WO2018101448A1 - Méthode de traitement du cancer à l'aide d'un anticorps anti-ccr4 et d'un anticorps anti-pd-1 - Google Patents

Méthode de traitement du cancer à l'aide d'un anticorps anti-ccr4 et d'un anticorps anti-pd-1 Download PDF

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WO2018101448A1
WO2018101448A1 PCT/JP2017/043200 JP2017043200W WO2018101448A1 WO 2018101448 A1 WO2018101448 A1 WO 2018101448A1 JP 2017043200 W JP2017043200 W JP 2017043200W WO 2018101448 A1 WO2018101448 A1 WO 2018101448A1
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antibody
seq
cancer
set forth
sequence set
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PCT/JP2017/043200
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English (en)
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Tetsuyoshi KAWAKAMI
Yukiya OHYAMA
Kazuto GEMMOTO
Alan J. Korman
Nils Lonberg
Shinta Cheng
Steven D. Averbuch
Margaret Marshall
Denis Healy
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Kyowa Hakko Kirin Co., Ltd.
Ono Pharmaceutical Co., Ltd.
Bristol Myers-Squibb, Company
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Publication of WO2018101448A1 publication Critical patent/WO2018101448A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates to a method of treating a cancer in a subject in need thereof comprising administering an anti-CCR4 antibody and an anti-PD-1 antibody to the subject.
  • the invention further provides a pharmaceutical composition comprising an anti-CCR4 antibody for use in treating a cancer in a subject in need thereof in combination with an anti-PD-1 antibody.
  • CCR4 CC-chemokine receptor 4
  • TARC thymus and activation-regulated chemokine
  • MDC macrophage-derived chemokine
  • CCR4 expresses on Th2 cells, CD4 + regulatory T cell (Treg) and T lymphoma cells, such as adult T cell leukemia-lymphoma (ATL), cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL).
  • immune checkpoint molecules such as programmed cell death-1 (PDCD1, PD-1), programmed cell death ligand 1 (PD-L1), cytotoxic T lymphocyte associated 4 (CTLA-4), and killer inhibitory receptor (KIR), became available for triggering an anti-tumor immune response in some cancers.
  • PDCD1, PD-1 programmed cell death-1
  • PD-L1 programmed cell death ligand 1
  • CLA-4 cytotoxic T lymphocyte associated 4
  • KIR killer inhibitory receptor
  • PD-1 (CD279) is a 55 kDa type I transmembrane protein that belongs to the immunoglobulin family and is reportedly expressed on immune cells, including particularly, activated T cells, regulatory T cells (Treg), B cells and NK cells.
  • PD-L1 B7 homolog-1; B7-H1, CD274
  • B7-H1, CD274 B7-H1, CD274
  • PD-L2 B7-DC or CD273
  • CTLA-4 is specifically expressed on activated CD4 + T cell, has a similar structure to CD28 and regulates T cell activity through binding CD80/CD86 (B7-1, B7-2) on antigen presenting cells (APCs) such as dendritic cells.
  • CD80/CD86 B7-1, B7-2
  • APCs antigen presenting cells
  • Therapeutic antibodies for the treatment of various cancers have been approved and/or have been developed for a number of immune checkpoint molecules.
  • An anti-PD-1 human IgG4 antibody, nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538), which blocks PD-1 activity (Patent Literature 1 and Non Patent Literature 3), has been approved for treatment of patients with unresectable or metastatic melanoma and diseases progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor in the US. It has also been approved in the U.S. for the treatment of metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.
  • OPDIVO (registered trademark) is approved to be administrated at 3 mg/kg, once every two weeks.
  • Opdivo registered trademark
  • pembrolizumab (formerly designated lambrolizumab, or MK-3475) has been approved for treatment of patients with unresectable or metastatic melanoma and diseases progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor in the US.
  • checkpoint inhibitor antibodies that are in development include anti-CTLA-4 antibodies (e.g., Ipilimumab, which is an active ingredient of YERVOY (registered trademark) and Tremelimumab), anti-PD-1 antibodies (e.g., MEDI0608), anti-PD-L1 antibodies (e.g., MEDI4736, MPDL3280A, and MSB0010718C) and PD-L2Ig (e.g., AMP-224).
  • anti-CTLA-4 antibodies e.g., Ipilimumab, which is an active ingredient of YERVOY (registered trademark) and Tremelimumab
  • anti-PD-1 antibodies e.g., MEDI0608
  • anti-PD-L1 antibodies e.g., MEDI4736, MPDL3280A, and MSB0010718C
  • PD-L2Ig e.g., AMP-224
  • the present invention provides a method of treating a cancer in a subject in need thereof comprising administering an anti-PD-1 antibody in combination with an anti-CCR4 antibody to the subject.
  • an invention includes a method of treating a cancer in a subject comprising administering an antibody or antigen-binding portion thereof which specifically binds to human CC-chemokine receptor 4 (CCR4) ("anti-CCR4 antibody or antigen binding portion thereof") and an antibody or antigen-binding portion thereof which specifically binds to human programmed death-1 (PD-1) ("anti-PD-1 antibody or antigen-binding portion thereof”) to the subject.
  • CCR4 CC-chemokine receptor 4
  • PD-1 antibody or antigen-binding portion thereof human programmed death-1
  • an invention includes a method of reducing a tumor size by at least about 1%, 5%, 10%, 15%, 20%, or 30% in a subject having a cancer comprising administering an anti-CCR4 antibody or antigen-binding portion thereof and an anti-PD-1 antibody or antigen-binding portion thereof to the subject.
  • the anti-CCR4 antibody is a chimeric antibody, a human antibody, or a humanized antibody.
  • the anti-CCR4 antibody or antigen-binding portion thereof for the method is selected from the group consisting of: (i) an antibody or antigen-binding portion thereof that binds to the same epitope as an antibody comprising one or more of a heavy chain variable region ("VH") complementarity determining region (CDR) 1 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 VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, and one or more of a light chain variable region (“VL”) CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO:6; (ii) an antibody or antigen-bind
  • VH heavy chain variable
  • the anti-PD-1 antibody is a chimeric antibody, a humanized antibody, or a human antibody.
  • 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 an antibody comprising one or more of a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, and one or more of a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO:16; (ii) an antibody or antigen-binding portion thereof comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO:
  • the cancer that is treatable by the methods of the invention is selected from the group consisting of melanoma cancer, hepatic cancer, hepatocellular cell carcinoma, bile duct carcinoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, cervical cancer, endometrial cancer, rectal cancer, cancer of the anal region, gastric cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of
  • the cancer is lung cancer, gastrointestinal cancer, or both.
  • the lung cancer is non-small cell lung cancer or small cell lung cancer
  • gastrointestinal cancer is esophageal cancer or gastric cancer
  • T-cell lymphoma is ATL, CTCL or PTCL.
  • the non-small cell lung cancer is non-squamous non-small cell lung cancer or squamous non-small cell lung cancer.
  • the cancer is melanoma.
  • the cancer is progressive, metastatic and/or unresectable cancer.
  • the anti-CCR4 antibody is administered at least about 0.1, 0.3, 0.5, 0.75, 1.0, 2.0, or 3.0 mg/kg. In certain embodiments, the anti-CCR4 antibody or antigen-binding portion thereof is administered at least once a week, at least once every two weeks or at least once a week followed by once every two weeks. In a particular embodiment, the anti-CCR4 antibody or antigen-binding portion thereof is administered once a week for four weeks after the first dose followed by once every two weeks.
  • the anti-PD-1 antibody or antigen-binding portion thereof is administered at least about 1 mg/kg, 2.0 mg/kg, 3.0 mg/kg, or 5 mg/kg, or at least about 240 mg/body as a flat dose. In other embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at least once every one week, at least once every two weeks, or at least once every three weeks. In still other embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at 2.0 mg/kg once every two weeks or at 3.0 mg/kg once every two weeks, or at 240 mg/body as a flat dose once every two weeks.
  • the anti-CCR4 antibody or antigen-binding portion thereof and the anti-PD-1 antibody or antigen-binding portion thereof are administered to the subject concurrently or sequentially. In other embodiments, the anti-CCR4 antibody or antigen-binding portion thereof is administered prior to or after the anti-PD-1 antibody. In other embodiments, the administration results in one or more of the following effects: (i) decreased CCR4 + T cells, (ii) decreased regulatory T cells, (iii) increased PD-L1 expression in tumor tissue, (iv) decreased PD-1 positive T cells, (v) increased tumor infiltrating lymphocytes (TIL) and (vi) any combination thereof.
  • the invention also includes a kit for use in treating a subject afflicted with a cancer comprising: (a) a dosage ranging from 0.1 to 10 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to the PD-1 ("an anti-PD-1 antibody or antigen-binding portion thereof "); (b) a dosage ranging from 0.1 to 10 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to the CCR4; ("an anti-CCR4 antibody or antigen-binding portion thereof "); and (c) instructions for using the anti-PD-1 antibody and the anti-CCR4 antibody in the methods.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising (a) an antibody or an antigen-binding portion thereof that specifically binds to PD-1 and inhibits PD-1 activity ("an anti-PD-1 antibody or antigen-binding portion thereof”) and an antibody or an antigen-binding portion thereof that specifically binds to and inhibits CCR4 ("an anti-CCR4 antibody or antigen-binding portion thereof”) for use in treating cancer.
  • FIG. 1 shows a schematic showing the administration schedule of an anti-CCR4 antibody (e.g., mogamulizumab) and an anti-PD-1 antibody (e.g., nivolumab).
  • FIG. 2 shows a result of clinical efficacy on combination therapy of anti-CCR4 antibody, mogamulizumab and anti-PD-1 antibody, nivolumab in hepatocellular cell carcinoma patients.
  • FIG. 2 indicates spider plot for each cancer patient.
  • the longitudinal axis indicates "tumor shrinkage rate of target region (%)" compared to pre-combination therapy and the horizontal axis indicates weeks after treatment initiation.
  • the "+" marker represents first occurrence of new lesion.
  • FIG. 1 shows a schematic showing the administration schedule of an anti-CCR4 antibody (e.g., mogamulizumab) and an anti-PD-1 antibody (e.g., nivolumab).
  • FIG. 2 shows a result of clinical efficacy on combination
  • FIG. 3 shows a result of clinical efficacy on combination therapy of anti-CCR4 antibody, mogamulizumab and anti-PD-1 antibody, nivolumab in pancreatic adenocarcinoma patients.
  • FIG. 3 indicates spider plot for each cancer patient.
  • the longitudinal axis indicates "tumor shrinkage rate of target region (%)" compared to pre-combination therapy and the horizontal axis indicates weeks after treatment initiation.
  • the "+" marker represents first occurrence of new lesion.
