WO2020250915A1 - サイトカイン阻害剤と組み合わせて使用するための抗ｔ細胞抗原結合分子 - Google Patents

サイトカイン阻害剤と組み合わせて使用するための抗ｔ細胞抗原結合分子 Download PDF

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WO2020250915A1
WO2020250915A1 PCT/JP2020/022771 JP2020022771W WO2020250915A1 WO 2020250915 A1 WO2020250915 A1 WO 2020250915A1 JP 2020022771 W JP2020022771 W JP 2020022771W WO 2020250915 A1 WO2020250915 A1 WO 2020250915A1
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administration
days
binding molecule
pharmaceutical composition
cell antigen
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PCT/JP2020/022771
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English (en)
French (fr)
Japanese (ja)
Inventor
敬弘 石黒
昇平 岸下
己貴子 中村
ローランド カネオ モーリー
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Priority to KR1020217041104A priority Critical patent/KR102486064B1/ko
Priority to US17/616,373 priority patent/US20220348658A1/en
Priority to AU2020291300A priority patent/AU2020291300A1/en
Priority to CA3140537A priority patent/CA3140537A1/en
Priority to CR20220008A priority patent/CR20220008A/es
Priority to KR1020237000158A priority patent/KR20230011470A/ko
Priority to CN202080051046.XA priority patent/CN114126649A/zh
Priority to JP2021526105A priority patent/JP7082245B2/ja
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Priority to EP20822960.9A priority patent/EP3981429A4/en
Priority to MX2021015007A priority patent/MX2021015007A/es
Publication of WO2020250915A1 publication Critical patent/WO2020250915A1/ja
Priority to IL288374A priority patent/IL288374A/en
Anticipated expiration legal-status Critical
Priority to JP2022085724A priority patent/JP2022116185A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising 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
    • A61K2039/505—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • the present disclosure relates to anti-T cell antigen-binding molecules for use in combination with cytokine inhibitors. Furthermore, the present disclosure relates to pharmaceutical compositions and methods for preventing, alleviating, or treating the side effects of cytokine production associated with the administration of anti-T cell antigen binding molecules.
  • Antibodies are attracting attention as pharmaceuticals because they are highly stable in plasma and have few side effects (Non-Patent Document 1 and Non-Patent Document 2). Antibodies not only bind to antigens, agonists and antagonists, but also ADCC (Antibody Dependent Cytotoxicity), ADCP (Antibody Dependent Cell phagocytosis), CDC (complementary). It is known that it induces cellular cytotoxicity (also referred to as effector function) by effector cells such as (dependent cellular cytotoxicity) and exerts an antitumor effect on cancer cells (Non-Patent Document 3). So far, a plurality of therapeutic antibodies exhibiting excellent antitumor effects have been developed as pharmaceuticals for the purpose of treating cancer (Non-Patent Document 4), and although existing therapeutic antibodies have excellent effects. The therapeutic outcomes obtained by administration of these antibodies are not yet satisfactory.
  • Bispecific antibody bispecific antibody
  • Antibodies that bind to two or more types of antigens with one molecule are being studied as molecules that inhibit multiple targets. If any of the antigens recognized by the Bispecific antibody is an antigen that is specifically expressed in cancer, one antigen is recognized because it exhibits cytotoxic activity against cancer cells regardless of binding to any antigen. It can be expected to have a more efficient antitumor effect than ordinary antibody drugs.
  • T cell-redirecting antibody which is an antibody whose antitumor effect is based on cytotoxicity that mobilizes T cells as effector cells
  • T cell redirecting antibodies are any of the constituent subsystems of the T cell receptor (TCR) complex on T cells. It is a bi-specific antibody containing an antibody against the antibody, particularly an antibody that binds to the CD3 epsilon chain and an antibody that binds to an antigen on a target cancer cell.
  • the T cell redirecting antibody simultaneously binds to the CD3 epsilon chain and the cancer antigen, causing the T cell to approach the cancer cell.
  • the cytotoxic effect of T cells exerts an antitumor effect on cancer cells.
  • a new T cell redirecting antibody that binds to the cancer antigen (GPC3) and the CD3 ⁇ chain expressed on T cells in each of the two Fabs and has an Fc region with reduced Fc ⁇ R-binding activity has been introduced. It is provided (Patent Documents 1 and 2).
  • Non-Patent Document 8 the occurrence of toxicity associated with the exertion of high antitumor activity of T cell redirecting antibody, for example, the occurrence of cytokine release syndrome (Cytokine Release Syndrome, CRS) has been reported (Non-Patent Document 8).
  • the present disclosure relates to a combination therapy containing an anti-T cell antigen-binding molecule and a cytokine inhibitor, a pharmaceutical composition for use in the combination therapy, and the like.
  • the inventors may prevent, alleviate, or treat cytokine release syndrome (CRS) associated with administration of an anti-T cell antigen-binding molecule in an individual by administration of a cytokine inhibitor. Found that it is possible.
  • CRS cytokine release syndrome
  • the disclosure relates to: (A1) A pharmaceutical composition containing an anti-T cell antigen-binding molecule, which is used for combination therapy with a cytokine inhibitor.
  • A1-1) The pharmaceutical composition according to (A1), wherein the cytokine inhibitor is administered before, simultaneously with, or after administration of the pharmaceutical composition.
  • A1-2 The pharmaceutical composition according to (A1) or (A1-1), wherein the cytokine inhibitor is administered before or at the same time as the administration of the pharmaceutical composition.
  • (A1-3) The cytokine inhibitor is administered 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the same day before the administration of the pharmaceutical composition, before the administration of the pharmaceutical composition.
  • A1-4 The cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the administration of the pharmaceutical composition, from (A1) to (A1-).
  • A1-5) The above-mentioned (A1) to (A1-4), wherein the cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • Pharmaceutical composition. (A1-6) The pharmaceutical composition according to (A1-5), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • A1-8) The pharmaceutical composition according to (A1) or (A1-7), wherein the cytokine inhibitor is administered when signs of CRS or CRS occur after administration of the pharmaceutical composition.
  • A1-9) The pharmaceutical composition according to (A1-7) or (A1-8), wherein the CRS is Grade 2 or higher, or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the pharmaceutical composition described in Crab. (A1-11) The pharmaceutical composition according to any one of (A1) to (A1-10), wherein the cytokine inhibitor is an anti-IL6R antibody.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • (A1-13) The pharmaceutical composition according to any one of (A1) to (A1-12), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A1-14 The pharmaceutical composition according to any one of (A1) to (A1-12), wherein the corticosteroid is further administered before, simultaneously with, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) Domain containing antibody variable region having cancer antigen binding activity,
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A1-18) The pharmaceutical composition according to any one of (A1) to (A1-17) for the treatment of cancer.
  • (A1-19) The pharmaceutical composition according to any one of (A1) to (A1-18) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure also provides administration of an anti-T cell antigen-binding molecule with pre-administration of the cytokine inhibitor, including each of the following aspects (for each dose of anti-T cell antigen-binding molecule, the cytokine inhibitor.
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, and here, in the combination therapy.
  • the pharmaceutical composition is repeatedly administered and
  • a pharmaceutical composition to which the cytokine inhibitor is administered before or at the same time as each administration of the pharmaceutical composition.
  • A2-1 The pharmaceutical composition according to (A2), wherein the pharmaceutical composition is repeatedly administered at the same dose.
  • the cytokine inhibitor is administered 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or on the day of each administration of the pharmaceutical composition before administration of the pharmaceutical composition.
  • the cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the pharmaceutical composition, from (A2) to (A2-).
  • cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • Pharmaceutical composition is provided.
  • A2-6) The pharmaceutical composition according to (A2-5), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • (A2) to (A2-6) which is an inhibitor of one or more cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the pharmaceutical composition described in Crab. (A2-8) The pharmaceutical composition according to any one of (A2) to (A2-7), wherein the cytokine inhibitor is an anti-IL6R antibody.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • A2-10) The pharmaceutical composition according to any one of (A2) to (A2-9), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A2-11 The pharmaceutical composition according to any one of (A2) to (A2-9), wherein the corticosteroid is further administered before, at the same time, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity, The pharmaceutical composition according to any one of (A2) to (A2-12), which is a bispecific antigen-binding molecule containing.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • A2-15 The pharmaceutical composition according to any one of (A2) to (A2-14) for the treatment of cancer.
  • A2-16) The pharmaceutical composition according to any one of (A2) to (A2-15) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure provides the following embodiments (when pre-administering a cytokine inhibitor for the first or more doses of an anti-T cell antigen-binding molecule):
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, and here, in the combination therapy.
  • the pharmaceutical composition is repeatedly administered and
  • the cytokine inhibitor is administered before or at the same time as each of the first, first, second, first to third, first to fourth, or first to fifth administrations of the pharmaceutical composition.
  • Pharmaceutical composition (A3-1) The pharmaceutical composition according to (A3), wherein the pharmaceutical composition is repeatedly administered at the same dose.
  • (A3-2) The pharmaceutical composition according to (A3) or (A3-1), wherein the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks. Stuff. (A3-3) 6 days, 5 days, 4 days, and 3 days before each administration of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th administrations of the pharmaceutical composition.
  • (A3-4) On the day, 1 day, 2 days, 3 days, 4 days after the first administration, 1st, 2nd, 1st, 3rd, 1st, 4th, or 1st to 5th administration of the pharmaceutical composition.
  • (A3-5) The above-mentioned (A3) to (A3-4), wherein the cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • Pharmaceutical composition. (A3-6) The pharmaceutical composition according to (A3-5), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15. , IL-17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, Any of (A3) to (A3-6), which is an inhibitor of one or more cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the pharmaceutical composition described in Crab. (A3-8) The pharmaceutical composition according to any one of (A3) to (A3-7), wherein the cytokine inhibitor is an anti-IL6R antibody. (A3-9) The cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • A3-10 The pharmaceutical composition according to any one of (A3) to (A3-9), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A3-12 The pharmaceutical composition according to (A3-10) or (A3-11), wherein the corticosteroid is dexamethasone, a pharmaceutically acceptable salt thereof, or a derivative thereof.
  • A3-13 The anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity, The pharmaceutical composition according to any one of (A3) to (A3-12), which is a bispecific antigen-binding molecule containing.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A3-15) The pharmaceutical composition according to any one of (A3) to (A3-14) for the treatment of cancer.
  • A3-16 The pharmaceutical composition according to any one of (A3) to (A3-15) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure provides the following aspects (when pre-administration of a cytokine inhibitor is performed for each administration cycle of the anti-T cell antigen-binding molecule).
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, and here, in the combination therapy.
  • the pharmaceutical composition is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle.
  • a pharmaceutical composition to which the cytokine inhibitor is administered before or at the same time as the first administration of the pharmaceutical composition in each administration cycle.
  • A4-1) The pharmaceutical composition according to (A4), wherein the pharmaceutical composition is repeatedly administered at the same dose.
  • (A4-2) The pharmaceutical composition according to (A4) or (A4-1), wherein the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks. .. (A4-3) In each administration cycle, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or on the day of the first administration of the pharmaceutical composition, before administration of the pharmaceutical composition.
  • the cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after the first administration of the pharmaceutical composition.
  • Pharmaceutical composition. (A4-6) The pharmaceutical composition according to (A4-5), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • (A4-10) The pharmaceutical composition according to any one of (A4) to (A4-9), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A4-11 The pharmaceutical composition according to any one of (A4) to (A4-9), wherein the corticosteroid is further administered before, at the same time, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity, The pharmaceutical composition according to any one of (A4) to (A4-12), which is a bispecific antigen-binding molecule comprising.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A4-15) The pharmaceutical composition according to any one of (A4) to (A4-14) for the treatment of cancer.
  • A4-16 The pharmaceutical composition according to any one of (A4) to (A4-15) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure includes the following embodiments (when premedication of a cytokine inhibitor is performed for each administration cycle of the anti-T cell antigen-binding molecule):
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, and here, in the combination therapy.
  • the pharmaceutical composition is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle.
  • (a) In the first administration cycle, the cytokine inhibitor is administered before or at the same time as each administration of the pharmaceutical composition, and (b) in the second and subsequent administration cycles, in each administration cycle.
  • a pharmaceutical composition to which the cytokine inhibitor is administered before or at the same time as the first administration of the pharmaceutical composition A pharmaceutical composition to which the cytokine inhibitor is administered before or at the same time as the first administration of the pharmaceutical composition.
  • A5-1 The pharmaceutical composition according to (A5), wherein the pharmaceutical composition is repeatedly administered at the same dose.
  • A5-2 The pharmaceutical composition according to (A5) or (A5-1), wherein the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks. ..
  • (A5-3) (a) In the first administration cycle, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day of each administration of the pharmaceutical composition, and (b) In the second and subsequent administration cycles, the said in each administration cycle, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day before the first administration of the pharmaceutical composition.
  • the pharmaceutical composition according to any one of (A5) to (A5-2), wherein the cytokine inhibitor is administered before administration of the pharmaceutical composition.
  • (A5-4) (a) In the first administration cycle, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after each administration of the pharmaceutical composition, and (b) In the second and subsequent administration cycles, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of the pharmaceutical composition in each administration cycle, further, the above.
  • the pharmaceutical composition according to any one of (A5) to (A5-3) to which a cytokine inhibitor is administered.
  • (A5-5) The above-mentioned (A5) to (A5-4), wherein the cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • Pharmaceutical composition (a) In the first administration cycle, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after each administration of the pharmaceutical composition, and (b) In the second and subsequent administration cycles, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • A5-11 The pharmaceutical composition according to any one of (A5) to (A5-9), wherein the corticosteroid is further administered before, simultaneously with, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity, The pharmaceutical composition according to any one of (A5) to (A5-12), which is a bispecific antigen-binding molecule containing.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A5-15) The pharmaceutical composition according to any one of (A5) to (A5-14) for the treatment of cancer.
