion thereof, comprising: VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, VH CDR2 comprising the sequence set forth in SEQ ID NO: 12 , VH CDR3 containing the sequence set forth in SEQ ID NO: 13, VL CDR 1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and SEQ ID NO: 15 VL CDR3 of the sequence set forth in NO: 16; (iii) antibody or antigen-binding portion thereof, comprising: comprising SEQ ID VH of the sequence set forth in NO: 17 and VL comprising the sequence set forth in SEQ ID NO: 18; (iv) Antibody, comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising SEQ The light chain of the sequence described in ID NO: 20; (v) antibody, which cross-competes with the antibody of (ii); (vi) nivolumab (nivolumab) or its antigen-binding portion; (vii) Pelican Mab (pembrolizumab) or its antigen binding portion; and (viii) MEDI0608 or its antigen binding portion. The method according to 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, and 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 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 myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic or acute leukemia of chronic lymphocytic leukemia, children's solid state Tumor, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, angiogenic tumor, gel Blastoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T cell lymphoma, including asbestos induced Their environment induces cancer, and any combination thereof. 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. 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. 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. The method of any one of claims 1 to 6, wherein the cancer is melanoma. The method of any one of claims 1 to 11, wherein the cancer is progressive, metastatic, and / or unresectable cancer. 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. 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. The method according to 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. 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 as a flat dose. 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. The method according to any one of claims 1 to 17, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at 2.0 mg / kg every two weeks. The method according to any one of claims 1 to 17, wherein the anti-PD-1 antibody or antigen-binding portion thereof is once every two weeks at 3.0 mg / kg, or once every two weeks at a flat dose of at least 240 mg / body Cast. 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. 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. The method of any one of claims 1 to 21, wherein the 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) decreased PD-1 positive T cells, and (v) increased tumor infiltrating lymphocytes (TIL). The method of any one of claims 1 to 22, further comprising administering an additional anticancer agent. The method of claim 23, wherein one or more tumors in the cancer exhibit PD-L1, PD-L2, CCR4, or any combination thereof. A method of treating one or more cancers, the cancer (s) is selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method includes one week after the first administration Mogizumab at 0.1, 0.3, 0.5, 0.75, 1.0, 2.0 or 3.0 mg / kg and nivolumab at 2.0 or 3.0 mg / kg once every two or three weeks, or 240 mg / body of nivolumab is administered as a flat-dose combination to individuals with the cancer (s). A method of treating one or more cancers, the cancer (s) is selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method includes one week after the first administration Mograizumab at 0.1, 0.3, 0.5, 0.75, 1.0, 2.0 or 3.0 mg / kg for four weeks at a time, and nivolumab at 2.0 mg / kg once every two weeks, or at 240 mg / body Nivolumab is administered as an even-dose combination to individuals with the cancer (s). A method of treating one or more cancers, the cancer (s) is selected from the group consisting of non-small cell lung cancer, esophageal cancer, liver cancer, gastric cancer, and any combination thereof, the method includes one week after the first administration Mograizumab at 0.1, 0.3, 0.5, 0.75, 1.0, 2.0 or 3.0 mg / kg once every four weeks, and nivolumab at 3.0 mg / kg once every two weeks, or at 240 mg / body Nivolumab is administered as an even-dose combination to individuals with the cancer (s). A kit for treating individuals suffering from cancer, the kit comprising: (a) an antibody or antigen-binding portion thereof that specifically binds to human PD-1 at a dose in the range of 0.1 to 10 mg / kg body weight ( "Anti-PD-1 antibody or antigen-binding portion"); (b) Antibodies or antigen-binding portions that specifically bind to human CCR4 at a dose in the range of 0.1 to 10 mg / kg body weight; ("Anti-CCR4 antibody Or an antigen-binding portion thereof "); and (c) instructions for using the anti-PD-1 antibody and the anti-CCR4 antibody in the method according to any one of claims 1 to 27. The kit as used 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 that binds to the same epitope as the antibody, which includes: comprising The heavy chain variable region ("VH") complementarity determining region (CDR) of the sequence set forth in SEQ ID NO: 1, the VH CDR2 containing the sequence set forth in SEQ ID NO: 2 and the SEQ ID NO: 3 One or more of the VH CDR3 of the sequence set forth in, and the light chain variable region ("VL") CDR1 containing the sequence set forth in SEQ ID NO: 4, including the set forth in SEQ ID NO: 5 One or more of the VL CDR2 of the sequence and the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) the antibody or antigen-binding portion thereof, comprising: comprising the sequence set forth in SEQ ID NO: 1 VH CDR1, VH CDR2 containing the sequence set forth in SEQ ID NO: 2, VH CDR3 