  • FIG. 4 shows a criteria for dose finding and expansion.
  • DLT is an abbreviation of dose-limiting toxicity.
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Routes of administration for the anti-PD-1 antibody include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
  • an agent is administered via a non-parenteral route, in certain embodiments, orally.
  • non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • an "adverse event” as used herein is any unfavorable and generally unintended or undesirable sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a medical treatment.
  • an adverse event can be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to a treatment.
  • a medical treatment can have one or more associated AEs and each AE can have the same or different level of severity.
  • Reference to methods capable of "altering adverse events” means a treatment regime that decreases the incidence and/or severity of one or more AEs.
  • an “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to PD-1 is substantially free of antibodies that bind specifically to antigens other than PD-1).
  • An isolated antibody that binds specifically to PD-1 can, however, have cross-reactivity to other antigens, such as PD-1 molecules from different species.
  • an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • an “anti-antigen” antibody refers to an antibody that binds specifically to the antigen.
  • an anti-PD-1 antibody binds specifically to PD-1 and an anti-CTLA-4 antibody binds specifically to CTLA-4.
  • an “antigen-binding portion" of an antibody refers to one or more fragments of an antibody that retain the ability to bind specifically to the antigen bound by the whole antibody.
  • a “cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth divide and grow results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. Following metastasis, the distal tumors can be said to be "derived from” the original, pre-metastasis tumor. Because the distal tumor is derived from the pre-metastasis tumor, the "derived from” tumor can also comprise the pre-metastasis tumor.
  • immunotherapy refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response.
  • Treatment or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.
  • a “therapeutically effective amount”, “effective amount”, “effective dosage” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • an antibody or combination of antibodies described herein promotes cancer regression in a subject or prevents further tumor growth.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • Promote cancer regression means that administering an effective amount of the drug, alone or in combination with an anti-neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the terms "effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • a therapeutically effective amount of an antibody or combination thereof can inhibit cell growth or tumor growth by at least about 10%, at least about 20%, by at least about 40%, by at least about 60%, or by at least about 80% relative to untreated subjects or, in certain embodiments, relative to patients treated with a standard-of-care therapy.
  • tumor regression can be observed and continue for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Notwithstanding these ultimate measurements of therapeutic effectiveness, evaluation of immunotherapeutic drugs must also make allowance for "immune-related" response patterns.
  • immunotherapeutic response pattern refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes.
  • This response pattern is characterized by a beneficial therapeutic effect that follows an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of traditional chemotherapeutic agents would be classified as disease progression and would be synonymous with drug failure. Accordingly, proper evaluation of immunotherapeutic agents can 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 any amount of the drug that, when administered alone or in combination with an anti-neoplastic agent to a subject at risk of developing a cancer (e.g., a subject having a pre-malignant condition) or of suffering a recurrence of cancer, inhibits the development or recurrence of the cancer.
  • the prophylactically effective amount prevents the development or recurrence of the cancer entirely. “Inhibiting" the development or recurrence of a cancer means either lessening the likelihood of the cancer’s development or recurrence, or preventing the development or recurrence of the cancer entirely.
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • the meaning of "about” or “comprising essentially of” should be assumed to be within an acceptable error range for that particular value or composition.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • CC-chemokine receptor 4" can be interchangeably used herein and mean a polypeptide comprising an amino acid sequence of SEQ ID NO:22 or a functional fragment thereof; a polypeptide comprising an amino acid sequence of GenBank Accession No.
  • NP_005499.1 a polypeptide comprising an amino acid sequence in which one or more amino acid residue(s) is/are deleted, substituted or added in the amino acid sequence represented by SEQ ID NO:22 or NP_005499.1, and having the activity of CCR4; a polypeptide comprising an amino acid sequence having at least about 85% homology, at least about 90% homology, at least about 93% homology, and at least about 95%, about 96%, about 97%, about 98% or about 99%, higher homology, with the amino acid sequence represented by SEQ ID NO:22, and having the activity of CCR4; and related polypeptides including SNP variants and the like.
  • the related polypeptides include SNPs variants, splice variants, fragments, substitution, deletion, and insertion, which retain CCR4 activities and/or functions.
  • CCR4 polypeptide includes a polypeptide encoded by a nucleotide sequence of SEQ ID NO:21 or GenBank Accession No. NM_005508.4.
  • a gene encoding CCR4 includes a nucleotide sequence having deletion(s), substitution(s) or addition(s) of one or more nucleotides in the nucleotide sequence of SEQ ID NO:21 or GenBank Accession No. NM_005508.4.
  • a CCR4 gene encodes a polypeptide having the function of CCR4 and comprises a nucleotide sequence having at least about 60% or higher homology, in some embodiments at least about 80% or higher homology, and in other embodiments at least about 95%, about 96%, about 97%, about 98% or about 99%, higher homology, with the nucleotide sequence of SEQ ID NO:21 or GenBank Accession No. NM_005508.4.
  • a CCR4 gene encodes a polypeptide having the function of CCR4 and comprises a nucleotide sequence which hybridizes with the nucleotide sequence of SEQ ID NO:21 or GenBank Accession No. NM_005508.4 under stringent conditions.
  • CCR4 nucleic acid molecule refers to a polynucleotide encoding a CCR4 polypeptide.
  • An exemplary CCR4 nucleic acid molecule is provided in SEQ ID NO:21 or GenBank Accession No. NM_005508.4.
  • nucleotide sequence of the gene encoding a protein of a eukaryote genetic polymorphism is often recognized.
  • the CCR4 gene used in the present invention also includes a gene in which small modification is generated in the nucleotide sequence by such polymorphism as the gene used in the present invention.
  • CCR4 is a G protein coupled seven transmembrane receptor cloned as K5-5 from a human immature basophilic cell line KU-812, and can have an amino acid sequence represented by SEQ ID NO:22.
  • the extracellular regions of CCR4 are positions 1-39, positions 99-111, positions 176-206, and positions 268-284 in the amino acid sequence, and the intracellular regions are positions 68-77, positions 134-150, positions 227-242, and positions 309-360 in the amino acid sequence (GenBank Accession No. NP_005499.1).
  • CCR4 can specifically bind to various molecules including, but not limited to, TARC (thymus and activation-regulated chemokine) produced from the thymus cells (J. Biol. Chem., 271, 21514, 1996) and MDC (macrophage-derived chemokine) isolated from macrophage (J. Exp. Med., 185, 1595, 1997), also known as STCP-1(stimulated T cell chemotactic protein-1) (J. Biol. Chem., 272, 25229, 1997).
  • TARC and MDC are also known as CCL17 and CCL22, respectively.
  • One or more functions of CCR4 include its binding ability to TARC and/or MDC.
  • Other functions of CCR4 in the present invention include a function of Ca 2+ influx on CCR4 expressing cells, cell migration of CCR4 expressing cells depending on CCR4 ligands such as CCL17 and/or CCL22.
  • PD-1 Programmed cell death-1
  • PD-1 comprises an amino acid sequence at least about 85%, at least about 90%, at least about 93%, at least about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% sequence identity to NCBI Accession No.
  • PD-1 also includes SNP variants, splice variants, fragments, substitutions, deletions, and insertions, which retain PD-1 activities and/or functions.
  • PD-1 comprises a polypeptide encoded by a nucleotide sequence of SEQ ID NO:23 or GenBank Accession No. NM_005018.2.
  • a PD-1 gene also includes a gene containing a DNA comprising a nucleotide sequence having deletion(s), substitution(s) or addition(s) of one or more nucleotides in the nucleotide sequence of SEQ ID NO:23 or GenBank Accession No. NM_005018.2.
  • PD-1 is encoded by a nucleotide sequence having at least about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the nucleotide sequence of SEQ ID NO:23 or GenBank Accession No. NM_005018.2, and has at least one function of PD-1 (e.g., activating T cells through PD-1 pathway and/or binding to PD-L1 or PD-L2).
  • PD-1 is encoded by a nucleotide sequence which hybridizes with the nucleotide sequence of SEQ ID NO:23 or GenBank Accession No. NM_005018.2 under stringent conditions and has a polypeptide having the function of PD-1.
  • PD-1 nucleic acid molecule refers to a polynucleotide encoding a PD-1 polypeptide.
  • An exemplary PD-1 nucleic acid molecule is provided in SEQ ID NO:23 or GenBank Accession No. NM_005018.2.
  • nucleotide sequence of the gene encoding a protein of a eukaryote genetic polymorphism is often recognized.
  • the PD-1 gene used in the present invention also includes a gene in which small modification is generated in the nucleotide sequence by such polymorphism as the gene used in the present invention.
  • PD-1 was cloned as 55 kDa of type I, membrane protein that belongs to an 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 (Immunoreceptor Tyrosine-based Switch Motif) and ITIM motifs (Immunoreceptor Tyrosine-based Inhibitory Motif) that may be a repression domain to immune reaction. Since PD-1-deficient mice develop lupus-like autoimmune disease such as glomerular nephritis and arthritis and a disease like dilated cardiomyopathy, PD-1 seems to be related to negative regulator of immune responses.
  • PD-L1 is known as a type I transmembrane protein as ligand for PD-1 and inhibitory ligand of T cell proliferation through binding to PD-1. It has immunoglobulin V like domain, C-like domain and cytoplasmic tail. PD-L1 is known to be expressed on antigen presenting cells, and some cancer cells.
  • an anti-CCR4 antibody refers to an antibody that selectively binds to a human CCR4 polypeptide.
  • Exemplary anti-CCR4 antibodies are provided herein, for example, an anti-CCR4 antibody binding to an epitope consisting of amino acid residues 2 to 29 of SEQ ID NO:22.
  • an anti-CCR4 antibody is mogamulizumab (Poteligeo (registered trademark)).
  • an anti-CCR4 antibody reduces, inhibits, or prevents one or more functions of CCR4.
  • an anti-CCR4 antibody cross-competes with mogamulizumab.
  • an anti-PD-1 antibody refers to an antibody that selectively binds to a PD-1 polypeptide. Exemplary anti-PD-1 antibodies are described for example in U.S. Patent No. 8,008,449, which is herein incorporated by reference.
  • an anti-PD-1 antibody is nivolumab (OPDIVO (registered trademark)).
  • OPDIVO registered trademark
  • an anti-PD-1 antibody reduces, inhibits, or prevents one or more functions of PD-1.
  • an anti-PD1 antibody cross-competes with nivolumab.
  • antibody refers to an immunoglobulin or a fragment or a derivative thereof, and encompasses any polypeptide comprising an antigen-binding site, regardless of whether it is produced in vitro or in vivo.
  • the term includes, but is not limited to, polyclonal, monoclonal, monospecific, polyspecific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, and grafted antibodies.