  • A5-16 The pharmaceutical composition according to any one of (A5) to (A5-15) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure also relates to the administration of an anti-T cell antigen-binding molecule with the pre-administration of a cytokine inhibitor according to the following aspects (in a regimen including an incremental administration period and a subsequent maintenance administration period, the anti-T cell antigen-binding molecule.
  • a regimen including an incremental administration period and a subsequent maintenance administration period, the anti-T cell antigen-binding molecule.
  • pre-administration of cytokine inhibitor is performed for each administration of.
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, wherein the combination therapy is described.
  • Including the incremental administration period of the pharmaceutical composition and the subsequent maintenance administration period is described.
  • A6-1) The pharmaceutical composition according to (A6), wherein the dose of the pharmaceutical composition is gradually increased during the incremental administration period.
  • A6-2 The pharmaceutical composition according to (A6) or (A6-1), wherein the pharmaceutical composition is administered twice, three times, four times, or five times during the gradual administration period.
  • A6-3 During the escalating administration period, the pharmaceutical composition is administered once a week, once every two weeks, or once every three weeks, from (A6) to (A6-2).
  • (A6-4) The pharmaceutical composition according to any one of (A6) to (A6-3), wherein the pharmaceutical composition is repeatedly administered at the same dose during the maintenance administration period. (A6-5) During the maintenance administration period, the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks, from (A6) to (A6-4). ).
  • the pharmaceutical composition according to any one of. (A6-6) At 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or on the day of each administration of the pharmaceutical composition during the incremental administration period and the maintenance administration period.
  • the cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after each administration of the pharmaceutical composition during the incremental administration period and the maintenance administration period.
  • A6-8) Any of (A6) to (A6-7), in which the cytokine inhibitor is further administered when signs of CRS or CRS occur after administration of the anti-T cell antigen-binding molecule.
  • the pharmaceutical composition according to. (A6-9) The pharmaceutical composition according to (A6-8), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15. , IL-17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, Any of (A6) to (A6-9), which is an inhibitor of one or more cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the pharmaceutical composition described in Crab. (A6-11) The pharmaceutical composition according to any one of (A6) to (A6-10), wherein the cytokine inhibitor is an anti-IL6R antibody.
  • the cytokine inhibitor is Tocilizumab, and Tocilizumab is administered at a dose of 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • A6-13 The pharmaceutical composition according to any one of (A6) to (A6-12), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A6-15 The pharmaceutical composition according to (A6-13) or (A6-14), wherein the corticosteroid is dexamethasone, a pharmaceutically acceptable salt thereof, or a derivative thereof.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity, The pharmaceutical composition according to any one of (A6) to (A6-15), which is a bispecific antigen-binding molecule comprising.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A6-18) The pharmaceutical composition according to any one of (A6) to (6-17) for the treatment of cancer.
  • (A6-19) The pharmaceutical composition according to any one of (A6) to (A6-18) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure relates to each of the following aspects (in the regimen including the incremental administration period and the subsequent maintenance administration period, when the cytokine inhibitor is pre-administered for the administration of the anti-T cell antigen binding molecule during the incremental administration period) :
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, wherein the combination therapy is described.
  • (A7-1) The pharmaceutical composition according to (A7), wherein the dose of the pharmaceutical composition is gradually increased during the incremental administration period.
  • (A7-2) The pharmaceutical composition according to (A7) or (A7-1), wherein the pharmaceutical composition is administered twice, three times, four times, or five times during the gradual administration period.
  • (A7-3) During the escalating dosing period, the pharmaceutical composition is administered once a week, once every two weeks, or once every three weeks, from (A7) to (A7-2).
  • the pharmaceutical composition according to any one of. (A7-4) The pharmaceutical composition according to any one of (A7) to (A7-3), wherein the pharmaceutical composition is repeatedly administered at the same dose during the maintenance administration period.
  • the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks, from (A7) to (A7-4). ).
  • the cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after each administration of the pharmaceutical composition during the escalating administration period.
  • A7-8 The above-mentioned (A7) to (A7-7), wherein the cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • Pharmaceutical composition. (A7-9) The pharmaceutical composition according to (A7-8), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • (A7-13) The pharmaceutical composition according to any one of (A7) to (A7-12), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A7-14 The pharmaceutical composition according to any one of (A7) to (A7-12), wherein the corticosteroid is further administered before, at the same time, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity,
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A7-19) The pharmaceutical composition according to any one of (A7) to (A7-18) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure provides the following aspects (in a regimen that includes an boosted dose period and a subsequent maintenance dose period, each incremental dose period and the first one or more anti-T cells during the maintenance dose period.
  • antigen-binding molecule pre-administration of cytokine inhibitor:
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, wherein the combination therapy is described.
  • i Including the incremental administration period of the pharmaceutical composition and the subsequent maintenance administration period.
  • the cytokine inhibitor is administered before or at the same time as each administration of the pharmaceutical composition, and (b) during the maintenance administration period, the drug during the maintenance administration period.
  • the cytokine inhibitor is administered before or at the same time as each of the first, first, second, first, third, first to fourth, or first to fifth administrations of the composition.
  • Pharmaceutical composition. (A8-1) The pharmaceutical composition according to (A8), wherein the dose of the pharmaceutical composition is gradually increased during the gradual administration period. (A8-2) The pharmaceutical composition according to (A8) or (A8-1), wherein the pharmaceutical composition is administered twice, three times, four times, or five times during the gradual administration period.
  • the pharmaceutical composition is administered once a week, once every two weeks, or once every three weeks, from (A8) to (A8-2).
  • the pharmaceutical composition according to any one of. (A8-4)
  • (A8-5) During the maintenance administration period, the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks, from (A8) to (A8-4).
  • (A8-6) (a) During the escalating administration period, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day of each administration of the pharmaceutical composition, and (b) In the maintenance administration period, each administration of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th administrations of the pharmaceutical composition in the maintenance administration period 6 1 day ago, 5 days ago, 4 days ago, 3 days ago, 2 days ago, 1 day ago, or on the day
  • the pharmaceutical composition according to any one of (A8) to (A8-5), wherein the cytokine inhibitor is administered before administration of the pharmaceutical composition.
  • (A8-7) (a) During the escalating administration period, on the day of each administration of the pharmaceutical composition, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days, and. (b) In the maintenance administration period, on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th administrations of the pharmaceutical composition in the maintenance administration period, 1 After days, 2 days, 3 days, 4 days, 5 days or 6 days, The pharmaceutical composition according to any one of (A8) to (A8-6), wherein the cytokine inhibitor is further administered.
  • Pharmaceutical composition. (A8-9) The pharmaceutical composition according to (A8-8), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • (A8-13) The pharmaceutical composition according to any one of (A8) to (A8-12), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A8-14 The pharmaceutical composition according to any one of (A8) to (A8-12), wherein the corticosteroid is further administered before, at the same time, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity,
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • A8-19 The pharmaceutical composition according to any one of (A8) to (A8-18) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure also relates to each of the following aspects (in a regimen that includes a escalating dosing period and a subsequent maintenance dosing period, the anti-T cell antigen binding molecule for each escalating dosing period and for each dosing cycle during the maintenance dosing period.
  • administration when pre-administration of cytokine inhibitor is performed:
  • a pharmaceutical composition containing an anti-T cell antigen-binding molecule which is a pharmaceutical composition for use in combination therapy with a cytokine inhibitor, wherein the combination therapy is described.
  • Including the incremental administration period of the pharmaceutical composition and the subsequent maintenance administration period is described.
  • the pharmaceutical composition is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles.
  • (iii) (a) The cytokine inhibitor is administered before or at the same time as each administration of the pharmaceutical composition during the incremental administration period, and (b) during the maintenance administration period, the said in each administration cycle.
  • (A9-1) The pharmaceutical composition according to (A9), wherein the dose of the pharmaceutical composition is gradually increased during the incremental administration period.
  • (A9-2) The pharmaceutical composition according to (A9) or (A9-1), wherein the pharmaceutical composition is administered twice, three times, four times, or five times during the gradual administration period.
  • the pharmaceutical composition is administered once a week, once every two weeks, or once every three weeks, (A9) to (A9-2).
  • the pharmaceutical composition according to any one of. (A9-4)
  • (A9-5) During the maintenance administration period, the pharmaceutical composition is repeatedly administered once a week, once every two weeks, or once every three weeks, from (A9) to (A9-4). ).
  • (A9-6) (a) During the escalating administration period, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day of each administration of the pharmaceutical composition, and (b) During the maintenance administration period, in each administration cycle, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day of the first administration of the pharmaceutical composition.
  • the pharmaceutical composition according to any one of (A9) to (A9-5), wherein the cytokine inhibitor is administered before administration of the pharmaceutical composition.
  • (A9-7) (a) In the gradual administration period, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after each administration of the pharmaceutical composition, and (b) During the maintenance administration period, in each administration cycle, on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of the pharmaceutical composition.
  • the pharmaceutical composition according to any one of (A9) to (A9-6), wherein the cytokine inhibitor is further administered.
  • (A9-8) The above-mentioned (A9) to (A9-7), wherein the cytokine inhibitor is further administered when CRS or signs of CRS occur after administration of the pharmaceutical composition.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • (A9-13) The pharmaceutical composition according to any one of (A9) to (A9-12), wherein the corticosteroid is not administered before or at the same time as the administration of the pharmaceutical composition.
  • A9-14 The pharmaceutical composition according to any one of (A9) to (A9-12), wherein the corticosteroid is further administered before, at the same time, or after the administration of the pharmaceutical composition.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) A domain containing an antibody variable region having cancer antigen-binding activity,
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (A9-19) The pharmaceutical composition according to any one of (A9) to (A9-18) for treating cancer while preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule. Stuff.
  • the present disclosure relates to: (A10) A container, (ii) a pharmaceutical composition in the container containing an anti-T cell antigen-binding molecule, and (iii) a cytokine inhibitor administered before, at the same time, or after administration of the pharmaceutical composition.
  • a kit including a document, instructing you to do.
  • (A10-1) The kit according to (A10-1), further comprising a label attached to a container indicating that the pharmaceutical composition can be used in the treatment of cancer.
  • (A10-2) The kit according to (A10) or (A10-1), wherein the formulation of the pharmaceutical composition is performed according to the instructions in the document.
  • kits according to (A10) or (A10-1) for treating cancer according to the formulation indicated in the document (A11) Use of an anti-T cell antigen-binding molecule in the manufacture of a pharmaceutical composition for combination therapy with a cytokine inhibitor. (A12) Use of anti-T cell antigen-binding molecule in combination therapy with cytokine inhibitors.
  • the present disclosure relates to: (A13) By administering an anti-T cell antigen-binding molecule to a subject, including in combination with a cytokine inhibitor, the cytokine release syndrome associated with the administration of the anti-T cell antigen-binding molecule can be prevented, alleviated, and / or How to treat cancer while treating it.
  • the present disclosure includes the following aspects;
  • (B1) A pharmaceutical composition containing a cytokine inhibitor, which is used for combination therapy with an anti-T cell antigen-binding molecule;
  • (B1-1) The pharmaceutical composition according to (B1) for administration before, simultaneously with, or after administration of the anti-T cell antigen-binding molecule;
  • (B1-2) The pharmaceutical composition according to (B1) or (B1-1) for administration before or at the same time as administration of the anti-T cell antigen-binding molecule;
  • (B1-3) For administration of the anti-T cell antigen-binding molecule 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the same day before administration of the anti-T cell antigen-binding molecule.
  • composition (B1) to (B1-2).
  • B1-4 From (B1) to (B1-3) for further administration on the day of administration of the anti-T cell antigen-binding molecule, 1 day before, 2 days before, 3 days before, 4 days before, 5 days before or 6 days before. ).
  • the pharmaceutical composition according to any one of. (B1-5)
  • Composition (B1-6) The pharmaceutical composition according to (B1-5), wherein the CRS is Grade 2 or higher or Grade 3 or higher.
  • (B1-7) The pharmaceutical composition according to (B1) or (B1-1), which is further administered after administration of the anti-T cell antigen-binding molecule.
  • (B1-8) The pharmaceutical composition according to (B1) or (B1-7), which is further administered when signs of CRS or CRS occur after administration of the anti-T cell antigen-binding molecule.
  • (B1-9) The pharmaceutical composition according to (B1-7) or (B1-8), wherein the CRS is Grade 2 or higher, or Grade 3 or higher.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15.
  • cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the pharmaceutical composition described in Crab. (B1-11) The pharmaceutical composition according to any one of (B1) to (B1-10), wherein the cytokine inhibitor is an anti-IL6R antibody.
  • the cytokine inhibitor is Tocilizumab, and the dose of Tocilizumab is 8 mg / kg or less for patients weighing 30 kg or more, and per dose for patients weighing less than 30 kg.
  • the anti-T cell antigen-binding molecule is (1) Domain containing antibody variable region having T cell receptor complex binding activity, and (2) Domain containing antibody variable region having cancer antigen binding activity, The pharmaceutical composition according to any one of (B1) to (B1-15), which is a bispecific antigen-binding molecule comprising.
  • the anti-T cell antigen-binding molecule is (1) A domain containing an antibody variable region having T cell receptor complex binding activity, (2) Domain containing antibody variable region having glypican 3-binding activity, and (3) Domains containing Fc regions with reduced binding activity to Fc ⁇ receptors,
  • (B1-18) The pharmaceutical composition according to any one of (B1) to (B1-17) for preventing or alleviating cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule.