containing the sequence set forth in SEQ ID NO: 3, VL CDR1 containing the sequence set forth in SEQ ID NO: 4, including VL CDR2 of the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (iii) Antibody or antigen binding Part, which comprises: VH comprising the sequence set forth in SEQ ID NO: 7 and VL comprising the sequence set forth in SEQ ID NO: 8; (iv) Antibody, comprising: contains the set forth in SEQ ID NO: 9 The heavy chain of the sequence and the light chain comprising the sequence set forth in SEQ ID NO: 10; (v) the antibody or antigen-binding portion thereof, which cross-competes with the antibody of (ii); and (vi) mogliflozin Anti-or antigen-binding portion. A kit as used 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 contains: one of VH CDR1 containing the sequence set forth in SEQ ID NO: 11, one of VH CDR2 containing the sequence set forth in SEQ ID NO: 12, and VH CDR3 containing the sequence set forth in SEQ ID NO: 13 Or more, and in VL CDR1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and VL CDR3 containing the sequence set forth in SEQ ID NO: 16. One or more of; (ii) an antibody or antigen-binding portion thereof, comprising: 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 VH CDR3 of the sequence set forth in SEQ ID NO: 13, VL CDR 1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and SEQ ID NO: VL CDR3 of the sequence set forth in 16; (iii) antibody or antigen-binding portion thereof, comprising: comprising SEQ ID NO: VH of the sequence set forth in 17 and VL comprising the sequence set forth in SEQ ID NO: 18; (iv) Antibodies comprising: a heavy chain comprising the sequence set forth in SEQ ID NO: 19 and comprising SEQ ID NO : Light chain of the sequence described in 20; (v) antibody, cross-competing with the antibody of (ii); (vi) nivolumab or its antigen-binding portion; (vii) peclizumab or its antigen A binding portion; and (viii) MEDI0608 or an antigen binding portion thereof. A pharmaceutical composition for treating cancer, comprising (a) an antibody or antigen-binding portion that specifically binds to human PD-1 ("anti-PD-1 antibody or antigen-binding portion thereof") and a specific binding to human CCR4 antibody or antigen binding portion thereof (anti-CCR4 antibody or antigen binding portion thereof). The pharmaceutical composition as used 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, which includes: 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 a SEQ ID NO: One or more of the VH CDR3 of the sequence set forth in 3, and the light chain variable region ("VL") CDR1 containing the sequence set forth in SEQ ID NO: 4, including the set forth in SEQ ID NO: 5 VL CDR2 of the sequence and one or more of the VL CDR3 comprising the sequence set forth in SEQ ID NO: 6; (ii) the antibody or antigen-binding portion thereof, comprising: comprising the set forth in SEQ ID NO: 1 VH CDR1 of the sequence, VH CDR2 of the sequence set forth in SEQ ID NO: 2, VH CDR3 of the sequence set forth in SEQ ID NO: 3, VL CDR1 of the sequence set forth in SEQ ID NO: 4 VL CDR2 containing the sequence set forth in SEQ ID NO: 5, and VL CDR3 containing the sequence set forth in SEQ ID NO: 6; (iii) antibody or anti- The original binding portion, comprising: VH comprising the sequence set forth in SEQ ID NO: 7 and VL comprising the sequence set forth in SEQ ID NO: 8; (iv) Antibody, comprising: containing SEQ ID NO: 9 The heavy chain of the sequence set forth and the light chain comprising the sequence set forth in SEQ ID NO: 10; (v) the antibody or antigen-binding portion thereof, cross-compete with the antibody of (ii); and (vi) Mogley Zumab or its antigen-binding portion. The pharmaceutical composition for use according to 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 Which includes: VH CDR1 containing the sequence set forth in SEQ ID NO: 11, VH CDR2 containing the sequence set forth in SEQ ID NO: 12, and VH CDR3 containing the sequence set forth in SEQ ID NO: 13 One or more, and VL CDR1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and VL CDR3 containing the sequence set forth in SEQ ID NO: 16. One or more of; (ii) an antibody or antigen-binding portion thereof, comprising: VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, VH CDR3 containing the sequence set forth in SEQ ID NO: 13, VL CDR 1 containing the sequence set forth in SEQ ID NO: 14, VL CDR2 containing the sequence set forth in SEQ ID NO: 15, and SEQ ID NO : VL CDR3 of the sequence described in 16; (iii) antibody or antigen-binding portion thereof, comprising: comprising S VH of the sequence set forth in EQ ID NO: 17 and VL containing the sequence set forth in SEQ ID NO: 18; (iv) antibodies, which include: heavy chains containing 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 that cross-competes with the antibody of (ii); (vi) nivolumab or its antigen-binding portion; (vii ) Palivizumab or its antigen binding portion; and (viii) MEDI0608 or its antigen binding portion. The pharmaceutical composition used in any one of claims 31 to 33, which is used to treat cancer. The pharmaceutical composition as claimed in claim 34, wherein the cancer is selected from the group consisting of melanoma cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, kidney 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 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 tumors of children, lymphocytic lymphoma , Bladder cancer, kidney or urinary tract cancer, carcinoma of the renal pelvis, central nervous system (CNS) tumor, primary CNS lymphoma, angiogenic tumor, glioblastoma , Spinal axis tumors, brainstem gliomas, pituitary adenoma, mesothelioma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, including asbestos-induced environment-induced cancer And any combination thereof.