  • antibody also includes antibody fragments (or antigen-binding fragments) such as Fab, F(ab′) 2 , Fv, single chain Fv (scFv), Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to bind CCR4, or PD-1 specifically.
  • the antibody molecule is composed of polypeptides, called a heavy chain (hereinafter, referred to as H chain) and a light chain (hereinafter, referred to as L chain).
  • H chain is constituted by regions of an H chain variable region (also referred to as V H or VH) and an H chain constant region (also referred to as CH) from its N-terminus
  • L chain is constituted by regions of an L chain variable region (also referred to as V L or VL) and an L chain constant region (also referred to as CL) from its N-terminus.
  • CH alpha, delta, epsilon, gamma and mu chains are known for each subclass.
  • CL lambda and kappa are known.
  • IgG antibodies have two heavy chains and two light chains, and form two antigen binding sites constituted of a VH and a VL. Therefore an IgG antibody is a bivalent antibody.
  • antibody fragment refers to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen. For instance, where an antigen is large, the antigen-binding domain may only bind to a part of the antigen. A portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as “epitope” or "antigenic determinant.”
  • An antigen-binding domain typically comprises an antibody light chain variable region (V L or VL) and an antibody heavy chain variable region (V H or VH). However, it does not necessarily have to comprise both. For example, a Fd antibody fragment consists only of a V H domain, but still retains some antigen-binding function of the intact antibody.
  • CDR complementarity determining region
  • Antigen-binding fragments of an antibody can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies.
  • Antigen-binding fragments include Fab, Fab', F(ab') 2 , Fv, and single-chain antibodies.
  • An antibody other than a "bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallize.
  • Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites.
  • Fab when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CH1 domain of the heavy chain.
  • mAb refers to monoclonal antibody.
  • Antibodies usable in the present invention comprise without limitation whole native antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and unconventional antibodies.
  • a domain refers to a functional structural unit constituting each polypeptide of the antibody molecules.
  • Fc usable in the present invention refers to a partial sequence and a partial structure of H chain constant region composed of a hinge domain, CH2 domain and CH3 domain.
  • CH is composed of a CH1 domain, a hinge domain, a CH2 domain and a CH3 domain from the N-terminus.
  • the CH1 domain, hinge domain, CH2 domain, CH3 domain, and Fc region in the present invention can be identified by the number of amino acid residues from the N-terminus according to the EU index [Kabat et al., Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)].
  • a number of amino acid residues are noted by the EU index by Kabat et al and in the present invention, a previous number of amino acid residue indicates original or parent residues of a polypeptide and an after number of amino acid residue indicates a replaced or substituted amino acid residues of the polypeptide.
  • 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
  • CH2 is identified by the amino acid sequence from positions 231 to 340 of the EU index
  • CH3 is identified by the amino acid sequence from positions 341 to 447 of the EU index, respectively.
  • recombinant antibody refers to antibodies produced by a recombination technology, as well as monoclonal antibodies obtained from hybridomas.
  • the recombinant antibodies include a chimeric antibody that is prepared by binding a human antibody constant region to a non-human antibody variable region, a humanized antibody (or CDR-grafted antibody) that is prepared by CDRs of H chain and L chain of a non-human antibody variable region into a framework region (hereinafter, abbreviated to FR) of a human antibody variable region, and a human antibody that is prepared by using a human antibody-producing animal, or the like.
  • FR framework region
  • chimeric antibody refers to an antibody in which the amino acid sequence of VH and VL of a non-human animal antibody are grafted into the corresponding VH and VL of a human antibody.
  • the chimeric antibody can be produced by obtaining cDNAs encoding VH and VL from a monoclonal antibody-producing hybridoma derived from a non-human animal, inserting them into an expression vector for animal cell having DNA encoding CH and CL of human antibody so as to construct a human chimeric antibody expression vector, and then introducing the vector into an animal cell so as to express the antibody.
  • a humanized antibody refers to an antibody in which the amino acid sequence of CDRs of VH and VL of a non-human animal antibody are grafted into the corresponding CDRs of VH and VL of a human antibody.
  • the region other than CDRs of VH and VL is referred to FR.
  • the humanized antibody can be produced in the following manner: (i) cDNA encoding an amino acid sequence of VH which consists of an amino acid sequence of CDR of VH of a non-human antibody and an amino acid sequence of framework region (FR) of VH of any human antibody, and cDNA encoding an amino acid sequence of VL which consists of an amino acid sequence of CDR of VL of a non-human animal antibody and an amino acid sequence of FR of VL of any human antibody are constructed; (ii) these cDNAs are inserted respectively into expression vectors for animal cells having DNA encoding CH and CL of a human antibody so as to construct a humanized antibody expression vector; and (iii) this vector is introduced into animal cells so as to express the antibody.
  • human antibody refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term "human antibody,” as used herein 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 human antibody also includes antibodies that are obtained from a human antibody phage library, cloning of immortalized human peripheral blood lymphocytes, or human antibody-producing transgenic animals prepared according to the technical advancement in genetic engineering, cell engineering, and development engineering in recent years.
  • the human antibody can be obtained by immunizing a mouse having human immunoglobulin genes (Tomizuka K. et al., Proc Natl Acad Sci USA. 97, 722-7, 2000) with a desired antigen.
  • a human antibody having a desired binding activity using a phage display library, which is formed by antibody gene amplification from human B cells, it is possible to obtain human antibodies without performing immunization (Winter G. et al., Annu Rev Immunol. 12: 433-55. 1994).
  • the human antibody phage library is a library of phages which are caused to express antibody fragments such as Fab and scFv on the surface thereof by insertion of antibody genes prepared from the human B cells into the gene of the phage. From this library, it is possible to recover phages which express antibody fragments having a desired antigen binding activity, by using binding activity with respect to an antigen-immobilized substrate as an index.
  • the antibody fragments can be also converted into a human antibody molecule consisting of two complete H chains and two complete L chains by genetic engineering technique.
  • the human antibody-producing transgenic animal refers to an animal obtained by integration of the human antibody gene into chromosomes of a host animal. Specifically, the human antibody gene is introduced to mouse ES cells. The ES cells are then grafted to the early embryo of another mouse. A human antibody-producing transgenic animal can be produced from the embryo.
  • a human antibody-producing hybridoma is obtained by a normal hybridoma preparation method. After culturing the hybridoma obtained from a mammal other than a human being, human antibodies can be produced and expressed in the culture.
  • the antibodies useful for the present disclosure can include amino acid sequences of VH and VL of a non-human animal antibody, a humanized antibody, and a human antibody that are produced by any methods known in the art, e.g., hybridomas or antibody-producing cells.
  • the amino acid sequence of CL in antibodies of the present invention can be any one of the amino acid sequence of human antibody or the amino acid sequence of non-human animal antibody.
  • the amino acid sequence of C kappa or C lambda of the human antibody is used.
  • CH in antibodies of the present invention can be any one belonging to immunoglobulin.
  • any of gamma 1(IgG1), gamma 2(IgG2), and gamma 4(IgG4) and their variants can be applicable to the antibody usable in the present invention.
  • effector function refers to a cytotoxic activity induced by an antibody including antibody-dependent cellular cytotoxicity (ADCC) by effector cells such as natural killer (NK) cells, complement-dependent cytotoxicity (CDC), antibody-dependent phagocytosis (ADP), or any combination thereof.
  • ADCC antibody-dependent cellular cytotoxicity
  • NK natural killer
  • CDC complement-dependent cytotoxicity
  • ADP antibody-dependent phagocytosis
  • the effector function of an antibody can be regulated by known methods.
  • ADCC activity can be regulated by controlling the amount of fucose (also referred to as "core fucose”) which is bound to N-acetylglucosamine (GlcNAc) through alpha1-6 bond in a reducing end of a complex type N-glycoside-linked sugar chain which is bound to asparagine (Asn) at position 297 according to the EU index (Kabat et al, Sequence of Proteins of immunological interests, 5th edition, 1991) in an Fc region of an antibody (See WO2005/035586, WO2002/31140, WO00/61739), each of which is incorporated herein by reference in its entirety.
  • ADCC and/or CDC can be regulated, for example, by modifying the amino acid residues of the Fc region of the antibody.
  • the effector activity of the antibody can be increased or reduced by controlling the amount of core fucose in a complex type N-glycoside-linked sugar chain which is bound to the Fc region of the antibody.
  • an antibody which does not have bound fucose can be obtained by expressing the antibody using a CHO cell which is deficient in alpha1,6-fucosyltransferase gene (FUT8).
  • An antibody without fucose has a high ADCC activity.
  • an antibody with fucose can be obtained by expressing an antibody using a host expressing the alpha1,6-fucosyltransferase gene.
  • the antibody with fucose has a lower ADCC activity than the antibody without fucose.
  • an anti-CCR4 antibody used in the present invention is the antibody which has a defucosylated N-glycoside-linked sugar chain bound to the Fc region of the antibody.
  • an anti-CCR4 antibody used in the present invention is an antibody which has a defucosylated N-glycoside linked sugar chain bound to an Fc region of the antibody, in some embodiments, about 50% or more.
  • the defucosylation range of an antibody is about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% or more.
  • the ADCC activity or CDC activity can be increased or decreased. Modification of amino acid residue(s) in the Fc region is performed to increase or decrease the binding activity for Fc gamma R, thereby controlling the ADCC activity. Modification of amino acid residue(s) in the Fc region is performed to increase or decrease binding activity of the complement, thereby controlling the CDC activity.
  • the CDC activity of the antibody can be increased by using the amino acid sequence of the Fc region described in the specification of US2007/0148165.
  • the ADCC activity or CDC activity can be increased or decreased by modifying the amino acid residues 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).
  • the anti PD-1 antibody has no effector function, and solely neutralizes PD-1 function through PD-L1 or PD-L2 binding.
  • anti-PD1 antibodies useful for the invention can be IgG2 or IgG4 subclass that exhibits a decreased or no effector function.
  • anti-PD-1 antibodies for the invention can have an Fc variant with decreased or no effector function.
  • the term “subject” includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows chickens, amphibians, reptiles, etc. Except when noted, the terms “patient” or “subject” are used interchangeably.
  • flat dose or "flat volume” with regard to the composition of the invention means a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent (e.g., the anti-CCR4 antibody and/or anti-PD-1 antibody).
  • the agent e.g., the anti-CCR4 antibody and/or anti-PD-1 antibody.
  • a 60 kg person and a 100 kg person would receive the same dose of the composition (e.g., 240 mg of an anti-PD1 antibody and 80 mg of an anti-CCR4 antibody).
  • weight based dose means that a dose that is administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg/kg of an anti-PD-1 antibody in combination with 1 mg/kg of an anti-CCR4 antibody, one can draw the appropriate amounts of the anti-PD-1 antibody (i.e., 180 mg) and the anti-CCR4 antibody (i.e., 60 mg).