  • the present disclosure includes the following aspects;
  • (B2) A pharmaceutical composition containing a cytokine inhibitor, which is a pharmaceutical composition for use in combination therapy with an anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered.
  • (ii) A pharmaceutical composition for administration before or at the same time as each administration of the repeated administration.
  • (B3) A pharmaceutical composition containing a cytokine inhibitor, which is a pharmaceutical composition for use in combination therapy with an anti-T cell antigen-binding molecule, and here, in the combination therapy.
  • the anti-T cell antigen-binding molecule is repeatedly administered.
  • B4 A pharmaceutical composition containing a cytokine inhibitor, which is a pharmaceutical composition for use in combination therapy with an anti-T cell antigen-binding molecule, and here, in the combination therapy.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses.
  • a pharmaceutical composition containing a cytokine inhibitor which is a pharmaceutical composition for use in combination therapy with an anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses.
  • (ii) (a) In the first administration cycle, the anti-T cell antigen-binding molecule is administered before or at the same time as each administration, and (b) in the second and subsequent administration cycles, the anti-T cell antigen-binding molecule is administered in each administration cycle.
  • a pharmaceutical composition containing a cytokine inhibitor which is a pharmaceutical composition for use in a combination therapy with an anti-T cell antigen-binding molecule, wherein the combination therapy is described.
  • (i) Includes the incremental administration period of the anti-T cell antigen-binding molecule and the subsequent maintenance administration period.
  • a pharmaceutical composition containing a cytokine inhibitor which is a pharmaceutical composition for use in combination therapy with an anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses.
  • (ii) (a) In the first administration cycle, the anti-T cell antigen-binding molecule is administered before or at the same time as each administration, and (b) in the second and subsequent administration cycles, the anti-T cell antigen-binding molecule is administered in each administration cycle.
  • a pharmaceutical composition containing a cytokine inhibitor which is a pharmaceutical composition for use in a combination therapy with an anti-T cell antigen-binding molecule, wherein the combination therapy is described.
  • (i) Includes the incremental administration period of the anti-T cell antigen-binding molecule and the subsequent maintenance administration period.
  • (ii) (a) During the incremental administration period, the anti-T cell antigen-binding molecule is administered before or simultaneously with each administration, and (b) during the maintenance administration period, the anti-T cell antigen during the maintenance administration period.
  • a pharmaceutical composition containing a cytokine inhibitor which is a pharmaceutical composition for use in a combination therapy with a T cell antigen-binding molecule, wherein the combination therapy is described.
  • (i) Includes the incremental administration period of the anti-T cell antigen-binding molecule and the subsequent maintenance administration period.
  • the anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles.
  • (iii) (a) During the escalation period, the anti-T cell antigen-binding molecule is administered before or at the same time as each administration, and (b) during the maintenance administration period, the anti-T cells in each administration cycle.
  • the present disclosure relates to: (B10) (i) a container, (ii) a pharmaceutical composition in the container containing a cytokine inhibitor, and (iii) administer the pharmaceutical composition before, at the same time, or after administration of the anti-T cell antigen-binding molecule.
  • a kit including a document, instructing you to do.
  • (B10-1) A label affixed to the container further indicating that the pharmaceutical composition can be used for the prevention, alleviation, and / or treatment of cytokine release syndrome associated with administration of an anti-T cell antigen binding molecule. Included, the kit according to (B10-1).
  • kit (B10-2) The kit according to (B10) or (B10-1), wherein the formulation of the pharmaceutical composition is performed according to the instructions in the document. (B10-3) to (B10) or (B10-1) for the prevention, alleviation, and / or treatment of cytokine release syndrome associated with administration of anti-T cell antigen binding molecules, according to the formulation indicated in the document. Described kit. (B11) Use of cytokine inhibitors in the manufacture of pharmaceutical compositions for combination therapy with anti-T cell antigen binding molecules. (B12) Use of cytokine inhibitors in combination therapy with anti-T cell antigen-binding molecules.
  • the present disclosure relates to: (B13) A method for preventing, alleviating, and / or treating a cytokine release syndrome associated with administration of an anti-T cell antigen-binding molecule, which comprises administering a cytokine inhibitor to a subject. (B14) A method for preventing and / or alleviating cytokine release syndrome associated with administration of an anti-T cell antigen-binding molecule, which comprises administering a cytokine inhibitor to a subject before or at the same time as administration of the anti-T cell antigen-binding molecule. ..
  • the present disclosure relates to: (C1) A method for treating cancer, which comprises administering an anti-T cell antigen-binding molecule and a cytokine inhibitor to a subject.
  • (C1-1) The method according to (C1), wherein the cytokine inhibitor is administered before, at the same time, or after the administration of the anti-T cell antigen-binding molecule.
  • (C1-2) The method according to (C1) or (C1-1), wherein the cytokine inhibitor is administered before or at the same time as the administration of the anti-T cell antigen-binding molecule.
  • (C1-3) At 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day before administration of the anti-T cell antigen-binding molecule, the cytokine inhibition before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is further administered on the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the anti-T cell antigen-binding molecule, from (C1).
  • the present disclosure comprises various embodiments of a combination therapy disclosed herein, comprising administering an anti-T cell antigen binding molecule and a cytokine inhibitor, a method of treating cancer by the combination therapy.
  • a combination therapy comprising administering an anti-T cell antigen binding molecule and a cytokine inhibitor, a method of treating cancer by the combination therapy.
  • methods for preventing, alleviating, and / or treating cytokine release syndrome associated with administration of anti-T cell antigen-binding molecules by the combination therapy is an object selected from prevention, alleviation, and treatment of cytokine release syndrome associated with administration of the anti-T cell antigen-binding molecule in a method for treating cancer, which comprises administering an anti-T cell antigen-binding molecule.
  • the present disclosure relates to: (C2) A method for combination therapy comprising the step of administering an anti-T cell antigen-binding molecule and the step of administering a cytokine inhibitor to a subject. (C3) Combination therapy comprising an anti-T cell antigen binding molecule and a cytokine inhibitor. (C4) Combination of anti-T cell antigen-binding molecule and cytokine inhibitor. (C5) A pharmaceutical composition containing an anti-T cell antigen-binding molecule and a cytokine inhibitor. (C5-1) The pharmaceutical composition according to (C5) for the treatment of cancer.
  • Anti-T cell antigen-binding molecules that bind to T cell antigens such as CD3 are attracting attention as a new therapeutic means for cancer that utilizes the antitumor action of T cells possessed by the living body.
  • T cell antigens such as CD3
  • it targets T cells that produce cytokines it may cause side effects due to cytokine production (for example, cytokine release syndrome). Therefore, there was a concern about unexpected side effects due to cytokine production when administering the anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is administered in combination with a cytokine inhibitor in advance, it is possible to prevent or reduce unexpected side effects caused by cytokines.
  • the number of days on the horizontal axis is the nominal time (Nominal time) calculated based on the clinical trial visit (visit) and blood sampling time defined in the study protocol.
  • the administration start date (1st day) is displayed as Day 0, and ERY974 was administered on Day 0, 7, 21 in this figure (Day 14 was withdrawn, Day 21 was dose-reduced).
  • the vertical axis represents the serum concentration of cytokines (pg / ml), and the horizontal axis represents the number of days since the first administration date.
  • the administration start date (1st day) is displayed as Day 0, and ERY974 was administered on Days 0, 7, 21, 28 in this figure (Day 14 was withdrawn, Day 21 was dose-reduced). ).
  • the number of days on the horizontal axis is the nominal time (Nominal time). It represents cytokine detection in cohort 10A, patient ID 840040003.
  • the vertical axis represents the serum concentration of cytokines (pg / ml), and the horizontal axis represents the number of days since the first administration date.
  • the administration start date (1st day) is displayed as Day 0, and ERY974 was administered on Days 0, 7, 14, 21, and 28 in this figure (note that the dose was reduced after Day 14). T).
  • the number of days on the horizontal axis is the nominal time (Nominal time). This is a simulation of changes in serum Tocilizumab concentration when tocilizumab was administered at 8 mg / kg (intravenous administration: IV) on Day 0, based on the population pharmacokinetic model reported in the paper by Frey et al. ..
  • the vertical axis represents the serum concentration of tocilizumab ( ⁇ g / ml), and the horizontal axis represents the number of days after administration of Tocilizumab.
  • the dashed line represents the target concentration of tocilizumab (10 ⁇ g / mL), and the alternate long and short dash line represents the Michaelis coefficient (Km value) (0.367 ⁇ g / mL) in the paper by Gibiansky et al.
  • Km value Michaelis coefficient
  • the dashed line represents the target concentration of tocilizumab (10 ⁇ g / mL), and the alternate long and short dash line represents the Michaelis coefficient (Km value) (0.367 ⁇ g / mL) in the paper by Gibiansky et al.
  • Km value Michaelis coefficient
  • the transition of Tocilizumab concentration in serum when each dose was administered (IV) was simulated based on the population pharmacokinetic model reported in the paper by Gibiansky et al.
  • Figure 8A shows the simulation results of QW
  • Figure 8B shows the simulation results of Q2W
  • Figure 8C shows the simulation results of Q3W
  • Figure 8D shows the simulation results of Q4W.
  • the vertical axis represents the serum concentration of tocilizumab ( ⁇ g / ml)
  • the horizontal axis represents the number of days after administration of Tocilizumab.
  • the dashed line represents the target concentration of tocilizumab (10 ⁇ g / mL), and the alternate long and short dash line represents the Michaelis coefficient (Km value) (0.367 ⁇ g / mL) in the paper by Gibiansky et al. Gibiansky et al. Described changes in serum IL-6 / IL-6R complex concentration when tocilizumab was administered at a dose of 8 mg / kg once a week (QW) from Day 0 at intervals (IV). This is a simulation based on the population pharmacokinetic model reported in this paper.
  • Fig. 9A shows the serum IL-6 concentration of 300 pg / mL
  • FIG. 9B shows the serum IL-6 concentration of 1000 pg / mL
  • Fig. 9C shows the serum IL-6 concentration of 3000 pg / mL
  • Fig. 9D shows the serum IL-6
  • Figure 9E shows the simulation results when the serum IL-6 concentration is 10000 pg / mL and the concentration is 5000 pg / mL.
  • the vertical axis represents the IL-6 / IL-6R complex concentration (nM), and the horizontal axis represents the number of days after the start of Tocilizumab administration. Changes in serum IL-6 / IL-6R complex concentration when tocilizumab was administered (IV) at a dose of 8 mg / kg once every two weeks (Q2W) from Day 0.
  • Fig. 10A shows the serum IL-6 concentration of 300 pg / mL
  • Fig. 10B shows the serum IL-6 concentration of 1000 pg / mL
  • Fig. 10C shows the serum IL-6 concentration of 3000 pg / mL
  • Fig. 10D shows the serum IL-6.
  • Figure 10E shows the simulation results when the serum IL-6 concentration is 10000 pg / mL and the concentration is 5000 pg / mL.
  • the vertical axis represents the IL-6 / IL-6R complex concentration (nM), and the horizontal axis represents the number of days after the start of Tocilizumab administration.
  • Fig. 11A shows the serum IL-6 concentration of 300 pg / mL
  • Fig. 11B shows the serum IL-6 concentration of 1000 pg / mL
  • FIG. 11C shows the serum IL-6 concentration of 3000 pg / mL
  • Fig. 11D shows the serum IL-6
  • Figure 11E shows the simulation results when the serum IL-6 concentration is 10000 pg / mL and the concentration is 5000 pg / mL.
  • the vertical axis represents the IL-6 / IL-6R complex concentration (nM), and the horizontal axis represents the number of days after the start of Tocilizumab administration.
  • Specific refers to a state in which one molecule of a molecule that specifically binds does not show any significant binding to a molecule other than the one or more of the other molecule to which it binds. It is also used when the domain containing the antibody variable region is specific to a specific epitope among a plurality of epitopes contained in a certain antigen. When an epitope to which a domain containing an antibody variable region binds is contained in a plurality of different antigens, an antigen-binding molecule having a domain containing the antibody variable region can bind to various antigens containing the epitope. ..
  • binding activity refers to the non-covalent interaction between one or more binding sites of a molecule (eg, an antibody) and a molecule's binding partner (eg, an antigen). It refers to the total strength.
  • binding activity is not strictly limited to a 1: 1 interaction between members of a binding pair (eg, antibody and antigen). For example, if the members of the binding pair reflect a 1: 1 interaction in monovalent, this binding activity is particularly referred to as the unique binding affinity (“affinity”). If the members of the binding pair are capable of both monovalent and multivalent binding, the binding activity is the sum of these binding forces.
  • the binding activity of the molecule X to its partner Y can generally be expressed by the dissociation constant (KD) or the "analyte binding amount per unit ligand amount" (hereinafter sometimes referred to as "binding amount").
  • KD dissociation constant
  • binding amount the “analyte binding amount per unit ligand amount”
  • Binding activity can be measured by conventional methods known in the art, including those described herein. Specific examples and exemplary embodiments for measuring binding activity (including affinity) are described below. Specific examples and exemplary embodiments for measuring binding affinity are described below.
  • anti-target antigen -binding antigen-binding molecule
  • target antigen can be any antigen protein that can be targeted, including, for example, T cell antigens, cancer antigens, cytokines, and cytokine receptors.
  • An antigen-binding molecule that binds to a target antigen is an antigen-binding molecule that can bind to the target antigen with sufficient affinity, and as a result, a diagnostic agent when the antigen-binding molecule targets the antigen. And / or an antigen-binding molecule that is useful as a therapeutic agent.