  • CCR4 is a member of the seven transmembrane type G-protein coupled receptor family that functions as a lymphocyte chemokine receptor for two chemokines, TARC (CCL17) and MDC (CCL22).
  • CCR4 is expressed on CD4 + Th2 cells including CD4 + regulatory T cell (Treg).
  • Treg CD4 + regulatory T cell
  • some cancers including adult T cell leukemia-lymphoma (ATL), cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and several solid tumors have been shown to express CCR4.
  • ATL adult T cell leukemia-lymphoma
  • CCL cutaneous T cell lymphoma
  • PTCL peripheral T cell lymphoma
  • Ligand binding by CCR4 induces Ca 2+ influx on CCR4 + cells and induces cell proliferation or cell migration toward ligand secreting tissue.
  • CD4 + Th2 cell is a regulatory cell in humoral immunity.
  • Th2 cell While the Th2 cell promotes the production of antibodies to extraneous antigens by B cells, the Th2 cell also suppresses Th1 cell function. Th2 cells function as a helper T cell through the production of immunosuppressive cytokines, such as interleukin (IL)-10, to thereby suppress cellular immunity.
  • IL interleukin
  • CD4, CD25, CTLA-4, and GITR are known Treg markers (Journal of Allergy and Clinical Immunology, 110: 693-701, 2002). Additionally, FoxP3 (fork-head box protein 3) transcription factor is the master gene involved in the differentiation and functional expression of regulatory T cells (Science, 299: 1057-61, 2003). Furthermore, CCR4 is also expressed on Treg cells (U.S. Publ. No.2006/0034841).
  • Treg cells are one of the T cell population suppressing the activation of autoreactive T cells and is responsible for immune self-tolerance - preventing the immune system from attacking self-tissue in healthy individuals (Immunological Review, 182: the whole volume, 2001). Treg cells suppress immune stimulation through direct and/or indirect pathways such as cell-cell interaction, secretion of inhibitory cytokines, interleukin-10 (IL-10), and transforming growth factor (TGF)-beta, exhaustion of T cell stimulatory cytokine, and IL-2.
  • direct and/or indirect pathways such as cell-cell interaction, secretion of inhibitory cytokines, interleukin-10 (IL-10), and transforming growth factor (TGF)-beta, exhaustion of T cell stimulatory cytokine, and IL-2.
  • the exemplary CCR4 expressed cells targeted in the method provided herein are a cell selected from a CCR4 + immune cell and a CCR4 + tumor cell.
  • the CCR4 + cell is a cell selected from a CCR4 + T cell, a CCR4 + Th2 cell, a CD4 + CD25 + CCR4 + T cell, a CCR4 + Foxp3 + T cell, a CD4 + CD25 + CCR4 + Foxp3 + T cell, a CD4 + CD25 + CCR4 + CD127 low T cell and a CD4 + CD25 + CD45RA - CCR4 + Foxp3 + T cell (known as effector Treg) (Miyara et al, Immunity, 2009; 30: 899-911), and "Treg cell” defined as regulatory T cell.
  • CCR4 + Treg defined by at least one marker set 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 exemplified.
  • T cell activation and inactivation in human body are simultaneously, complicatedly regulated through many membrane proteins.
  • PD-1 was cloned as 55 kDa type I membrane protein (Ishida et al., EMBO J., 1992; 11; 3887-3895).
  • PD-1 is expressed on a number of cell types, activated T cells, regulatory T cell (Treg), activated B cells, and natural killer (NK) cells and it has been known that PD-1 regulates T cell activation through binding to its ligands, PD-L1 and PD-L2.
  • An intracellular domain of PD-1 contains ITSM motifs and ITIM motifs that could be a suppressor domain to immune reaction.
  • PD-1 bound by PD-L1 induces an inhibitory signal in T cell or other PD-1 expressed cells, thereby blocking the activation of T cells or other PD-1 expressed cells, cell proliferation and/or inflammatory cytokine release or placing T cells in anergy.
  • PD-L1 human PD-L1 cDNA, AF233516) and PD-L2 (human PD-L2 NM_025239) are ligands of PD-1.
  • PD-L1 is expressed on a number of cells, including antigen-presenting cells such as activated monocytes and dendritic cells (Freeman et al., Journal of Experimental Medicine (2000), 19; 1027-1034).
  • antigen-presenting cells such as activated monocytes and dendritic cells (Freeman et al., Journal of Experimental Medicine (2000), 19; 1027-1034).
  • PD-L1 and PD-L2 expressions have been confirmed in not only normal cells but also several cancers.
  • 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).
  • IHC immunohistochemistry
  • a mean of "PD-1 positive” indicates at least about 0.1%, at least about 1%, at least about 5%, at least about 10% or at least about 20% or more staining of cells, tissue, body fluid from a human subject.
  • "PD-L1 positive” or “PD-L2 positive” as used herein can be interchangeably used with "PD-L1 and/or PD-L2 expression of at least about 1%.”
  • the PD-L1 and/or PD-L2 expression can be used by any methods known in the art.
  • the PD-L1 and/or PD-L2 expression is measured by an automated in situ hybridization (IHC).
  • IHC automated in situ hybridization
  • a PD-L1 and/or PD-L2 positive tumor can thus have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% of tumor cells expressing PD-L1 as measured by an automated IHC.
  • An anti-CCR4 antibody useful for the invention can specifically bind to human CCR4.
  • an anti-CCR4 antibody can reduce, inhibit, or prevent at least one function of the CCR4 protein.
  • an anti-CCR4 antibody reduces or depletes CCR4 + immune suppressive cells and/or CCR4 + cancer cells.
  • an anti-CCR4 antibody binds to CCR4 expressed on the immune suppressive cell or cancer cell, and reduces or depletes the cell number by an antibody effector function: for example, antibody-dependent cellular cytotoxicity (ADCC) induced by mainly natural killer (NK) cells, complement dependent cytotoxicity (CDC), or antibody dependent phagocytosis (ADP) by phagocytes, such as macrophages or dendritic cells, and/or neutralizing CCR4 ligands.
  • ADCC antibody-dependent cellular cytotoxicity
  • NK natural killer
  • CDC complement dependent cytotoxicity
  • ADP antibody dependent phagocytosis
  • an anti-CCR4 antibody used in the present methods binds to an extracellular region of a CCR4 molecule and expresses ADCC activity.
  • an anti-CCR4 antibody binds to an epitope in amino acids 2-29 of a CCR4 protein (e.g., amino acids 2-29 corresponding to SEQ ID NO: 22) and expresses ADCC activity.
  • an anti-CCR4 antibody binds to an epitope in amino acids 12-29 of a CCR4 protein (e.g., amino acids 12-29 of SEQ ID NO: 22) and expresses ADCC activity.
  • an anti-CCR4 antibody cross-competes with an antibody comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6, for binding to CCR4.
  • an anti-CCR4 antibody or antigen-binding portion thereof used in the present invention binds to the same epitope bound by an antibody comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6 or mogamulizumab.
  • an anti-CCR4 antibody useful for the present invention comprises one or more of a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, and one or more of a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6.
  • an anti-CCR4 antibody comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 6.
  • an anti-CCR4 antibody comprises a VH comprising the sequence set forth in SEQ ID NO:7 and a VL comprising the sequence set forth in SEQ ID NO:8.
  • an anti-CCR4 antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 9 and a light chain comprising the sequence set forth in SEQ ID NO:10.
  • the Fc region of the anti-CCR4 antibody comprises core fucoses not bound to N-acetylglucosamine at position 297 of the Fc region.
  • an anti-CCR4 antibody is mogamulizumab (Poteligeo (registered trademark)).
  • an anti-CCR4 antibody used for the method or composition has a lower fucosylated, defucosylated or afucosylated N-glycoside-linked sugar chain bound to a Fc region of the antibody.
  • the lower fucosylated, defucosylated or afucosylated antibody can have a higher ADCC activity than that of a fucosylated antibody.
  • the anti-CCR4 antibody used in the method or in the composition of the present invention can be produced from cells which have lower or no alpha1,6-fucosyltransferase (FUT8) activity.
  • an anti-CCR4 antibody used in the method or composition of the present invention has essentially free core fucose bound to N-acetylglucosamine through alpha1,6-bond in a N-glycoside-linked sugar chain bound to Asn 297 in the Fc region.
  • the method further comprises identifying CCR4 expression prior to the administration of the anti-CCR4 antibody.
  • CCR4 + T cell or CCR4 + Treg cell population infiltrated in tumor tissues and/or in tissue effluent such as abdominal, pleural, of a patient, reduction/depletion level of CCR4 + T cell or CCR4 + Treg can be monitored before, during and/or after the treatment.
  • CCR4 expression can be also analyzed on a cancer cell itself by any methods known in the art.
  • an antibody or antigen-binding portion thereof that specifically binds to human PD-1 and inhibits hPD-1 activity (“an anti-PD-1 antibodies”) is used for the methods of the invention.
  • an anti-PD-1 antibody or antigen-binding portion thereof blocks, inhibits, prevents, or neutralizes PD-1 expression on cells, or PD-1 related functions of tumor immune response.
  • Anti-PD-1 antibodies used in the method of the present invention bind to PD-1 with high specificity and affinity, block the binding of PD-L1, and/or inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an anti-PD-1 antibody includes an antigen-binding fragment that binds to PD-1 and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and upregulating the immune system.
  • an anti-PD-1 antibody for the present invention comprises one or more of a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13 and one or more of a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 16.
  • an anti-PD-1 antibody comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO: 16.
  • an anti-PD-1 antibody comprises a VH comprising the sequence set forth in SEQ ID NO: 17 and a VL comprising the sequence set forth in SEQ ID NO: 18.
  • an 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.
  • anti-PD-1 antibodies are of IgG2, IgG4 or their variants with a reduced effector activity.
  • the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1 and the anti-PD-1 antibody or antigen-binding fragment thereof binds to the same epitope region of human PD-1 as nivolumab.
  • the anti-PD-1 monoclonal antibody, or antigen-binding fragments thereof is a chimeric, humanized or human monoclonal antibody or a fragment thereof.
  • the monoclonal antibody is a humanized antibody.
  • the antibody is a human antibody.
  • antibodies of an IgG1, IgG2, IgG3 or IgG4 isotype, or their antibody Fc variants can be used for the methods and compositions.
  • an anti-PD-1 antibody, or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype, or any applicable IgG variants.
  • the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen-binding portion thereof contains an S228P mutation which replaces a serine residue in the hinge region with the proline residue normally found at the corresponding position in IgG1 isotype antibody.