  • the degree of binding of the antigen-binding molecule to an unrelated non-target antigen protein (eg, radioimmunoassay).
  • an unrelated non-target antigen protein eg, radioimmunoassay.
  • less than about 10% of the antigen-binding molecule binds to the target antigen.
  • the antigen-binding molecule that binds to the target antigen is ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, Dissociation constants of ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (eg, 10 -8 M or less, eg 10 -8 M to 10 -13 M, eg 10 -9 M to 10 -13 M) Having (Kd).
  • the antigen-binding molecule binds to an epitope of a target antigen that is conserved between target antigens from different species.
  • An antigen-binding molecule that "binds to the same epitope" as a reference antigen-binding molecule is an antigen-binding molecule that blocks 50% or more of the reference antigen-binding molecule from binding to its own antigen in a competitive assay, and vice versa.
  • the reference antigen-binding molecule blocks 50% or more of the above-mentioned antigen-binding molecule from binding to its own antigen in a competitive assay.
  • An exemplary competitive assay is provided herein.
  • the immobilized antigen (eg, GPC3, CD3 and / or IL-6 receptor) is associated with a first labeled antigen-binding molecule that binds to that antigen and its binding to that antigen.
  • a solution containing a second unlabeled antigen-binding molecule tested for its ability to compete with the first antigen-binding molecule.
  • the second antigen-binding molecule can be present in the hybridoma supernatant.
  • the immobilized antigen is incubated in a solution containing a first labeled antigen binding molecule but not a second unlabeled antigen binding molecule.
  • the term "antigen-binding molecule” is used in the broadest sense and is not limited to, but is not limited to, a monoclonal antibody, a polyclonal antibody, or a multispecific antibody (as long as it exhibits a desired antigen-binding activity). Includes various antibody structures, including, for example, bispecific antibodies), antibody derivatives and antibody fragments.
  • the antibodies provided herein may be further modified to include additional non-protein moieties known and readily available in the art (as referred to as "" "Antibody derivative”).
  • Suitable moieties for derivatizing antibodies include, but are not limited to, water-soluble polymers.
  • water-soluble polymers are, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly 1,3.
  • the polymer may have any molecular weight and may or may not be branched.
  • the number of polymers added to the antibody can vary, and they can be the same molecule or different molecules as long as one or more polymers are added. In general, the number and / or type of polymer used for derivatization is not limited to these, but the specific properties or functions of the antibody to be improved, the antibody derivative under specified conditions. It can be decided based on consideration such as whether or not it is used for therapy.
  • Antibody fragment refers to a molecule other than the complete antibody, which comprises a portion of the complete antibody that binds to the antigen to which the complete antibody binds.
  • Examples of antibody fragments are, but are not limited to, Fv, Fab, Fab', Fab'-SH, F (ab') 2 ; Diabody; Linear antibody; Single chain antibody molecule (eg, scFv). ); And includes multispecific antibodies formed from antibody fragments.
  • an "antibody that binds to the same epitope" as a reference antibody is an antibody that blocks 50% or more of the reference antibody from binding to its own antigen in a competitive assay, and conversely, a reference antibody is a competitive assay. In, the above-mentioned antibody blocks 50% or more of binding to its own antigen.
  • An exemplary competitive assay is provided herein.
  • chimeric antibody is one in which a portion of the heavy and / or light chain is derived from a particular source or species, while the rest of the heavy and / or light chain is derived from a different source or species. It refers to an antibody.
  • the "class" of an antibody refers to the type of constant domain or constant region provided in the heavy chain of an antibody.
  • Heavy chain constant domains corresponding to different classes of immunoglobulins are referred to as ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the constant regions of each isotype of IgG1, IgG2, IgG3, and IgG4 are called C ⁇ 1, C ⁇ 2, C ⁇ 3, and C ⁇ 4, respectively.
  • the amino acid sequences of the polypeptides constituting the Fc region of human C ⁇ 1, C ⁇ 2, C ⁇ 3, and C ⁇ 4 are exemplified in SEQ ID NOs: 23, 24, 25, and 26.
  • the relationship between the amino acid residues constituting each amino acid sequence and the EU numbering of kabat (also referred to as EU INDEX in the present specification) is shown in FIG.
  • the term "Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least part of the constant region.
  • the term includes the Fc region of a native sequence and the mutant Fc region.
  • the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl end of the heavy chain.
  • the C-terminal lysine (Lys447) or glycine-lysine (Gly446-Lys447) in the Fc region may or may not be present.
  • the numbering of amino acid residues in the Fc region or constant region is Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, follow the EU numbering system (also known as the EU index) described in MD 1991.
  • Fc receptor refers to a receptor that binds to the Fc region of an antibody.
  • the FcR is a native human FcR.
  • the FcR is one that binds to an IgG antibody (gamma receptor) and forms the receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses by allelic variants and alternative splicing of these receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (“activating receptor”) and Fc ⁇ RIIB (“inhibiting receptor”), which have similar amino acid sequences that differ primarily in their cytoplasmic domain.
  • the activation receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • the inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • Fc receptor or “FcR” also refers to the transfer of maternal IgG to the fetal (Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol. 24: 249. (1994)) and includes the neonatal receptor FcRn, which is responsible for the regulation of immunoglobulin homeostasis. Methods for measuring binding to FcRn are known (eg, Ghetie and Ward., Immunol. Today 18 (12): 592-598 (1997); Ghetie et al., Nature Biotechnology, 15 (7): 637- 640 (1997); Hinton et al., J. Biol. Chem. 279 (8): 6213-6216 (2004); See WO2004 / 92219 (Hinton et al.)).
  • the term "Fc region-containing antibody” refers to an antibody containing an Fc region.
  • the C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) or the C-terminal glycine-lysine of the Fc region (residues 446-447) can be used, for example, during antibody purification or in the nucleic acid encoding the antibody. It can be removed by recombination. Therefore, the composition containing the antibody having the Fc region according to the present invention is an antibody with G446-K447, an antibody with G446 without K447, an antibody from which G446-K447 is completely removed, or an antibody of the above three types. Can include a mixture of.
  • the Fc region in which the binding activity to the Fc receptor is decreased includes the Fc region in which the binding activity to any Fc ⁇ receptor of Fc ⁇ I, Fc ⁇ IIA, Fc ⁇ IIB, Fc ⁇ IIIA and / or Fc ⁇ IIIB is decreased.
  • Fc ⁇ I, Fc ⁇ IIA, Fc ⁇ IIB, Fc ⁇ IIIA and / or Fc ⁇ IIIB has reduced binding activity to the Fc ⁇ receptor, as well as FACS and ELISA formats known to those skilled in the art, as well as ALPHA screens (Amplified Luminescent Proximity Homogeneous). It can be confirmed by the BIACORE method using the Assay) or surface plasmon resonance (SPR) phenomenon (Proc.Natl.Acad.Sci.USA (2006) 103 (11), 4005-4010).
  • the antigen-binding molecule or antibody containing the Fc region having reduced Fc receptor-binding activity includes an antigen-binding molecule or antibody with reduced effector function.
  • Antigen-binding molecules or antibodies with reduced effector function include those with one or more substitutions of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (US Pat. No. 6,737,056). ..
  • Such Fc variants include the so-called "DANA" Fc variants (US Pat. No. 7,332,581) with substitutions of residues 265 and 297 for alanine, at amino acid positions 265, 269, 270, 297, and 327. Includes Fc variants with two or more substitutions.
  • the antibody variant undergoes one or more amino acid substitutions that improve ADCC (eg, substitutions at positions 298, 333, and / or 334 (residues in EU numbering) of the Fc region). Includes the accompanying Fc region.
  • the Fc region with reduced Fc receptor binding activity comprises an Fc variant of the Fc region exemplified herein.
  • variable domain FR refers to variable domain residues other than hypervariable region (HVR) residues.
  • a variable domain FR usually consists of four FR domains: FR1, FR2, FR3, and FR4.
  • sequences of HVR and FR usually appear in VH (or VL) in the following order: FR1-H1 (L1) -FR2-H2 (L2) -FR3-H3 (L3) -FR4.
  • full-length antibody “complete antibody,” and “whole antibody” are used interchangeably herein and have a structure substantially similar to that of a native antibody, or are defined herein.
  • host cell refers to cells into which foreign nucleic acids have been introduced, including progeny of such cells. ..
  • Host cells include “transformants” and “transformants”, which include primary transformants and progeny derived from those cells regardless of the number of passages. Offspring do not have to be exactly identical in content to the parent cell and nucleic acid and may contain mutations. Variant progeny with the same function or biological activity as those used when the original transformed cells were screened or selected are also included herein.
  • human antibody is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by humans or human cells or an antibody derived from a non-human source using a human antibody repertoire or other human antibody coding sequences. This definition of human antibody explicitly excludes humanized antibodies that contain non-human antigen-binding residues.
  • the "human consensus framework” is a framework that shows the most commonly occurring amino acid residues in the selection group of human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
  • the subgroups of the array are the subgroups in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3.
  • the subgroup is the subgroup ⁇ I by Kabat et al. Above.
  • the subgroup is Subgroup III by Kabat et al. Above.
  • Humanized antibody refers to a chimeric antibody that contains amino acid residues from non-human HVR and amino acid residues from human FR.
  • the humanized antibody comprises substantially all of at least one, typically two variable domains, in which all or substantially all HVRs (eg, CDRs) are non-existent.
  • all or substantially all FRs correspond to those of human antibodies.
  • the humanized antibody may optionally include at least a portion of the antibody constant region derived from the human antibody.
  • the "humanized form" of an antibody (eg, a non-human antibody) refers to an antibody that has undergone humanization.
  • hypervariable region As used herein, the terms "hypervariable region”, “HVR” or “CDR” are hypervariable in sequence (“complementarity determining regions” or “complementarity determining regions”) and / or are structurally defined. Refers to each region of the variable domain of an antibody that forms a loop (“supervariable loop”) and / or contains antigen contact residues (“antigen contact”). Usually, the antibody contains 6 CDRs: 3 for VH (H1, H2, H3) and 3 for VL (L1, L2, L3).
  • Illustrative CDRs herein include: (a) At amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3).
  • the resulting hypervariable loop (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)); (b) At amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3).
  • the resulting CDR (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.
  • the "individual”, “subject” or “subject” is a mammal. Mammals are, but are not limited to, domestic animals (eg, cows, sheep, cats, dogs, horses), primates (eg, non-human primates such as humans and monkeys), rabbits, and , Includes rodents (eg, mice and rats). In certain embodiments, the individual or subject is a human.
  • an "isolated" antigen-binding molecule is one that has been isolated from its original environmental components.
  • electrophoresis eg, SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatograph eg, ion exchange or reverse phase HPLC. Purified to a purity greater than 95% or 99%. See, for example, Flatman et al., J. Chromatogr. B 848: 79-87 (2007) for a review of methods for assessing antibody purity.
  • isolated nucleic acid refers to a nucleic acid molecule that has been isolated from its original environmental components.
  • An isolated nucleic acid contains a nucleic acid molecule contained within a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule is on a chromosome that is extrachromosomal or different from its original chromosomal location. Exists in position.
  • An "isolated nucleic acid encoding an antigen-binding molecule” encodes one or more polypeptide chains or fragments thereof (in the case of an antibody, the heavy and light chains of the antibody or fragments thereof) of the antigen-binding molecule.
  • One or more nucleic acid molecules including nucleic acid molecules on one vector or separate vectors, and nucleic acid molecules present at one or more positions in a host cell.
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a substantially uniform population of antibodies. That is, the individual antibodies that make up the population are possible mutant antibodies (eg, mutant antibodies that contain naturally occurring mutations, or mutant antibodies that occur during the production of monoclonal antibody preparations, such variants are usually slightly present. Except for the amount present), it binds to the same and / or the same epitope.
  • Each monoclonal antibody in a monoclonal antibody preparation is for a single determinant on an antigen, as opposed to a polyclonal antibody preparation that typically comprises different antibodies against different determinants (epitopes).
  • the modifier "monoclonal” should not be construed as requiring the production of an antibody by any particular method, indicating the characteristic of the antibody that it is obtained from a substantially homogeneous population of antibodies.
  • the monoclonal antibody used according to the present invention is not limited to these, but is a hybridoma method, a recombinant DNA method, a phage display method, and a transgenic animal containing all or a part of the human immunoglobulin locus. It may be made by a variety of methods, including methods that utilize, such methods and other exemplary methods for making monoclonal antibodies are described herein.
  • package insert is commonly included in commercial packaging of therapeutic products and contains information about the indications, dosages, doses, dosages, concomitant medications, contraindications, and / or warnings regarding the use of such therapeutic products. It is used to refer to the instruction manual.
  • Percent (%) amino acid sequence identity to a reference polypeptide sequence is any conservative substitution sequence after aligning the sequences for maximum percent sequence identity and, if necessary, introducing gaps. It is defined as the percentage ratio of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence when not considered part of the identity. Alignment for the purpose of determining percent amino acid sequence identity can be done by various methods within the skill of the art, such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software, or GENETYX®®. This can be achieved by using publicly available computer software such as Company Genetics. One of ordinary skill in the art can determine the appropriate parameters for sequence alignment, including any algorithm required to achieve maximum alignment over the overall length of the sequence being compared.
  • the ALIGN-2 Sequence Comparison Computer Program is the work of Genetec, the source code of which was submitted to the United States Copyright Office (Washington DC, 20559) along with user documentation under the United States Copyright Registration Number TXU510087. It is registered.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California and may be compiled from source code.