  • the antibody comprises a light chain constant region which is a human kappa or lambda constant region.
  • 8,008,449 has been demonstrated to exhibit one or more of the following characteristics: (a) binds to human PD-1 with a K D of 1 x 10 -7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) increases T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increases interferon- ⁇ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates antigen-specific memory responses; (i) stimulates antibody responses; and (j) inhibits tumor cell growth in vivo.
  • MLR Mixed Lymphocyte Reaction
  • Anti-PD-1 antibodies usable in the present invention include monoclonal antibodies that bind specifically to human PD-1 and exhibit at least one, in some embodiments, at least five, of the preceding characteristics.
  • the anti-PD-1 antibody is nivolumab.
  • the anti-PD-1 antibody is pembrolizumab.
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab also known as "OPDIVO (registered trademark)"; formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538
  • OPDIVO registered trademark
  • 5C4, BMS-936558, MDX-1106, or ONO-4538 is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions
  • P-L1 and PD-L2 PD-1 ligands
  • the anti-PD-1 antibody cross-competes with or binds to the same epitope as pembrolizumab.
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab also known as "Keytruda (registered trademark)", lambrolizumab, and MK-3475
  • Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.
  • the anti-PD-1 antibody cross-competes with or binds to the same epitope as MEDI0608 (formerly AMP-514), which is a monoclonal antibody.
  • the anti-PD-1 antibody is MEDI0608.
  • Anti-PD-1 antibodies usable in the disclosed methods or the disclosed composition also include isolated antibodies that bind specifically to human PD-1 and cross-compete for binding to human PD-1 with nivolumab (see, e.g., U.S. Patent No. 8,008,449 and 8,779,105; WO 2013/173223).
  • the ability of antibodies to cross-compete for binding to an antigen can indicate that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region.
  • These cross-competing antibodies are expected to have functional properties very similar to those of nivolumab by virtue of their binding to the same epitope region of PD-1.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
  • the anti-PD-1 antibody is nivolumab (OPDIVO (registered trademark)). In other embodiments, the anti-PD-1 antibody is pembrolizumab (Keytruda (registered trademark)). In other embodiments, the anti-PD-1 antibody is chosen from the human antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in U.S. Patent No. 8,008,449. In still other embodiments, the anti-PD-1 antibody is MEDI0608 (formerly AMP-514) or AMP-224.
  • an anti-PD-1 antibody used in the methods or compositions specifically binds to PD-1 and inhibits PD-1 activity (e.g., binding to PD-L1 and/or PD-L2) are useful for the treatment of cancers such as lung cancer (e.g., non-small cell lung cancer), esophageal cancer or gastric cancers.
  • cancers such as lung cancer (e.g., non-small cell lung cancer), esophageal cancer or gastric cancers.
  • the anti-PD-1 antibody used in the methods or compositions of the present invention includes: (i) an antibody that cross-competes for binding to human PD-1 with the antibody comprising one or more of a heavy chain CDR1 comprising the sequence set forth in SEQ ID NO: 11, a heavy chain CDR2 comprising the sequence set forth in SEQ ID NO: 12, a heavy chain CDR3 comprising the sequence set forth in SEQ ID NO: 13, and one or more of a light chain CDR1 comprising the sequence set forth in SEQ ID NO: 14, a light chain CDR2 comprising the sequence set forth in SEQ ID NO: 15 and a light chain CDR3 comprising the sequence set forth in SEQ ID NO: 16; (ii) an antibody that binds to the same epitope region as that of the antibody comprising a heavy chain CDR1 comprising the sequence set forth in SEQ ID NO: 11, a heavy chain CDR2 comprising the sequence set forth in SEQ ID NO: 12, a heavy chain CDR3 comprising the sequence set forth in SEQ ID NO
  • anti-PD-1 antibodies used in the present invention can exert a neutralizing or blocking activity against PD-1; namely the anti-PD-1 antibody can block PD-1 activity through PD-L1 binding that suppresses T cell proliferation, cytokine release, and any combination thereof.
  • anti-PD-1 antibodies ONO-4538, BMS-936558, nivolumab/OPDIVO are exemplary anti-PD-1 antibodies that specifically bind to PD-1 and block the binding of PD-1 to PD-L1 and PD-L2.
  • Nivolumab can relieve PD-1-mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
  • the present invention is directed to a method of treating a cancer comprising administering a CCR4 antagonist and a PD-1 antagonist wherein the CCR4 antagonist comprises any small or large molecule that binds to, interferes with, or otherwise blocks binding of CCR4 (e.g., an anti-CCR4 antibody) to its ligand, e.g., CCL17 and/or CCL22, and the PD-1 antagonist comprises any small or large molecule that binds to, interferes with, or otherwise blocks binding of PD-1 (e.g., an anti-PD-1 antibody) to its ligand, e.g., PD-L1.
  • CCR4 antagonist comprises any small or large molecule that binds to, interferes with, or otherwise blocks binding of CCR4 (e.g., an anti-CCR4 antibody) to its ligand, e.g., CCL17 and/or CCL22
  • the PD-1 antagonist comprises any small or large molecule that binds to, interferes with, or otherwise blocks binding
  • the present invention includes a method of treating at least one cancer in a subject in need thereof comprising administering an anti-CCR4 antibody in combination with an anti-PD-1 antibody.
  • an administration schedule of the present methods includes an administration schedule for a cancer patient comprising administering an anti-CCR4 antibody in combination with an anti-PD-1 antibody.
  • the anti-CCR4 antibody and the anti-PD-1 antibody are administered at effective amounts to treat the cancer.
  • Also provided herein is a method of reducing a tumor size at least about by 1%, 5%, 10%, 15%, 20%, or 30% in a subject having a cancer comprising administering (i) an anti-CCR4 antibody or antigen-binding portion thereof and (ii) an anti-PD-1 antibody or antigen-binding portion thereof to the subject.
  • the combination methods of the invention increase the anti-tumor efficacy compared to a monotherapy of an anti-CCR4 antibody or an anti-PD-1 antibody.
  • the anti-CCR4 antibody and the anti-PD-1 antibody are administered at effective amounts to reduce the tumor size of the cancer.
  • combination methods of the present invention can bring one or more beneficial effects on anti-tumor immune therapy in cancer patients by reducing or depleting CCR4 + Treg cells that suppress anti-tumor immune responses; thus, an anti-CCR4 antibody cancels the immune suppressing effects of CCR4+ Treg cells and provokes and increases the anti-tumor immune responses.
  • an anti-PD-1 antibody blocks or neutralizes a negative regulator of T cells, PD-1, to cytotoxic T cells which attacks tumor cells in tumor microenvironment; thus an anti-PD-1 antibody cancels the negative signal to T cells and provokes anti-tumor immune responses.
  • Doses of administration of the anti-CCR4 antibody used in the method include any doses from about 0.1 mg/kg to about 10.0 mg/kg per administration.
  • a dose of the 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.
  • Doses of administration of the anti-PD-1 antibody used in the method include any doses from about 1.0 mg/kg to about 10.0 mg/kg per administration.
  • a dose of the 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.
  • a dose of the anti-PD-1 antibody is about 2.0 mg/kg.
  • a dose of the anti-PD-1 antibody is about 3.0 mg/kg.
  • a dose of the anti-PD-1 antibody is about 240 mg/body as a flat dose.
  • a dose of the anti-PD-1 antibody is at least about at least about 100 mg/body, 120 mg/body, 140 mg/body, 160 mg/body, 180 mg/body, 200 mg/body, 220 mg/body, 240 mg/body, 260 mg/body, 280 mg/body, 300 mg/body, 400 mg/body, 420 mg/body, 440 mg/body, 460 mg/body, 480 mg/body, 500 mg/body, 520 mg/body, 540 mg/body, 560 mg/body or 600 mg/body.
  • a dose of the anti-PD-1 antibody is a flat dose of 480 mg/body.
  • Administration cycles of antibodies used in the method include any convenient administration cycle for each antibody.
  • Administration cycle is defined as about once a week (Q1W), once about every two weeks (Q2W), once about every three weeks (Q3W), or once about every four weeks or about once every month (Q4W).
  • An administration cycle of the anti-CCR4 antibody used in the method includes once a week (Q1W) for four weeks to eight weeks, once a week (Q1W) for four weeks and once every two weeks (Q2W).
  • the anti-CCR4 antibody is administrated once every week for four weeks (induction phase) after the first dose followed by once every two weeks (maintenance phase).
  • An administration cycle of the anti-PD-1 antibody used in the method includes once every two, three or four weeks.
  • the method of the present invention includes a method of treating at least one cancer in subjects comprising administering 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, about once a week for four weeks after the first dose and then once about every two weeks, and combined with administering 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/body 200 mg/body, 220 mg/body, 240 mg/body, 260 mg/body, 280 mg/body, 300 mg/body, 400 mg/body, 420 mg/body, 440 mg/body, 460 mg/body, 480 mg/body, 500 mg/body, 520 mg/body, 540 mg/body, 560 mg/body, 580 mg/body, or 600 mg/body as a flat dose of anti-PD
  • the method of the present invention includes treating at least one cancer in subjects comprising administering; (i) 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 an anti-CCR4 antibody, about once a week for four weeks after the first dose and then about once every two weeks, and combined with administering about 2.0 mg/kg of an anti-PD-1 antibody, about once every two weeks; (ii) about 0.1 mg/kg, about 0.3 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, or about 3.0 mg/kg of an anti-CCR4 antibody, about once a week for four weeks after the first dose and then about once every two weeks, and combined with administering about 3.0 mg/kg of an anti-PD-1 antibody 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,
  • the method of the present invention includes a method of treating at least one cancer in subjects comprising administering 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, about once a week for four weeks after the first dose and then about once every two weeks, and combined with administering 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 about once every two weeks, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks, wherein the anti-CCR4 antibody competitively binds to CCR4 with the antibody comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL
  • the method of the present invention includes a method of treating cancer patients comprising administering 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, about once a week for four weeks and then about once every two weeks, and combined with administering 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 about once every two weeks, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks, wherein the anti-CCR4 antibody binds to same epitope bound by the antibody comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth
  • the method of the present invention includes a method of treating cancer patients comprising administering 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, about once a week for four weeks and then about once every two weeks, and combined with administering 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, about once every two weeks, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks, wherein the anti-CCR4 antibody comprises a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, a VL CDR1 comprising the sequence set forth in SEQ ID NO: 4, a VL
  • the method of the present invention includes a method of treating cancer patients comprising administering 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, mogamulizumab, about once a week for four weeks and then about once every two weeks, and combined with administering 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, nivolumab, about once every two weeks or about 480 mg/body as a flat dose of anti-PD-1 antibody, nivolumab, about once every four weeks.