  • the ALIGN-2 program is compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not fluctuate. In situations where ALIGN-2 is used for amino acid sequence comparison,% amino acid sequence identity (or given amino acid sequence) of a given amino acid sequence A to, to, or to a given amino acid sequence B.
  • a given amino acid sequence A which has or contains some% amino acid sequence identity to, to, or to B) is calculated as: fraction X / Y: Hundredfold.
  • X is the number of amino acid residues scored by the sequence alignment program ALIGN-2 as a match that is identical in the alignment of A and B in that program
  • Y is the total number of amino acid residues in B. ..
  • pharmaceutical formulation is a preparation in a form in which the biological activity of the active ingredient contained therein can exert its effect and is unacceptable to the subject to whom the formulation is administered. Refers to a preparation that does not contain any additional toxic elements.
  • “Pharmaceutically acceptable carrier” refers to an ingredient other than the active ingredient in a pharmaceutical formulation that is non-toxic to the subject.
  • Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.
  • treatment and its grammatical derivatives such as “treat”, “treat”, etc. are clinically intended to alter the natural course of the individual being treated. It means intervention and can be performed both for prevention and during the course of the clinical condition. Desirable effects of treatment are, but are not limited to, prevention of the onset or recurrence of the disease, relief of symptoms, reduction of any direct or indirect pathological effects of the disease, prevention of metastasis, prevention of disease Includes reduced rate of progression, recovery or alleviation of disease state, and ameliorated or improved prognosis.
  • the antibodies of the invention are used to delay the onset of a disease or slow the progression of a disease.
  • variable region refers to the heavy or light chain domain of an antibody involved in binding the antibody to an antigen.
  • the heavy and light chain variable domains of native antibodies are similar, with each domain usually containing four conserved framework regions (FR) and three hypervariable regions (HVR).
  • FR conserved framework regions
  • HVR hypervariable regions
  • antibodies that bind to a particular antigen may be isolated by screening a complementary library of VL or VH domains using the VH or VL domains from the antibody that binds to that antigen. See, for example, Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).
  • vector refers to a nucleic acid molecule that can augment another nucleic acid to which it is linked.
  • the term includes a vector as a self-replicating nucleic acid structure and a vector incorporated into the genome of the host cell into which it has been introduced. Certain vectors can result in the expression of nucleic acids to which they are operably linked. Such vectors are also referred to herein as "expression vectors.”
  • the antigen binding molecule (or antibody) provided herein is a multispecific antibody (eg, a bispecific antibody).
  • Multispecific antibodies are monoclonal antibodies that have binding specificity at at least two different sites.
  • Multispecific antibodies eg, bispecific antibodies
  • Multispecific antibodies manipulate electrostatic steering effects to create Fc heterodimer molecules (WO2009 / 089004A1); crosslink two or more antibodies or fragments (US patent). See Nos.
  • Modified antibodies with three or more functional antigen binding sites are also included herein (see, eg, US Patent Application Publication No. 2006/0025576 A1).
  • an antigen-binding molecule or fragment also includes a "dual-acting Fab" or "DAF” that includes one antigen-binding site that binds to one particular antigen and another different antigen (eg, US Patent Application Publication). 2008/0069820).
  • the "anti-T cell antigen-binding molecule” is an antigen-binding molecule that binds to an antigen on T cells and an antigen-binding molecule that binds to a T cell receptor complex. Contains molecules.
  • the anti-T cell antigen binding molecule is a multispecific antigen binding molecule.
  • the anti-T cell antigen binding molecule comprises "a domain comprising an antibody variable region having T cell receptor complex binding activity" and "a domain comprising an antibody variable region having cancer antigen binding activity". It is a highly specific antigen-binding molecule, preferably a bispecific antibody.
  • the bispecific antibody may have the structure of a single chain antibody, eg, a structure in which an antibody variable region is linked with a linker.
  • the anti-T cell antigen binding molecule further comprises an Fc region with reduced binding activity to the Fc ⁇ receptor.
  • the domain containing the antibody variable region having the T cell receptor complex binding activity is preferably a domain containing the antibody variable region having the T cell receptor binding activity, and more preferably CD3 binding.
  • a domain containing an active antibody variable region is provided by a variable domain of one or a plurality of antibodies, and preferably, the domain containing the antibody variable region is an antibody light chain variable region (VL) and an antibody weight. Includes chain variable region (VH).
  • domains containing such antibody variable regions include various antibody fragments, such as “scFv (single chain Fv)", “single chain antibody”, “Fv”, and “scFv2 (single chain Fv2)”. , “Fab” or “F (ab') 2" and the like are preferably mentioned.
  • a domain containing an antibody variable region having a cancer antigen-binding activity is specifically bound to and complementary to a part or all of a cancer antigen. A portion of an antibody that includes a region of interest.
  • cancer-specific antigen means an antigen expressed by a cancer cell that makes it possible to distinguish between a cancer cell and a healthy cell, and for example, an antigen expressed as the cell becomes malignant. , Contains abnormal sugar chains that appear on the cell surface and protein molecules when cells become cancerous. Specifically, for example, GPC3, ALK receptor (playotrophin receptor), playotrophin, KS 1/4 pancreatic cancer antigen, ovarian cancer antigen (CA125), prostatic acid phosphate, prostate-specific antigen (PSA).
  • GPC3, ALK receptor playotrophin receptor
  • playotrophin KS 1/4 pancreatic cancer antigen
  • CA125 ovarian cancer antigen
  • PSA prostate-specific antigen
  • Melanoma-related antigen p97 Melanoma antigen gp75, High molecular weight melanoma antigen (HMW-MAA), Prostate-specific membrane antigen, Carcinoembryonic embryo antigen (CEA), Polymorphic epithelial mutin antigen, Human milk fat globule antigen, CEA, TAG -72, CO17-1A, GICA19-9, CTA-1 and LEA and other colonic rectal tumor-related antigens, Berkit lymphoma antigen-38.13, CD19, human B lymphoma antigen-CD20, CD33, ganglioside GD2, ganglioside GD3, ganglioside Melanoma-specific antigens such as GM2 and ganglioside GM3, tumor antigens induced by viruses such as tumor-specific transplanted cell surface antigens (TSTA), T antigens, DNA tumor viruses and envelope antigens of RNA tumor viruses, CEA of the colon, 5T4 Car
  • the cancer-specific antigen that is the target of the cancer-specific antigen-binding domain of the present invention is particularly preferably one that is expressed on the cell surface, and such cancer-specific antigens include, for example, CD19, CD20, EGFR, and HER2. , EpCAM, EREG.
  • domain containing antibody variable region having glypican 3 (GPC3) binding activity is specific to a part or all of the above GPC3 protein or a partial peptide thereof. A portion of an antibody comprising a region that is binding and complementary to.
  • glypican 3 is a group of heparan sulfate proteoglycans bound to the cell surface via glycosylphosphatidylinositol, that is, a protein belonging to the glypican family (Filmus, J. Clin. Invest., 2001, 108, 497-501). Glypicans play important roles in cell proliferation, differentiation, and migration. GPC3 is expressed in more than 70% of hepatocellular carcinoma tissue obtained by surgical resection or biopsy, and is completely or almost unexpressed in adjacent non-neoplastic liver lesions and most adult tissues. Not (Zhu-Zu-W, Gut, 2001, 48, 558-564, Yamauchi, Mod. Pathol., 2005, 18, 1591-1598).
  • a domain containing an antibody variable region having a T cell receptor complex binding activity is one of the T cell receptor complexes.
  • a portion of a T cell receptor complex antibody comprising a region that is specifically bound and complementary to a portion or all.
  • the T cell receptor complex may be the T cell receptor itself or an adapter molecule that constitutes the T cell receptor complex together with the T cell receptor.
  • a suitable adapter is a CD3.
  • domain containing antibody variable region having T cell receptor binding activity is specific to a part or all of T cell receptors.
  • the portion of the T cell receptor to which the domain of the present invention binds may be a variable region or a constant region, but is preferably an epitope present in the constant region.
  • T cell receptor ⁇ chain of RefSeq registration number CAA26636.1 (SEQ ID NO: 9)
  • T cell receptor ⁇ chain of RefSeq registration number C25777 (SEQ ID NO: 10)
  • RefSeq registration number A26659 T cell receptor ⁇ 1 chain (SEQ ID NO: 11)
  • T cell receptor ⁇ 2 chain of RefSeq registration number AAB63312.1 (SEQ ID NO: 12)
  • T cell receptor ⁇ chain of RefSeq registration number AAA61033.1 SEQ ID NO:: The sequence of 13) can be mentioned.
  • domain containing antibody variable region having CD3 binding activity refers to a region that specifically binds to and is complementary to a part or all of CD3. The portion of the CD3 antibody that contains it.
  • the domain containing the antibody variable region having CD3 binding activity according to the present invention may bind to any epitope present in the ⁇ chain, ⁇ chain or ⁇ chain sequence constituting human CD3.
  • the present invention preferably comprises a light chain variable region (VL) of an anti-CD3 antibody that binds to an epitope present in the extracellular region of the ⁇ chain of a human CD3 complex and a heavy chain variable region (VH) of an anti-CD3 antibody. Domains are preferably used. Such domains include the light chain variable region (VL) of the anti-CD3 antibody and the heavy chain variable region (VH) of the anti-CD3 antibody described in Examples, as well as the OKT3 antibody (Proc. Natl. Acad. Sci. USA).
  • a CD3 binding domain containing 1980) 77, 4914-4917) and various known CD3 antibody light chain variable regions (VL) and CD3 antibody heavy chain variable regions (VH) is preferably used.
  • a domain containing an antibody variable region originating from an anti-CD3 antibody having desired properties obtained by immunizing a desired animal with the ⁇ chain, ⁇ chain or ⁇ chain constituting human CD3 by the above method Can be used as appropriate.
  • the anti-CD3 antibody that is the origin of the domain containing the antibody variable region having CD3 binding activity a humanized antibody or a human antibody as described above is appropriately used.
  • the structure of the ⁇ chain, ⁇ chain, or ⁇ chain that constitutes CD3 has its polynucleotide sequence as SEQ ID NO: 9 (NM_000073.2), 10 (NM_000732.4) and 11 (NM_000733.3).
  • the sequences are described in SEQ ID NOs: 12 (NP_000064.1), 13 (NP_000723.1) and 14 (NP_000724.1) (RefSeq registration numbers are shown in parentheses).
  • the domain containing the antibody variable region in the antigen-binding molecule of the present invention can bind to the same epitope.
  • the same epitope can be present in a protein consisting of the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 14.
  • the domains containing the antibody variable region in the antigen-binding molecule of the present invention can bind to different epitopes.
  • different epitopes can be present in the protein consisting of the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 14.
  • the decrease in the binding activity to the Fc ⁇ receptor means, for example, that the test antigen binding is compared with the binding activity of the control antigen-binding molecule.
  • the binding activity of the molecule is 50% or less, preferably 45% or less, 40% or less, 35% or less, 30% or less, 20% or less, 15% or less, particularly preferably 10% or less, 9% or less, 8% or less. , 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less.
  • an antigen-binding molecule having an Fc region of IgG1, IgG2, IgG3 or IgG4 monoclonal antibody can be appropriately used.
  • an antigen-binding molecule having a variant of the Fc region of a specific isotype antibody is used as a test substance
  • an antigen-binding molecule having an Fc region of the specific isotype antibody is used as a control.
  • the effect of the mutation possessed by the mutant on the binding activity to the Fc ⁇ receptor will be verified.
  • an antigen-binding molecule having a mutant of the Fc region whose binding activity to the Fc ⁇ receptor has been verified to be reduced is appropriately prepared.
  • mutants are deletions of the amino acid 231A-238S identified according to EU numbering (WO 2009/011941), C226S, C229S, P238S, (C220S) (J. Rheumatol (2007) 34, 11), C226S, C229S (Hum.Antibod.Hybridomas (1990) 1 (1), 47-54), C226S, C229S, E233P, L234V, L235A (Blood (2007) 109, 1185-1192) It is known.
  • any of the following amino acids identified according to EU numbering at positions 220, 226, 229, 231, 232, 233, and 234. , 235th, 236th, 237th, 238th, 239th, 240th, 264th, 265th, 266th, 267th, 269th, 270th, 295th, 296th, 297th, 298th, 299th
  • Preferable examples thereof include antigen-binding molecules having an Fc region in which the positions, 300, 325, 327, 328, 329, 330, 331, and 332 are substituted.
  • the isotype of the antibody that is the origin of the Fc region is not particularly limited, and the Fc region that originates from IgG1, IgG2, IgG3 or IgG4 monoclonal antibody can be appropriately used, but the Fc region that originates from the IgG1 antibody is preferably used. Will be done.
  • amino acids that make up the Fc region of IgG1 antibody one of the following substitutions specified according to the EU numbering (the position of the amino acid residue whose number is specified according to the EU numbering, the one-letter amino acid located before the number) The symbol represents the amino acid residue before replacement, and the one-letter amino acid symbol located after the number represents the amino acid residue before replacement); (A) L234F, L235E, P331S, (B) C226S, C229S, P238S, (C) C226S, C229S, (D) C226S, C229S, E233P, L234V, L235A (E) L234A, L235A or L235R, N297A (F) L235A or L235R, S239K, N297A
  • An antigen-binding molecule having an Fc region in which the above is applied or an Fc region in which the amino acid sequence at positions 231 to 238 is deleted can also be used as appropriate.