  • the combination of antibodies can be concurrently (or simultaneously) or sequentially administered into cancer patients.
  • concurrently or “simultaneously” means that at least two antibodies are dissolved in a pharmaceutically acceptable aqueous liquid, such as saline or Ringer's alone or mixture thereof, and administered into a patient through an intravenous line, and/or an infusion bag at the same time.
  • sequentialially means that one antibody is administered into cancer patients, followed by the second antibody, which is administered to them after the first antibody administration at a permissible later time.
  • the present disclosure includes a method of treating patients having HCC, wherein the progression free survival (PFS) is at least 100 days, at least 101 days, at least 102 days, at least 103 days, at least 104 days, at least 105 days, at least 106 days, at least 107 days, at least 108 days, at least 109 days, at least 110 days, at least 111 days, at least 112 days, at least 113 days, at least 114 days, at least 115 days, at least 116 days, at least 117 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
  • the PFS of the present combination therapy of an anti-CCR4 antibody and an anti-PD-1 antibody is greater than (at least a week, at least two weeks, at least three weeks, at least four weeks, at least a 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 greater than) the PFS of an anti-CCR4 antibody monotherapy and/or an anti-PD-1 antibody monotherapy.
  • the disclosure provides a method of treating patients having HCC, wherein the overall survival is at least about 200 days, at least about 210 days, at least about 220 days, at least about 230 days, at least about 240 days, at least about 250 days, at least about 260 days, at least about 270 days, at least about 280 days, at least about 290 days, at least about 300 days, at least about 310 days, at least about 320 days, at least about 330 days, at least about 340 days, at least about 350 days, at least about 360 days, at least about 370 days, at least about 380 days, at least about 390 days, or at least about 400 days.
  • the OS of the present methods is greater than (at least about a month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about 11 months, at least about 12 months, at least about 15 months, at least about 20 months, at least about two years, at least about 25 months, at least about 30 months, at least about 35 months, at least about three years, at least about 40 months, at least about 3.5 years, at least about 4 years, at least about 4.5 years, or at least about 5 years greater than) the OS of an anti-CCR4 antibody monotherapy and/or an anti-PD-1 antibody monotherapy.
  • Kit comprising anti-CCR4 antibody and anti-PD-1 antibody for use in treating cancer
  • the present invention also comprises a kit for use in treating a subject afflicted with a cancer comprising: (a) a dosage ranging from about 0.1 mg/kg to about 10 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to the PD-1 and/or inhibits PD-1 activity ("an anti-PD-1 antibody or antigen-binding portion thereof"); (b) a dosage ranging from about 0.1 mg/kg to about 10 mg/kg body weight of an antibody or an antigen-binding portion thereof that specifically binds to the CCR4 and/or inhibits CCR4 activity; ("an anti-CCR4 antibody or antigen-binding portion thereof”); and (c) instructions for using the anti-PD-1 antibody and the anti-CCR4 antibody in any method disclosed herein.
  • Kits typically include a label indicating the intended use of the contents of the kit and instructions for use.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • 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 an antibody comprising one or more of a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 3, and one or more of a VL CDR 1 comprising the sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a VL CDR3 comprising the sequence set forth in SEQ ID NO:6; (ii) an antibody or antigen-binding portion thereof comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 2, a VH CDR3 comprising the
  • 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 an antibody comprising one or more of a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, and a VH CDR3 comprising the sequence set forth in SEQ ID NO: 13, and one or more of a VL CDR1 comprising the sequence set forth in SEQ ID NO: 14, a VL CDR2 comprising the sequence set forth in SEQ ID NO: 15, and a VL CDR3 comprising the sequence set forth in SEQ ID NO:16; (ii) an antibody or antigen-binding portion thereof comprising a VH CDR1 comprising the sequence set forth in SEQ ID NO: 11, a VH CDR2 comprising the sequence set forth in SEQ ID NO: 12, a VH CDR3 comprising the sequence
  • Composition comprising anti-CCR4 antibody and anti-PD-1 antibody for use in treating cancer
  • composition of the present invention comprises an anti-CCR4 antibody and an anti-PD-1 antibody for use in treating cancer.
  • the composition for use in the present invention is prepared to be administered at a dose of 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 an anti-CCR4 antibody, about once weekly for four weeks and then about once every two weeks, in combination 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 as a flat dose at about once every two weeks, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks.
  • the composition is prepared to be administered at a dose of about 2.0 mg/kg or about 3.0 mg/kg or about 240 mg/body as a flat dose of an anti-PD-1 antibody, about once every two weeks, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks in combination with an anti-CCR4 antibody at a dose of 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 at about once weekly for four weeks and then about once every two weeks.
  • the composition is prepared to be administered at a dose of 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 an anti-CCR4 antibody at about once weekly for four weeks and then about once every two weeks in combination 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 as a flat dose at about once every two week, or about 480 mg/body as a flat dose of anti-PD-1 antibody about once every four weeks.
  • the composition is prepared to be administered at a dose of about 2.0 mg/kg or about 3.0 mg/kg or about 240 mg/body as a flat dose of an anti-PD-1 antibody, about once every two weeks in combination with an anti-CCR4 antibody 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 at about once a week for four weeks and then about once every two weeks.
  • the composition for use in the present invention comprises an anti-CCR4 antibody, mogamulizumab, for treating a cancer in a subject at dose of 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 at about once a week for four weeks and then about once every two weeks in combined with 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 as a flat dose at about once every two weeks or about 480 mg/body as a flat dose at about once every four weeks.
  • an anti-PD-1 antibody nivolumab
  • the composition comprises an anti-PD-1 antibody, nivolumab, at a dosage of about 2.0 mg/kg or about 3.0 mg/kg, or about 240 mg/body as a flat dose at about once every two weeks or about 480 mg/body as a flat dose at about once every four weeks in combination with an anti-CCR4 antibody (mogamulizumab) at a dose of 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, or about 3.0 mg/kg at about once a week for four weeks and then about once every two weeks.
  • an anti-CCR4 antibody mogamulizumab
  • the composition for use in the present invention is prepared as flat dosing compositions; for example, a flat dose of an anti-CCR4 antibody can be at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least about 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, at least about 290 mg, or at least about 300mg.
  • a flat dose of an anti-CCR4 antibody can
  • the dosage of an anti-CCR4 antibody ranges from about 1 mg to about 200 mg, from about 2 mg to about 180 mg, from about 3 mg to about 170 mg, or from about 6mg to about 160mg.
  • the composition comprises an anti-CCR4 antibody at a dosage ranging from about 6 mg to about 60 mg, from about 10 mg to about 80 mg, or from about 20 mg to about 70 mg.
  • the dosage of the anti-CCR4 antibody is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, or about 180 mg.
  • the composition for use of the invention is administered as a flat doses, wherein the dosage of the anti-PD-1 antibody is at least about 1mg, at least about 5mg, 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
  • the dosage of the anti-PD-1 antibody ranges from 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 80 mg to 240 mg.
  • the dosage of the anti-PD-1 antibody is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg
  • composition of the present invention includes any composition for use comprising a combination of an anti-CCR4 antibody and an anti-PD-1 antibody with the above described activity as an active ingredient (s), and in one embodiment, it is provided as a drug formulation that is typically prepared by mixing each antibody with one or more pharmaceutically acceptable carriers according to any method well-known in the pharmaceutical fields. Furthermore, the antibodies used in the present invention are also provided as a drug formulation that is typically prepared by mixing it with one or more pharmaceutically acceptable carriers according to any method well-known in the pharmaceutical fields.
  • an antibody of the invention is provided as an aseptic solution, where it is dissolved in an aqueous carrier, such as water, or an aqueous solution of salt, glycine, glucose or human albumin is used. It is also possible to add a pharmaceutically acceptable additive, such as buffer or tonicity agent for making the preparation solution more similar to the physiological conditions and examples thereof include sodium acetate, sodium chloride, sodium lactate, potassium chloride, sodium citrate or the like. It can be also preserved by freeze-drying and, in actual use, it can be used by dissolving in an appropriate solvent.
  • an aqueous carrier such as water, or an aqueous solution of salt, glycine, glucose or human albumin is used.
  • a pharmaceutically acceptable additive such as buffer or tonicity agent for making the preparation solution more similar to the physiological conditions and examples thereof include sodium acetate, sodium chloride, sodium lactate, potassium chloride, sodium citrate or the like. It can be also preserved by freeze-drying and, in actual use, it can be used by dis
  • the most effective route for the treatment is used.
  • oral administration and parenteral administration such as intraoral, tracheobronchial, intrarectal, subcutaneous, intramuscular, intrathecal, and intravenous administrations.
  • Intrathecal or intravenous administration can be used.
  • Capsule, tablet, powder, granule, or the like can be prepared using excipients, such as lactose, glucose, sucrose, mannitol or the like, disintegrating agents, such as starch, sodium alginate or the like, lubricants, such as magnesium stearate, talc or the like, binders, such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin or the like, surfactants, such as fatty acid ester or the like, plasticizers, such as glycerin or the like, as additives.
  • excipients such as lactose, glucose, sucrose, mannitol or the like
  • disintegrating agents such as starch, sodium alginate or the like
  • lubricants such as magnesium stearate, talc or the like
  • binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin or the like
  • surfactants such as fatty acid ester or the like
  • plasticizers such
  • Examples of the preparation suitable for parenteral administration may include an injectable formulation, suppository, air spray or the like.
  • an injectable formulation is prepared using a carrier including a salt solution, a glucose solution or a mixture thereof.
  • Suppository is prepared using a carrier such as cacao butter, hydrogenated fat, carboxylic acid or the like.
  • Air spray is prepared using, for example, a carrier which does not stimulate the antibody itself, and the mouth and the airway mucous membrane of a person to be administered, and which disperses the antibody into fine particles and makes the absorption easy.
  • the carrier include lactose, glycerin or the like.
  • the carrier include lactose, glycerin or the like.
  • aerosol, dry powder, or the like it is possible to prepare aerosol, dry powder, or the like.
  • components exemplified as additives in the oral preparation may be added.
  • a cancer patient in the present invention includes any cancer patient capable of being effectively treated by the method or the composition of the present invention.
  • a cancer patient is at least one cancer patient with a cancer selected from lung cancer, gastrointestinal cancer, gastric cancer (or stomach cancer), colon cancer, colorectal cancer, esophageal cancer, pancreatic adenocarcinoma, hepatic cancer, renal cancer, ovarian cancer, breast cancer, head and neck cancer, skin cancer, melanoma and hematopoietic cancers including leukemia, lymphoma.
  • cancers in the present invention includes any stages of cancer, primary/metastatic cancers, local advanced/metastasis cancers, relapsed/refractory cancers, and surgically resectable/unresectable cancers.
  • a cancer patient has at least one cancer selected from the group consisting of a lung cancer comprising small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, carcinomas with pleomorphic sarcomatoid or sarcomatous elements, cartinoid tumor and carcinomas of salivary-gland type are categorized, gastric cancer, hepatic cancer, hepatocellular cell carcinoma, bile duct carcinoma, breast cancer, renal cancer, melanoma, and any combination thereof.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • squamous cell carcinoma adenocarcinoma
  • large cell carcinoma adenosquamous carcinoma
  • carcinomas with pleomorphic sarcomatoid or sarcomatous elements cartinoid tumor and carcinomas of salivary-gland type are categorized, gastric cancer, hepatic cancer
  • the cancer patient has a pancreatic adenocarcinoma selected from the group consisting of pancreatic ductal cancer, pancreatic head cancer, pancreatic body cancer, pancreatic tail cancer, and any combination thereof.
  • the patient has a head and neck cancer selected from the group consisting of oral cancer, pharynx cancer, laryngeal cancer, neck cancer, salivary gland cancer, and any combination thereof.
  • a cancer patient can be diagnosed prior to the administration of the combination therapy.
  • a diagnostic method can be performed by a method known in the present background arts, such as X-ray graphics, computed-tomography (CT), positron emission tomography-CT (PET-CT), magnetic resonance imaging (MRI) and/or the analysis of one or several biomarkers in plasma, serum, peripheral blood, tumor tissues of the patient.
  • CT computed-tomography
  • PET-CT positron emission tomography-CT
  • MRI magnetic resonance imaging
  • cancer progressions, disease stages, and/or responses to treatment can be analyzed by known method and parameters in combination with the above imaging and biomarkers.
  • FDG-PET tumor metabolism related to glucose consumption
  • FDG-PET on the basis of an up-take of radio isotope labeled-glucose, such as 18 F-fluorodeoxyglucose (FDG) into cancer tissues.
  • FDG is highly accumulated in cancer tissues, because cancer cells highly metabolite glucose and need much amount of glucose than normal tissues.
  • an analysis of cell population in peripheral blood lymphocyte (PBL), lymphocytes in pleural effluent (LPE) and/or tumor infiltrated lymphocytes (TIL) can be used to evaluate immune response status in each tissue and/or whole body of each patient.
  • PBL peripheral blood lymphocyte
  • LPE lymphocytes in pleural effluent
  • TIL tumor infiltrated lymphocytes
  • markers such as CD4, CD8, CD25, CD45RA, CD45RO, CCR4, CD127, PD-1, PD-L1 (B7-H1, CD274), PD-L2, CTLA-4 (CD152), IFN-gamma, IL-2, IL-4, IL-12 and Foxp3 can be used to predict immune response status of each patient.
  • Treg cells expressing CD4 + CD25 + CCR4 + , CD25 + Foxp3 + , CCR4 + Foxp3 high , CD4 + CCR4 + Foxp3 + , or CD4 + CD25 + CD45RA - CCR4 + Foxp3 + are detected, and when the activated T cells increase and/or Treg cells decrease in a patient, it is considered that an immune response in the patient is increased.
  • T cells, effector Tregs, exhausted T cells, activated T cell, effector T cells, anergic T cells or myeloid derived suppressor cells (MSDCs) identified by expression of CD4, CD8, CD25, CD45RA, CD45RO, CCR4, CD127, PD-1, PD-L1 (B7-H1, CD274), PD-L2, CTLA-4 (CD152), IFN-gamma, IL-2, IL-4, IL-12 and/or Foxp3, or peripheral/micro environmental cytokines can be analyzed prior to and/or after the administration of the combination therapy.
  • the combination therapy of an anti-CCR4 antibody and an anti-PD-1 antibody can result in the decrease of Treg cells and/or increase of activated T cells in peripheral blood, pleural effluent and/or tumor tissues of a patient.
  • the combination of the antibodies can increase an immune response to cancer cells in the patient.
  • the method further comprises analyzing or measuring an PD-L1, PD-L2 or CCR4 expression level on tumor cells prior to the administration in order to determine a patient suitable for the combination therapy.
  • a PD-L1 or PD-L2 expression in a patient can be considered as a marker in a patient suitable for the combination therapy of the present invention.
  • IDO activity in plasma sample of a patient can be analyzed in the present invention.
  • IDO indoleamine 2,3-dioxygenase
  • organs such as lung, small intestine, placenta
  • the molecule is highly expressed on many cancer cells, inhibits immune response and induces immune tolerance of cancer cells.
  • analysis of IDO activity can detect immune response status.
  • IDO activity is usually detected by analyzing a change in the levels of tryptophan, kynurenine and kynurenine metabolites. When IDO activity is increased in a patient, tryptophan, kynurenine and kynurenine metabolites are also increased, thereby resulting in a lowered immune response in the patient.
  • the combination therapy of the anti-CCR4 antibody and the anti-PD-1 antibody increases the number of Treg cells in the patient and/or decreases an IDO activity in the patient.
  • Clinical pharmaceutical evaluation of treatment would be usually assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, as well as by the immune-related response criteria (irRC) (Wolchok et al., Clin. Cancer Res.; 2009, 15: 7412-7420).
  • RECIST Solid Tumors
  • irRC immune-related response criteria
  • Study Population Histologically or cytologically confirmed locally advanced or metastatic solid tumors.
  • Dose Escalation Phase Subjects with histologically or cytologically confirmed locally advanced or metastatic solid tumors will be enrolled.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • GC gastric cancer
  • Hepatocellular Cell Carcinoma Pancreatic Adenocarcinoma and Esophageal Cancer
  • the primary objective is to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or the recommended fixed dose of the combinations of mogamulizumab and nivolumab in subjects with locally advanced or metastatic solid tumors.
  • MTD maximum tolerated dose
  • the first secondary objective is to evaluate the anti-tumor activity of the combinations of mogamulizumab and nivolumab in subjects with locally advanced or metastatic solid tumors based on the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Best overall response rate (BOR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) will be assessed for the anti-tumor activity.
  • BOR Best overall response rate
  • TTR time to response
  • DOR duration of response
  • PFS progression-free survival
  • OS overall survival
  • the second secondary objective characterizes the pharmacokinetic (PK) profile of mogamulizumab and nivolumab in combination regimens of mogamulizumab and nivolumab.
  • An additional secondary objective is to evaluate the immunogenicity of mogamulizumab and nivolumab.
  • Subjects who have voluntarily signed and dated Institutional Review Board approved informed consent form in accordance with regulatory and institutional guidelines are included. Written informed consent must be obtained prior to performing any study-related procedure. The inclusion criteria include the following: -Subjects with an age of 20 years or older at the informed consent. -Subjects who have an evaluable lesion per guideline of RECIST version 1.1. -Subjects with a life expectancy > 12 weeks. -Subjects with an ECOG performance status 0 - 1.
  • Dose-escalation phase Subjects may have distologically or cytologically confirmed locally advanced or metastatic solid tumors (excluding primary CNS or hematologic malignancies).
  • Subjects may have distologically or cytologically confirmed locally advanced or metastatic solid tumors including but not limited to NSCLC, SCLC, GC, Hepatic cancer, Hepatocellular Cell Carcinoma, Pancreatic Adenocarcinoma and Esophageal Cancer (excluding primary CNS or hematologic malignancies).
  • Exclusion criteria include female subjects who are pregnant or breast-feeding, or all subjects expecting to be pregnant.
  • Exclusion criteria further include subjects with an uncontrolled and significant inter-current illness.
  • Exclusion criteria further include subjects with known CNS metastases and/or leptomeninges metastases.
  • Subjects with asymptomatic brain metastases who have been treated, are considered stable, and who have not received corticosteroids or anti-convulsants for at least 28 days prior to Cycle 1 Day 1 may be included.
  • CTLA-4 anti-Cytotoxic T-lymphocyte-associated antigen-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways are excluded.
  • Subjects who have received a live, attenuated vaccine(s) within 28 days prior to Cycle 1 Day 1 are excluded.
  • Subjects with any unresolved toxicity Grade being 1 or less (defined by CTCAE v4.03) from previous anti-cancer therapy are excluded.
  • Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss) at the discretion of the principal or sub investigator are excluded.
  • Subjects who have been received systemic steroid therapy within 28 days prior to Cycle 1 Day 1 or any other form of immunosuppressive medication are excluded; however, subjects with topical immunosuppressive medication may be included at the discretion of the principal or sub investigator.
  • Subjects who have known active autoimmune disease or syndrome e.g., rheumatoid arthritis, uveitis, systemic erythematodes, Wegener’s granulomatosis or sarcoidosis
  • Subjects with leukoderma, alopecia or a history of autoimmune disease or syndrome who have not required systemic steroids or immunosuppressive agents for 3 years prior to written informed consent would not be excluded from this study.
  • Subjects who have active inflammatory bowel disease e.g., inflammatory colitis, and ulcerative colitis
  • Crohn’s disease e.g., irritable bowel disease, celiac disease, or other serious GI chronic conditions associated with diarrhea.
  • subjects with a history of chronic GI disease who have not required any therapy for 3 years prior to written informed consent may be included.
  • HIV human immunodeficiency virus
  • HTLV-1 human T-cell leukemia virus type I
  • hepatitis B surface antigen hepatitis C virus antibody
  • Subjects with other invasive malignancy within 5 years prior to Cycle 1 Day 1 are excluded.
  • subjects with noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured may enroll.
  • the dose-escalation phase is a parallel 3+3 design that will identify the MTD or the recommended fixed dose of the combination regimen.
  • MTD is defined as one level lower dose of mogamulizumab and nivolumab studied in which more than 2 subjects in a cohort of 6 subjects experience dose-limiting toxicity (DLT);
  • the recommended fixed dose for the cohort-expansion phase will be determined from either the MTD or the dose level in cohort 2 in case the MTD is not determined.
  • the dose-escalation phase will enroll approximately 3 to 18 subjects (3 to 6 subjects per cohort in up to 3 cohorts). The dose levels and schedules are described in below. See also FIG. 1.
  • the cohort-expansion phase will further explore safety, PK, PD, and anti-tumor activity for each combination in up to 6 tumor types.
  • the cohort-expansion phase will further explore safety, PK, PD, and anti-tumor activity for each combination in up to 6 tumor types.
  • approximately 90 subjects with locally advanced or metastatic solid tumors including but not limited to NSCLC, SCLC, GC, Hepatocellular Cell Carcinoma, Pancreatic Adenocarcinoma and Esophageal Cancer will be enrolled; additional tumor types may be considered as warranted by the observations in the dose-escalation phase in order to evaluate further safety.