  • any of the following substitutions specified according to the EU numbering (the position of the amino acid residue whose number is specified according to the EU numbering, the one-letter amino acid located before the number) The symbol represents the amino acid residue before replacement, and the one-letter amino acid symbol located after the number represents the amino acid residue before replacement); (G) H268Q, V309L, A330S, P331S (H) V234A (I) G237A (J) V234A, G237A (K) A235E, G237A (L) V234A, A235E, G237A An antigen-binding molecule having an Fc region that has been subjected to
  • any of the following substitutions specified according to the EU numbering (the position of the amino acid residue whose number is specified according to the EU numbering, the one-letter amino acid located before the number) The symbol represents the amino acid residue before replacement, and the one-letter amino acid symbol located after the number represents the amino acid residue before replacement);
  • (M) F241A (N) D265A (O) V264A An antigen-binding molecule having an Fc region that has been subjected to
  • any of the following substitutions specified according to the EU numbering (the position of the amino acid residue whose number is specified according to the EU numbering, the one-letter amino acid located before the number) The symbol represents the amino acid residue before replacement, and the one-letter amino acid symbol located after the number represents the amino acid residue before replacement.
  • P L235A, G237A, E318A
  • Q L235E
  • R F234A, L235A
  • any of the following amino acids identified according to EU numbering 233, 234, 235, 236, 237, 327, 330
  • antigen-binding molecules having an Fc region in which the EU numbering of the corresponding IgG2 or IgG4 is replaced with the corresponding amino acid at the position 331.
  • Preferred examples include antigen-binding molecules having an Fc region.
  • the type of amino acid present after the substitution is not particularly limited, but an antigen-binding molecule having an Fc region in which one or more amino acids at positions 234, 235, and 297 are replaced with alanine is particularly preferable.
  • amino acids constituting the Fc region of the IgG1 antibody one of the following amino acids identified according to EU numbering; an antigen-binding molecule having an Fc region in which the 265th position is replaced by another amino acid Preferred.
  • the type of amino acid present after the substitution is not particularly limited, but an antigen-binding molecule having an Fc region in which the amino acid at position 265 is substituted with alanine is particularly preferable.
  • the anti-T cell antigen binding molecule is (1) a domain containing an antibody variable region having glypican 3-binding activity, (2) T. It is a bispecific antibody containing a domain containing an antibody variable region having a cell receptor complex binding activity and (3) a domain containing an Fc region having a reduced binding activity to the Fc ⁇ receptor.
  • the antibody variable region having glypican 3-binding activity and the antibody L-chain variable region contained in the antibody variable region having T cell receptor complex binding activity of the present invention are H having binding activity to glypican 3. Obtain a common L chain that can impart binding ability to both the chain and the H chain that has binding activity to the T cell receptor complex, and use this as the common L chain variable region of the bispecific antibody. Is preferable.
  • Examples of the antibody H chain variable region contained in the antibody variable region having preferable glypican 3 binding activity in the present disclosure include the antibody H chain variable region shown in Table 1 or the amino acid sequences of CDR1, CDR2 and CDR3 in Table 1.
  • the antibody H chain variable region having the same CDR sequence as the amino acid sequence of CDR1, CDR2 and CDR3 of the antibody H chain variable region described in 1 or the antibody H chain variable region functionally equivalent to the variable region can be mentioned. ..
  • an antibody variable region having a preferable T cell receptor complex binding activity in the present disclosure an antibody variable region having a binding activity to a T cell receptor can be mentioned.
  • T cell receptors CD3 is preferable, and CD3 ⁇ is particularly preferable.
  • the antibody H chain variable region included in such an antibody variable region include the antibody H chain variable region shown in Table 2, or the antibody H chain variable regions in which the amino acid sequences of CDR1, CDR2 and CDR3 are shown in Table 2. Examples thereof include an antibody H chain variable region having the same CDR sequence as the amino acid sequences of CDR1, CDR2 and CDR3 possessed by the region, or an antibody H chain variable region functionally equivalent to the variable region.
  • an antibody L chain variable region having the same CDR sequence as the amino acid sequence of CDR3, or an antibody L variable region functionally equivalent to the variable region can be mentioned.
  • the combination of the antibody variable region having glypican 3-binding activity and the antibody variable region having T cell receptor complex binding activity includes, for example, the combination of the antibody H chain variable regions shown in Table 4 or the combination of the antibody H chain variable regions shown in Table 4.
  • preferred common L chains include, for example, L0000, L0011, L0201, L0203, L0204, L0206, L0208, L0209, L0211, L0212, L0222, or a common L in which the amino acid sequences of CDR1, CDR2, and CDR3 of the common L chain have the same CDR sequence as the amino acid sequences of CDR1, CDR2, and CDR3 of these common L chains. You can raise a chain.
  • Specific preferred combinations include, for example, the combination of the antibody H chain variable region and the common L chain shown in Table 5, or the antibody variable region and the common L chain in which the amino acid sequences of CDR1, CDR2 and CDR3 are shown in Table 5. Examples thereof include a combination of antibody variable regions having the same CDR sequence as the amino acid sequences of CDR1, CDR2 and CDR3 possessed by the antibody, or a combination of an antibody H chain variable region and a common L chain functionally equivalent to the variable region.
  • the Fc region contained in the anti-T cell antigen-binding molecule is not particularly limited as long as it is an Fc region in which the binding activity to the Fc ⁇ receptor is reduced, but the preferred Fc region is, for example, , The combination of the Fc region part of E22Hh and the Fc region part of E22Hk, the combination of the Fc region part of E2702GsKsc and the Fc region part of E2704sEpsc, and the combination of the Fc region part of E2702sKsc and the Fc region part of E2704sEpsc.
  • the anti-T cell antigen binding molecule of the present disclosure is ERY974.
  • ERY974 has (1) a domain containing an antibody variable region having glypican 3-binding activity, (2) a domain containing an antibody variable region having T cell receptor complex binding activity, and (3) a domain containing an antibody variable region having Fc ⁇ receptor binding activity. It is a bispecific antibody containing a domain containing a lowered Fc region, TR01H113 (SEQ ID NO: 168) as the heavy chain variable region on the CD3 side, and E2702sKsc (SEQ ID NO: 62) as the heavy chain constant region on the CD3 side.
  • the CD3 side heavy chain of ERY974 comprises the amino acid sequence of SEQ ID NO: 402
  • the GPC3 side heavy chain comprises the amino acid sequence of SEQ ID NO: 385
  • the common light chain comprises the amino acid sequence of SEQ ID NO: 410.
  • the amino acids contained in the amino acid sequence in the present disclosure may be modified after translation.
  • the N-terminal glutamine residue (Q) becomes pyroglutamic acid (pGlu) by pyroglutamylation.
  • pGlu pyroglutamic acid
  • bispecific antibodies having an antibody variable region having binding activity to glypican 3 and an antibody variable region having binding activity to CD3 ⁇ . More preferably, the cytotoxic activity is equal to or higher than that of the bispecific antibody GPC3_ERY22_rCE115 (disclosed in Example 1 of WO2015156268).
  • bispecific antibodies include the bispecific antibody having an H chain and an L chain shown in Example 3 (Table 13) of WO2015156268, or an epitope that overlaps with an epitope to which the antibody binds.
  • a bispecific antibody having an Fc region that binds to the above-mentioned Fc ⁇ receptor and has a reduced binding activity to the Fc ⁇ receptor can be mentioned.
  • “functionally equivalent” means a cell expressing glypican 3 or a cell having the same binding affinity for an antigen or when used as a bispecific antibody. It means that the cytotoxic activity against the tissue containing is equivalent. Binding affinity and cytotoxic activity can be measured based on the description herein.
  • a desired cell expressing GPC3 or a desired tissue containing the cell may be used, for example, PC-10 or NCI-, which is a human cancer cell line expressing GPC3. H446 can be used.
  • the decrease in the binding activity to the Fc ⁇ receptor may be equivalent.
  • an antibody H chain variable region functionally equivalent to the antibody H chain variable region (original H chain variable region) described in the present specification is described in the present specification as a pair of the original H chain.
  • the binding affinity is equivalent, or when used as a bispecific antibody, it is applied to cells expressing glypican 3 or tissues containing the cells. It means that the cytotoxic activity is equivalent.
  • an antibody L-chain variable region functionally equivalent to the antibody L-chain variable region (original L-chain variable region) described in the present specification is described in the present specification as a pair of the original L-chain.
  • the binding affinity is equivalent, or when used as a bispecific antibody, cells expressing glypican 3 or cells containing the cells. It means that the injury activity is equivalent.
  • “equivalent” does not necessarily have to be the same degree of activity, and the activity may be enhanced.
  • the value (KD value / parent KD value) compared with the binding affinity (parent KD value) of the control antibody variable region is 1.5 or less. It can.
  • the value of the KD value / parent KD value is preferably 1.3 or less, more preferably 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less.
  • the value of the KD value / parent KD value is preferably 10 -6 to 1.5x10 -0 , more preferably 10 -6 to 10 -1 , and more preferably 10 -6 to 10 -2. , More preferably 10 -6 to 10 -3 .
  • the value (cell growth suppression rate / parent cell growth suppression rate) compared with the cell growth suppression rate (parent cell growth suppression rate) of the control bispecific antibody is 0.7 or more is mentioned. be able to.
  • the concentration of the multispecific antigen-binding molecule to be added is appropriately determined, but is preferably measured at, for example, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, or 1 nM, preferably 0.05 nM or 0.1 nM.
  • the value of cell growth inhibition rate / parent cell growth inhibition rate is preferably 0.8 or more, more preferably 0.9 or more, 1.0 or more, 1.2 or more, 1.5 or more, 2 or more, 3 or more, 5 or more, 10 or more, or 20. That is all. There is no upper limit, but it may be, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , or 10 6 .
  • the case where the concentration) is 1.5 or less can be mentioned.
  • the 50% growth inhibitory concentration is the concentration of the multispecific antigen-binding molecule required to halve the cell proliferation rate as compared with the case where the multispecific antigen-binding molecule is not added.
  • the value of "cell 50% growth inhibitory concentration / parent cell 50% growth inhibitory concentration” is preferably 1.3 or less, more preferably 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less. , Or 0.5 or less.
  • the lower limit there is no limit to the lower limit, but it may be, for example, 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , or 10 -6 . Specifically, it is preferably 10 -6 to 1.5x10 -0 , more preferably 10 -6 to 10 -1 , more preferably 10 -6 to 10 -2 , and more preferably 10 -6 to 10 -3 .
  • the KD value for GPC3 (for example, human GPC3) may be, for example, 5x10 -9 M or less, preferably 4x10 -9 M or less, for example, 3x10 -9.
  • the KD value for the human T cell receptor complex is determined.
  • it may be less 2x10 -7 M, preferably no more than 1.5 ⁇ 10 -7 M, for example, 1.4 ⁇ 10 -7 M or less, 1.3 x 10 -7 M or less, 1.2x10 -7 M or less, 1x10 -7 M or less, 3x10 - 8 M or less, 2x10 -8 M or less, 1x10 -8 M or less, 8x10 -9 M or less, 5x10 -9 M or less, 4x10 -9 M or less, 3x10 -9 M or less, 2x10 -9 M or less, 1x10 -9 M below, 8x10 -10 M or less, 5x10 -10 M or less, 4x10 -10 M or less, 3x10 -10 M or less, 2x10 -10 M or less, 1x10 -10 M or less, 1x10 -10 M or less, 1x10 -10 M or less, 1x10 -10 M or less, 1x10 -10 M or less
  • the bispecific antibodies of the present disclosure preferably have KD values for human GPC3 and human T cell receptor complexes (eg, human CD3 ⁇ chain) of 5x10 -9 M or less and 2x10 -7 M or less, respectively. Preferably, they are 1x10 -9 M or less and 5x10 -8 M or less, respectively.
  • the "functionally equivalent" antibody variable region is not particularly limited as long as it is an antibody H chain variable region and / or an antibody L chain variable region that satisfies the above conditions.
  • antibody variable regions for example, one or more amino acids (for example, 1, 2, 3, 4, 5 or 10 amino acids) are substituted or deleted in the amino acid sequences of the variable regions shown in Tables 1 to 3 above.
  • a method well known to those skilled in the art for substituting, deleting, adding and / or inserting one or more amino acids in an amino acid sequence is a method of introducing a mutation into a protein.
  • the properties of the amino acid side chain include hydrophobic amino acids (A, I, L, M, F, P, W, Y, V) and hydrophilic amino acids (R, D, N, C, E, Q, G, H, K, S, T), amino acids with aliphatic side chains (G, A, V, L, I, P), amino acids with hydroxyl group-containing side chains (S, T, Y), sulfur atom-containing side chains Amino acids (C, M), amino acids with carboxylic acid and amide-containing side chains (D, N, E, Q), amino acids with base-containing side chains (R, K, H), and aromatic-containing sides Amino acids having a chain (H, F, Y, W) can be mentioned (all in parentheses represent the one-letter notation of amino acids).
  • substitutions of amino acids within each of these groups are referred to as conservative substitutions. It is already known that a polypeptide having an amino acid sequence modified by deletion, addition and / or substitution with another amino acid of one or more amino acid residues to an amino acid sequence maintains its biological activity. (Mark, D. F. et al., Proc. Natl. Acad. Sci. USA (1984) 81: 5662-6; Zoller, M. J. and Smith, M., Nucleic Acids Res. (1982) 10 : 6487-500; Wang, A. et al., Science (1984) 224: 1431-3; Dalbadie-McFarland, G.
  • variable region of the present invention containing such an amino acid modification is at least 70%, more preferably at least 75%, more preferably at least 80% of the CDR sequence, FR sequence or the amino acid sequence of the entire variable region before modification. , More preferably at least 85%, even more preferably at least 90%, and most preferably at least 95% amino acid sequence identity.
  • sequence identity is the amino acid sequence of the original H chain variable region or L chain variable region after the sequences are arranged as necessary so as to maximize the sequence identity and a gap is introduced as appropriate. Is defined as the proportion of residues that are identical to the residues in.
  • the identity of the amino acid sequence can be determined by the method described below.
  • the "functionally equivalent antibody variable region” includes, for example, a nucleic acid that hybridizes to a nucleic acid consisting of a base sequence encoding the amino acid sequence of the variable region shown in Tables 1 to 3 above under stringent conditions. It is also possible to obtain from.
  • the stringent hybridization conditions for isolating a nucleic acid that hybridizes to a nucleic acid consisting of a base sequence encoding a variable region amino acid sequence under stringent conditions are 6 M urea, 0.4% SDS, and 0.5 x. Examples of SSC, 37 ° C. or equivalent stringency hybridization conditions can be exemplified.
  • Washing conditions after hybridization include, for example, 0.5xSSC (1xSSC is 0.15 M NaCL, 0.015 M sodium citrate, pH 7.0) and 0.1% SDS, washing at 60 ° C., more preferably 0.2xSSC, and 0.1% SDS, Cleaning at 60 ° C, more preferably 0.2xSSC and 0.1% SDS, cleaning at 62 ° C, more preferably 0.2xSSC and 0.1% SDS, cleaning at 65 ° C, more preferably 0.1xSSC and 0.1% SDS, 65 ° C Cleaning in.
  • the sequence of the isolated nucleic acid can be determined by a known method described later.
  • the homology of the isolated nucleic acid is at least 50% or more, more preferably 70% or more, still more preferably 90% or more (for example, 95%, 96%, 97%, 98%, 99%) in the entire base sequence. It has the same sequence as above).
  • it is variable by using a gene amplification method using a primer synthesized based on the base sequence information encoding the amino acid sequence of the variable region, for example, a polymerase chain reaction (PCR) method.
  • PCR polymerase chain reaction
  • compositions Containing Anti-T Cell Antigen Binding Molecular From another perspective, the present disclosure describes an anti-T cell antigen binding molecule, preferably (1) a domain comprising an antibody variable region having glypican 3-binding activity, (2). A bispecific antibody containing a domain containing an antibody variable region having T cell receptor complex binding activity and (3) a domain containing an Fc region having decreased binding activity to Fc ⁇ receptor is contained as an active ingredient.
  • the present disclosure also relates to a pharmaceutical composition that induces cytotoxicity containing the anti-T cell antigen-binding molecule as an active ingredient.
  • the pharmaceutical compositions of the present disclosure are administered to an individual who induces the cytotoxicity, particularly T cell-dependent cytotoxicity, and has or may relapse the disease whose activity is necessary for prevention or treatment. Is preferable.
  • a domain containing an antibody variable region having glypican 3-binding activity (2) Domain containing antibody variable region having T cell receptor complex binding activity, and (3) Cytotoxic T cells and cell growth inhibitors containing a multispecific antigen-binding molecule containing a domain containing an Fc region having reduced Fc ⁇ receptor-binding activity as an active ingredient are the anti-T cells. It can also be expressed as a method of inducing cytotoxicity including the step of administering an antigen-binding molecule to an individual, or the use of the anti-T cell antigen-binding molecule in the production of a cytotoxic agent and a cell growth inhibitor.
  • a domain containing an antibody variable region having a glypican 3-binding activity (2) a domain containing an antibody variable region having a T cell receptor complex binding activity, and (3) an Fc ⁇ receptor.
  • Constaining a multispecific antigen-binding molecule containing a domain containing an Fc region having reduced binding activity as an active ingredient means that the anti-T cell antigen-binding molecule is contained as a main active ingredient. It does not limit the content of the anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule of the present invention preferably a bispecific antibody
  • a method of making a drug a sustained-release drug is also known, and the method can be applied to the anti-T cell antigen-binding molecule of the present invention (J. Biomed. Mater. Res. (1981) 15, 267-277. , Chemtech. (1982) 12, 98-105, US Patent No. 3773719, European Patent Publications EP58481 and EP133988, Biopolymers (1983) 22, 547-556).
  • the pharmaceutical composition containing the anti-T cell antigen-binding molecule in the present disclosure can be administered to a patient by either oral or parenteral administration.
  • Parenteral administration is preferred.
  • Specific examples of the administration method include injection administration, nasal administration, pulmonary administration, and transdermal administration.
  • Examples of the injection administration include intravenous injection, intramuscular injection, intraperitoneal injection, and subcutaneous injection.
  • the pharmaceutical composition of the present invention, or a cytotoxic inducer and a cell growth inhibitor can be administered systemically or locally by injection administration.
  • the administration method can be appropriately selected depending on the age and symptoms of the patient.
  • the dose for example, the dose can be selected in the range of 0.0001 mg to 1000 mg per 1 kg of body weight per administration. Alternatively, for example, the dose may be selected in the range of 0.001 mg / body to 100,000 mg / body per patient.
  • the pharmaceutical composition of the present invention, or the cytotoxic inducer and the cell growth inhibitor is not limited to these doses.
  • the pharmaceutical composition containing the anti-T cell antigen-binding molecule in the present disclosure can be formulated according to a conventional method (for example, Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, USA) and is pharmaceutically acceptable. It may contain both a carrier and an additive. For example, surfactants, excipients, colorants, fragrances, preservatives, stabilizers, buffers, suspending agents, tonicity agents, binders, disintegrants, lubricants, fluidity promoters, flavoring agents. And so on. Further, the present invention is not limited to these, and other commonly used carriers can be appropriately used.
  • the disclosure is for use in combination therapy with cytokine inhibitors, including anti-T cell antigen binding molecules, such as bispecific antibodies, preferably bispecific antibodies that bind to cancer antigens and CD3.
  • cytokine inhibitors including anti-T cell antigen binding molecules, such as bispecific antibodies, preferably bispecific antibodies that bind to cancer antigens and CD3.
  • the cytokine inhibitor is an IL6 inhibitor, preferably an anti-human IL-6 receptor antibody, most preferably Tocilizumab. Details of the combination therapy are disclosed in "V. Combination therapy" herein.
  • a "cytokine inhibitor” or “cytokine antagonist” refers to a substance capable of inhibiting, inactivating, or reducing its expression level or activity level. Cytokine inhibitors, for example, bind to cytokines and partially or wholly block, reduce, prevent, delay activation, inactivate, desensitize, or desensitize their activity. Alternatively, it is a compound that down-regulates expression, such as an antagonist. In another example, a cytokine inhibitor partially or totally blocks, reduces, or prevents cytokine activity by binding to a cytokine receptor or by inhibiting the binding of a cytokine to a receptor.
  • Cytokine inhibitors include polypeptide inhibitors such as antigen-binding molecules, antibodies, antibody derivatives, antibody fragments, soluble receptors, their derivatives, and nucleic acid inhibitors such as siRNA or antisense RNA, their derivatives, soluble factors. Genetically modified forms of, such as, but not limited to, types with altered activity, as well as naturally occurring and synthetic soluble factor antagonists, small molecule compounds, and the like.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL. -17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, VEGF, It is an inhibitor of one or more cytokines selected from RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, and RAGE.
  • the cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL. -17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, VEGF, An antibody, antibody derivative or antibody fragment that binds to one or more cytokines or receptors thereof selected from RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin and RAGE.
  • a cytokine inhibitor is an inhibitor of a cytokine whose plasma concentration increases when a cytokine release syndrome (CRS) occurs in an individual.
  • the cytokine inhibitor is an IL-6 inhibitor, more preferably an anti-IL-6 receptor antibody.
  • the cytokine inhibitor is Tocilizumab.
  • a cytokine inhibitor is an inhibitor of IL-6 signaling, such as an inhibitor of IL-6 or IL-6 receptor.
  • the inhibitor is an anti-IL-6 antigen binding molecule, an anti-IL-6 antibody (including a chimeric anti-IL-6 antibody, a humanized anti-IL-6 antibody, a human anti-IL-6 antibody), and its antigen binding. It may be a fragment or an antibody derivative.
  • the inhibitor is an anti-IL-6 receptor (IL-6R) antigen binding molecule, an anti-IL-6R antibody (chimeric anti-IL-6R antibody, humanized anti-IL-6R antibody, human anti-IL-6R).
  • inhibitors may be (including an antibody) or an antigen-binding fragment thereof or an antibody derivative.
  • these inhibitors may be soluble gp130 (sgp130) or fragments thereof that can block IL-6 signaling.
  • sgp130 or a fragment thereof may be a fusion protein fused to a heterologous domain, eg, an Fc domain, eg, a gp130-Fc fusion protein such as FE301.
  • the anti-IL-6 antibody is, for example, Siltuximab, Olokizumab, CDP6038, Elsilimomab, Sirukumab, CNTO136, Clazakizumab, ALD518, BMS-945429. Includes Gerilimzumab, ARGX109) and FM101.
  • the anti-IL-6R antibody comprises, for example, Tocilizumab, Satralizumab, Sarilumab.
  • the inhibitor of IL-6 signaling comprises a small molecule such as CPSI-2364.
  • the anti-IL-6 receptor antibody is an antigen-binding molecule, antibody, antibody derivative or capable of binding to the human IL-6 receptor and blocking IL-6 signaling. It is an antibody fragment.
  • the anti-IL-6 receptor antibody is a heavy chain CDR1 set forth in SEQ ID NO: 433, a heavy chain CDR2 set forth in SEQ ID NO: 434, and a heavy chain CDR3 set forth in SEQ ID NO: 435, and An antibody or antibody fragment that binds to a human IL-6 receptor, comprising the light chain CDR1 set forth in SEQ ID NO: 436, the light chain CDR2 set forth in SEQ ID NO: 437, and the light chain CDR3 set forth in SEQ ID NO: 438. Or an antibody derivative.
  • the anti-IL-6 receptor antibody binds to a human IL-6 receptor comprising the heavy chain variable region set forth in SEQ ID NO: 439 and the light chain variable region set forth in SEQ ID NO: 440.
  • An antibody, antibody fragment or antibody derivative In a different preferred embodiment, the anti-IL-6 receptor antibody binds to a human IL-6 receptor comprising the heavy chain variable region set forth in SEQ ID NO: 441 and the light chain variable region set forth in SEQ ID NO: 442.
  • An antibody, antibody fragment or antibody derivative. More preferably, the anti-IL-6 receptor antibody is an IgG antibody.
  • Tocilizumab is a humanized immunoglobulin G1 (IgG1) kappa anti-human IL-6R monoclonal antibody.
  • Satralizumab is a humanized, immunoimmunoglobulin G2 (IgG2) kappa anti-human IL-6R monoclonal antibody.
  • Tocilizumab and satralizumab block the binding of IL-6 to soluble and membrane-bound IL-6 receptors (IL-6R) and thus inhibit classical and trans-IL-6 signaling.
  • the amino acid sequence of the heavy chain of tocilizumab (SEQ ID NO: 441) is shown below.
  • the part shown in bold is the heavy chain variable region (SEQ ID NO: 439) of tosirizumab, and the underlined part is the heavy chain CDR1 (SEQ ID NO: 433), heavy chain CDR2 (SEQ ID NO: 434), in that order.
  • Heavy chain CDR3 (SEQ ID NO: 435).
  • the amino acid sequence of the light chain of tocilizumab (SEQ ID NO: 442) is shown below.
  • the part shown in bold is the light chain variable region (SEQ ID NO: 440) of tocilizumab, and the underlined part is the light chain CDR1 (SEQ ID NO: 436), light chain CDR2 (SEQ ID NO: 437), in that order.
  • Light chain CDR3 (SEQ ID NO: 438).
  • the amino acids contained in the amino acid sequence in the present disclosure may be modified after translation.
  • the N-terminal glutamine residue (Q) becomes pyroglutamic acid (pGlu) by pyroglutamylation.
  • pGlu pyroglutamic acid
  • compositions containing cytokine inhibitors preferably anti-human IL-6 receptor antibodies, more preferably tocilizumab as active ingredients. ..
  • the present disclosure also relates to a pharmaceutical composition containing the cytokine inhibitor as an active ingredient to prevent cytokine release syndrome (CRS) associated with administration of an anti-T cell antigen-binding molecule or to treat CRS.
  • CRS cytokine release syndrome
  • the pharmaceutical compositions of the present disclosure should be administered to an individual who may develop CRS with administration of an anti-T cell antigen binding molecule and / or who develop CRS or signs of CRS and require treatment. Is preferable.
  • the present disclosure is selected as a step of administering an anti-T cell antigen-binding molecule to a subject and a step of selecting a subject who has a sign of CRS associated with the anti-T cell antigen-binding molecule and needs treatment.
  • a method for treating cytokine release syndrome (CRS) associated with administration of an anti-T cell antigen-binding molecule which comprises the step of administering a cytokine inhibitor to a subject.
  • CRS cytokine release syndrome
  • a pharmaceutical composition containing a cytokine inhibitor as an active ingredient is a method for preventing or treating CRS associated with administration of an anti-T cell antigen-binding molecule, which comprises a step of administering the cytokine inhibitor to an individual. , Or it can also be expressed as the use of the cytokine inhibitor in the manufacture of a CRS preventive agent or a CRS therapeutic agent.
  • containing a cytokine inhibitor as an active ingredient means that the cytokine inhibitor is contained as a main active ingredient, and does not limit the content rate of the cytokine inhibitor.