  • nivolumab Treatment of Combination Therapy: In the dose-escalation and cohort-expansion phases, subjects will receive a combination treatment of mogamulizumab and nivolumab. Each subject will receive 3.0 mg/kg of nivolumab as an intravenous (IV) infusion over at least 1 hour on Days 1 and 15. Each subject will also receive either 0.1, 0.3 or 1.0 mg/kg of mogamulizumab as an IV infusion over at least 1 hour on Days 1, 8, 15 and 22 of the first cycle and on Days 1 and 15 of subsequent cycles. The combination regimen will be repeated at Day 29. On Days 1 and 15 of each cycle, mogamulizumab will be administered after the completion of nivolumab administration and 1-hour observation. Subjects will receive the combination therapy until progression of disease or death.
  • IV intravenous
  • Safety and Efficacy Assessments All subjects will be monitored for safety on Days 1, 8, 15 and 22 during Cycle 1 according to the Schedule of Events; in subsequent cycles, safety assessments will be performed every 2 weeks on Days 1 and 15.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • -Best overall response (BOR) evaluated using RECIST version 1.1.
  • TTR Time to response
  • DOR Days from the first assessment date of confirmed CR/PR through the date of death or PD, whichever is earlier -Progression-free survival (PFS): Days from Cycle 1 Day 1 through the date of death or PD, whichever is earlier -Overall survival (OS): Days from Cycle 1 Day 1 through the date of death
  • Statistical Analysis includes all subjects who received at least one dose of the study drug (even a partial dose).
  • Adverse events will be tabulated by body system, severity, and relation to treatment. Similar presentations will be provided for serious adverse events, AEs leading to withdrawal from study, and AEs leading to death for the Safety Analysis and Full Analysis Sets.
  • the ORR will be calculated as the proportion of subjects who are responders, i.e., complete response (CR) and partial response (PR); the 95% exact confidence interval for response will be calculated.
  • the disease control rate (CR, PR, SD) will also be calculated.
  • the anti-CCR4 antibody e.g., mogamulizumab
  • the anti-PD-1 antibody e.g., nivolumab
  • Phase 1 will identify the MTD or the highest protocol-defined dose in absence of exceeding the MTD, of the combination regimen of mogamulizumab and nivolumab subjects. Phase 1 will enroll up to 12 subjects.
  • Phase 2 will explore the safety, efficacy and anti-tumor activity of the highest tolerated dose of the combination regimen.
  • Phase 2 will enroll up to 184 subjects (21 to 36 subjects per tumor type) with locally advanced or metastatic disease in the following tumor types: squamous cell non-small cell lung cancer (NSCLC); programmed cell death ligand 1 (PD-L1)-nonexpressing non-squamous cell NSCLC; squamous cell carcinoma of the head and neck (SCCHN); non-microsatellite instability (non-MSI) high colorectal carcinoma (CRC); ovarian cancer, hepatocellular cell carcinoma (HCC), and pancreatic adenocarcinoma (PA).
  • NSCLC squamous cell non-small cell lung cancer
  • PD-L1 programmed cell death ligand 1
  • SCCHN squamous cell carcinoma of the head and neck
  • non-MSI non-microsatellite instability
  • CRC ovarian cancer
  • HCC
  • the primary objective is to characterize the safety and tolerability and to determine the MTD or the highest protocol-defined dose in the absence of exceeding the MTD, of the combination regimen of mogamulizumab and nivolumab in subjects with locally advanced or metastatic solid tumors.
  • the secondary objective is to evaluate the anti-tumor activity of the combination of mogamulizumab and nivolumab based on RECIST v. 1.1. Anti-tumor activity will be assessed as overall response rate (ORR), TTR, DOR, PFS, and OS.
  • ORR overall response rate
  • the exploratory objectives are: -to assess serum concentrations of mogamulizumab and nivolumab when administered in combination; -to evaluate the immunogenicity of mogamulizumab and nivolumab when administered in combination; -to evaluate the pharmacodynamic (PD) profile of the combination of mogamulizumab and nivolumab and determine which biomarkers may correlate with safety and/or anti-tumor activity; -to evaluate the ORR of the combination of mogamulizumab and nivolumab based on the immune-related RECIST (irRECIST) v 1.1.
  • PD pharmacodynamic
  • Subjects must meet each one of the following inclusion criteria during the Screening period in order to be eligible for participation in the study.
  • subjects participating in Phase 2 must meet all the inclusion criteria and have none of the exclusion criteria for the relevant tumor type.
  • Subjects will not be eligible to participate in this study if any of the following exclusion criteria is met during the Screening period.
  • subjects participating in Phase 2 must meet all the inclusion criteria and have none of the exclusion criteria specified for the relevant tumor type. -Female subjects who are pregnant or breast-feeding, or any subjects expecting to conceive or father a child during this study; -Subjects with uncontrolled and significant inter-current illness.
  • Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 4 weeks prior to enrollment. In addition, subjects must be off corticosteroids for 4 weeks prior to enrollment.
  • Phase 1 dose finding study has a 3+3 design that will identify the MTD or the highest protocol-defined dose, in the absence of exceeding the MTD, for the combination regimen.
  • Phase 1 study will enroll up to 12 subjects (3 to 6 subjects per cohort).
  • a starting dose level and an optional dose level are planned.
  • the dose levels and schedules are described in Table 3.
  • the MTD is defined as one dose level below the dose level of the cohort where one-third or more of the subjects experience DLT.
  • the recommended dose regimen for Phase 2 is intended to be either the MTD or the highest dose level tested.
  • squamous cell non-small cell lung cancer NSCLC
  • PD-L1 programmed cell death ligand 1
  • SCCHN squamous cell carcinoma of the head and neck
  • non-MSI non-microsatellite instability
  • CRC colorectal carcinoma
  • ovarian cancer hepatocellular cell carcinoma
  • PA pancreatic adenocarcinoma
  • Subjects will be treated with the highest dose of the combination regimen that was considered tolerable in Phase 1. The safety and tolerability of the dosing regimen used in each expansion cohort will be monitored.
  • -Mogamulizumab 0.3 or 1.0 mg/kg administered as an intravenous infusion over at least 1 hour on Days 1, 8, 15, and 22 in Cycle 1 then on Days 1 and 15 of each subsequent 28-day cycle.
  • -Nivolmab 240 mg of nivolumab administered as an intravenous infusion over at least 30 minutes on Days 1 and 15 of each 28-day cycle.
  • Subjects can receive the combination therapy for up to 96 weeks from Cycle 1 Day 1.
  • Subjects who stop treatment without disease progression and who experience disease progression within 12 months of their last dose of IMP can additionally receive additional IMP for up to 48 weeks, provided that they have not received other systemic therapy for their cancer.
  • Tumor assessments by CT or MRI will be performed during the Screening period, at Week 10, then at least every 12 weeks thereafter until unequivocal disease progression or death. Tumor biopsies will be required during the Screening period (except for the subjects who present archival tumor tissues) and at Week 10 (unless the tumor is inaccessible for biopsy).
  • Safety and tolerability will be evaluated by assessing AEs, and changes in physical examination findings, vital sign measurements, 12-lead ECG readings, and clinical laboratory evaluations.
  • Evaluation of the data for this study will consist primarily of data listings and summary displays. Demographic and other baseline characteristic information will be summarized for the Safety Analysis and Efficacy Analysis Sets. Adverse events will be tabulated by body system, severity, and relation to treatment. Similar presentations will be provided for SAEs, AEs leading to discontinuation of IMP and AEs leading to death. The tabulation of laboratory parameters will indicate the normal range for each parameter. Each value will be classified as falling above, below, or within the normal range. Subjects will be evaluated for tumor response, TTR, DOR, PFS and OS. The ORR will be calculated as the proportion of subjects who are responders, i.e., complete response (CR) and partial response (PR); the 95% exact confidence interval for ORR will be calculated.
  • CR complete response
  • PR partial response
  • the ORR will be derived using both the RECIST v. 1.1 and the irRECIST v. 1.1, based on the efficacy-evaluable subjects in the expansion cohorts for combination therapy, which includes all subjects who receive combination therapy in Cycle 1 Day 1. Duration of response, OS, and PFS will be estimated using the Kaplan-Meier methodology.
  • SEQ ID NO. 1 Description of the artificial sequence
  • KW-0761_VH CDR1 SEQ ID NO. 2 Description of the artificial sequence
  • KW-0761_VH CDR2 SEQ ID NO. 3 Description of the artificial sequence
  • KW-0761_VH CDR3 SEQ ID NO. 4 Description of the artificial sequence
  • KW-0761_VL CDR1 SEQ ID NO. 5 Description of the artificial sequence
  • KW-0761_VL CDR2 SEQ ID NO. 6 Description of the artificial sequence
  • KW-0761_VL CDR3 SEQ ID NO. 7 Description of the artificial sequence
  • KW-0761_VH SEQ ID NO. 8 Description of the artificial sequence

Abstract

L'invention concerne une méthode de traitement du cancer comprenant l'administration d'un anticorps du récepteur 4 de la chimokine anti-CC (CCR4) et d'un anticorps anti-mort programmée 1 (PD-1) à un sujet. L'invention concerne également une composition ou une trousse destinée à être utilisée dans le traitement d'un cancer comprenant un anticorps anti-CCR4 et un anticorps anti-PD-1.
PCT/JP2017/043200 2016-11-30 2017-11-30 Méthode de traitement du cancer à l'aide d'un anticorps anti-ccr4 et d'un anticorps anti-pd-1 WO2018101448A1 (fr)

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US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
WO2020047030A1 (fr) * 2018-08-29 2020-03-05 Chemocentryx, Inc. Polythérapie faisant appel à des antagonistes de récepteurs 4 de chimiokines c-c (ccr4) et à un ou plusieurs inhibiteurs de points de contrôle immunitaires
JP2021536442A (ja) * 2018-08-29 2021-12-27 ケモセントリックス，インコーポレイティド Ｃ−ｃケモカイン受容体４（ｃｃｒ４）拮抗薬および１種以上のチェックポイント阻害剤を用いる併用療法
EP3843734A4 (fr) * 2018-08-29 2022-05-25 ChemoCentryx, Inc. Polythérapie faisant appel à des antagonistes de récepteurs 4 de chimiokines c-c (ccr4) et à un ou plusieurs inhibiteurs de points de contrôle immunitaires
US11446289B2 (en) 2018-08-29 2022-09-20 Chemocentryx, Inc. Combination therapy using C-C chemokine receptor 4 (CCR4) antagonists and one or more immune checkpoint inhibitors
RU2810717C2 (ru) * 2018-08-29 2023-12-28 Кемосентрикс, Инк. Комбинированная терапия с использованием антагонистов c-c хемокинового рецептора 4 (ccr4) и одного или более ингибиторов контрольных точек

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