  • the cytokine inhibitor of the present invention is encapsulated in microcapsules (microcapsules such as hydroxymethyl cellulose, gelatin, poly [methyl methacrylate]), and a colloidal drug delivery system (liposomes, albumin microspheres, microemulsions, etc.) It may be a nano-particles, and nano-capsules) ( "Remington's Pharmaceutical Science 16 th edition", Oslo Ed. (1980) see the like). Furthermore, a method of making a drug a sustained-release drug is also known, and the method can be applied to the cytokine inhibitor of the present invention (J. Biomed. Mater. Res. (1981) 15, 267-277, Chemtech. (1982) 12, 98-105, US Patent No. 3773719, European Patent Publication Nos. EP58481 and EP133988, Biopolymers (1983) 22, 547-556).
  • microcapsules such as hydroxymethyl cellulose, gelatin, poly [methyl methacrylate]
  • the pharmaceutical composition containing the cytokine inhibitor in the present disclosure can be administered to a patient by either oral or parenteral administration.
  • Parenteral administration is preferred.
  • Specific examples of the administration method include injection administration, nasal administration, pulmonary administration, and transdermal administration.
  • Examples of the injection administration include intravenous injection, intramuscular injection, intraperitoneal injection, and subcutaneous injection.
  • the pharmaceutical composition of the present invention, or a cytotoxic inducer and a cell growth inhibitor can be administered systemically or locally by injection administration.
  • the administration method can be appropriately selected depending on the age and symptoms of the patient.
  • the dose for example, the dose can be selected in the range of 0.0001 mg to 1000 mg per 1 kg of body weight per administration. Alternatively, for example, the dose may be selected in the range of 0.001 mg / body to 100,000 mg / body per patient.
  • the pharmaceutical compositions of the present invention are not limited to these doses.
  • tocilizumab when the cytokine inhibitor is tocilizumab, tocilizumab is about 4-12 mg / kg per dose, eg, for patients weighing 30 kg or more, a dose of 8 mg / kg or less per dose, body weight. For patients weighing less than 30 kg, a single dose of 12 mg / kg or less is administered by intravenous injection over the course of, for example, 0.5 hours, 1 hour, 2 hours, or 3 hours.
  • tocilizumab administration can be added up to 3 times. In one example, when tocilizumab is continuously administered in this way, it is necessary to wait at least 8 hours from the previous administration.
  • the pharmaceutical composition containing the cytokine inhibitor in the present disclosure can be formulated according to a conventional method (for example, Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, USA), and a pharmaceutically acceptable carrier or addition. It may include both things. For example, surfactants, excipients, colorants, fragrances, preservatives, stabilizers, buffers, suspending agents, tonicity agents, binders, disintegrants, lubricants, fluidity promoters, flavoring agents. And so on. Further, the present invention is not limited to these, and other commonly used carriers can be appropriately used.
  • the disclosure is an anti-T cell antigen binding comprising a cytokine inhibitor, preferably an IL-6 inhibitor, more preferably an IL-6 receptor antibody, most preferably Tocilizumab. It relates to a pharmaceutical composition for use in combination therapy with a molecule.
  • the anti-T cell antigen binding molecule is, for example, a bispecific antibody, preferably a bispecific antibody that binds to a cancer antigen and CD3. Details of the combination therapy are disclosed in "V. Combination therapy" herein.
  • Cytokine Release Syndrome is a drug, eg, an antibody drug (eg, an anti-T cell antibody) or a T cell drug (eg, a chimeric antigen receptor, CAR) T cell (CAR-T). It is a serious and life-threatening side effect that can occur when cells)) are administered.
  • Administration of antibody drugs and T cell drugs activates the immune response in the body more than necessary and releases inflammatory cytokines, etc., resulting in chills, nausea, malaise, headache, fever, tachycardia, blood pressure fluctuations, etc.
  • Various symptoms occur. Severe cases are sometimes referred to as cytokine storms.
  • CRS is the result of high levels of immune activation when a large number of lymphocytes and / or myeloid cells release inflammatory cytokines upon activation.
  • the severity of CRS and the timing of onset of symptoms can vary depending on the scale of immune cell activation in the individual, the type of drug administered, and / or the degree of systemic tumor tissue.
  • the onset of symptoms is typically days to weeks after administration of T cell therapy, for example, if there is a peak of T cell proliferation in vivo. See, for example, Lee et al. Blood. 124.2 (2014): 188-95.
  • the symptoms of CRS may include neurotoxicity, disseminated intravascular coagulation, cardiac dysfunction, adult respiratory distress syndrome, renal failure, and / or liver failure.
  • the symptoms of CRS are fever / high fever with or without cold, fatigue, discomfort, muscle pain, vomiting, headache, nausea, loss of appetite, joint pain, diarrhea, rash, hypoxia, hyperventilation, hypoxia.
  • Blood pressure increased pulse pressure, potential decrease in cardiac output (late), increased cardiac output (early), hypernitrogenemia, hypoxia with or without bleeding, D-dimer It may include elevation, hyperbilylbinemia, hypertransaminaseemia, confusion, dementia, changes in mental status, illusions, tremor (tremor), attacks, changes in gait, difficulty speaking, overt aphrodisiac, or dementia.
  • D-dimer It may include elevation, hyperbilylbinemia, hypertransaminaseemia, confusion, dementia, changes in mental status, illusions, tremor (tremor), attacks, changes in gait, difficulty speaking, overt aphrodisiac, or dementia.
  • CRS is characterized by increased concentrations of several cytokines in the individual.
  • the cytokines are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, VEGF, RANTES, eotaxin , EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, RAGE, but not limited to.
  • the cytokine comprises IL-6, IL-1 beta, or TNF-alpha, or any combination thereof. Most preferably, the cytokine is IL-6. In one aspect, patients with large tumor volumes have a higher incidence and severity of cytokine syndrome.
  • cytokine concentration includes measurements of concentration, magnitude of multiple change, magnitude of percent (%) change, or magnitude of rate of change. You can do it.
  • methods for measuring cytokines in blood, saliva, serum, urine, plasma, and / or serum are well known in the art.
  • CRS can be categorized into 1-5 severity (Grade).
  • Grade 1 CRS only symptomatic treatment is required (eg, nausea, fever, fatigue, myalgia, discomfort, headache) and the symptoms are not life-threatening.
  • Grade 2 CRS symptoms require modest intervention and generally respond to moderate intervention.
  • Individuals with Grade 2 CRS develop hypotension in response to liquids or low-dose pressor agents; or they respond to Grade 2 organ toxicity or low flow rates of oxygen (less than 40% oxygen). It develops mild respiratory symptoms.
  • Grade 3 CRS hypotension is generally not reversible by liquid therapy or one low-dose pressor agent.
  • the CRS rating is based on the common terminology criteria for adverse events v4.03 (Common Terminology Criteria for Adverse Events (CTCAE) v4.03) and the common terminology criteria for adverse events shown in Table 7 (v5.0).
  • CTCE Common Terminology Criteria for Adverse Events
  • 2014 Lee Criteria Lee DW, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 124 (2014), 124 (2014), pp. 188-195
  • 2019 ASTCT CRS Consensus Grading Lee DW, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immuno-Effector Cells.
  • CRS grading is based on CTCAE v4.03, CTCAE v5.0, or Lee's 2014 criteria.
  • CRS as used herein refers to CRS according to the criteria in Table 8 (Lee's Criteria for 2014).
  • the symptoms of CRS occur within minutes, hours, or days after the start of drug administration, but some are delayed.
  • the symptoms of CRS occur within about 96 hours, about 72 hours, or about 48 hours after the start of administration of the anti-T cell antigen-binding molecule, and more preferably, administration of the anti-T cell antigen-binding molecule. It occurs from the day of administration to the next day.
  • the severity of CRS symptoms correlates with peak cytokine concentrations.
  • the signs of CRS refer to CRS-like symptoms that are a precursor to the above-mentioned CRS (regardless of Grade). Specific examples include, but are not limited to, fever or hypotension that occur first after administration of the anti-T cell antigen binding molecule.
  • methods of treating CRS include inflammatory cytokine inhibitors, IL-6 inhibitors or IL-6 receptor (IL-6R) inhibitors (eg, Tocilizumab or Satralizumab). ), Bazedoxyphene, SGP130 blockers, vasoactive agents, systemic corticosteroids (eg, corticosteroids), immunosuppressants, and mechanical artificial ventilation.
  • IL-6R IL-6 receptor
  • the inflammatory cytokine inhibitors are IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15. , IL-17, IL-1Ra, IL-2R, IFN- ⁇ , IFN- ⁇ , MIP-1 ⁇ , MIP-1 ⁇ , MCP-1, TNF ⁇ , GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factor, An inhibitor or antagonist inhibitor of one or more cytokines selected from VEGF, RANTES, eotaxin, EGF, HGF, FGF- ⁇ , CD30, CD30L, CD40, CD40L, ferritin, RAGE. Preferred cytokine inhibitors are disclosed herein in "III. Cytokine Inhibitors”.
  • tocilizumab is about 4-12 mg / kg per dose, for example 8 mg / kg or more for patients weighing 30 kg or more.
  • tocilizumab administration can be added up to 3 times. In one example, when tocilizumab is continuously administered in this way, it is necessary to wait at least 8 hours from the previous administration.
  • vasodilators include, but are not limited to, angiotensin-11, endoserin-1, alpha adrenaline agonists, rostanoids, phosphodiesterase inhibitors, endoserin antagonists, circulatory agents (eg, adrenaline, dobutamine, isoprenaline, ephedrine). ), Pressor agents (eg, noradrenaline, vasopressin, metallaminol, vasopressin, methylene blue), cardiotonic vasodilators (eg, milrinone, levocimendan), and dopamine.
  • angiotensin-11 include, but are not limited to, angiotensin-11, endoserin-1, alpha adrenaline agonists, rostanoids, phosphodiesterase inhibitors, endoserin antagonists, circulatory agents (eg, adrenaline, dobutamine, isoprenaline, ephedrine). ), Pressor agents (eg, noradrenaline, va
  • vasopressors include, but are not limited to, norepinephrine, dopamine, phenylephrine, epinephrine, and vasopressin.
  • the pressor agent comprises a high dose pressor agent and a low dose pressor agent.
  • the high-dose pressor agents are: norepinephrine monotherapy greater than 20 ⁇ g / min, dopamine monotherapy greater than 10 ⁇ g / kg / min, phenylephrine monotherapy greater than 200 ⁇ g / min, and / or 10 ⁇ g / min. Includes one or more of the above phenylephrine monotherapy.
  • the low dose vasopressor is a vasopressor administered at a dose less than one or more of the doses listed above for a high dose vasopressor.
  • Exemplary corticosteroids include, but are not limited to, dexamethasone, hydrocortisone, and methylprednisolone.
  • a dose of 0.5 mg / kg of dexamethasone is used by oral or intravenous administration.
  • a single dose of 8-20 mg of dexamethasone, a pharmaceutically acceptable salt thereof, or a derivative thereof is used by oral or intravenous administration. It will be understood by those skilled in the art that the dose of dexamethasone is not limited to the above and may be appropriately changed depending on the condition of the individual and the severity of CRS.
  • An exemplary immunosuppressant includes a TNF-alpha inhibitor or an IL-1 inhibitor.
  • the TNF-alpha inhibitor comprises an anti-TNF-alpha antibody, eg, a monoclonal antibody, eg, Infliximab.
  • the TNF-alpha inhibitor comprises a soluble TNF-alpha receptor (eg, Etanercept).
  • the IL-1 or IL-1R inhibitor comprises Anakinra.
  • the present disclosure relates to the combination of an anti-T cell antigen binding molecule and a cytokine inhibitor.
  • the disclosure relates to a pharmaceutical composition comprising an anti-T cell antigen binding molecule for use in combination therapy with a cytokine inhibitor.
  • the disclosure relates to a pharmaceutical composition comprising a cytokine inhibitor for use in combination therapy with an anti-T cell antigen binding molecule.
  • the present disclosure relates to methods of treating cancer in an individual, including administration of anti-T cell antigen binding molecules and cytokine inhibitors.
  • administration of a cytokine inhibitor prevents, alleviates, or treats cytokine release syndrome (CRS) associated with administration of an anti-T cell antigen-binding molecule in an individual.
  • CRS cytokine release syndrome
  • the present disclosure may be rephrased as a method for preventing, reducing, or treating the occurrence of CRS associated with the administration of an anti-T cell antigen-binding molecule, which comprises administering a cytokine inhibitor.
  • the present disclosure is a method for any of the objectives selected from the prevention, alleviation, and treatment of CRS associated with the administration of anti-T cell antigen binding molecules, including the step of administering a cytokine inhibitor, or a combination thereof. I will provide a.
  • the cytokine inhibitor is administered subcutaneously or intravenously to the individual before, simultaneously or after administration of the anti-T cell antigen binding molecule.
  • the cytokine inhibitor is administered intravenously to the individual before, simultaneously or after administration of the anti-T cell antigen binding molecule.
  • the cytokine inhibitor when it is administered before or at the same time as the administration of the anti-T cell antigen-binding molecule, it has the effect of preventing or reducing the occurrence of CRS associated with the administration of the anti-T cell antigen-binding molecule. Have.
  • the cytokine inhibitor is the anti-T cell antigen-binding molecule 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or the day before administration of the anti-T cell antigen-binding molecule. Be administered. Alternatively, the cytokine inhibitor may be administered at the same time as the anti-T cell antigen-binding molecule on the day of administration of the anti-T cell antigen-binding molecule (in the present disclosure, the cytokine inhibitor before administration of the anti-T cell antigen-binding molecule). And the administration of cytokine inhibitors that are performed at the same time as the administration of anti-T cell antigen-binding molecules are collectively referred to as "pre-administration of cytokine inhibitors").
  • pre-administration of a cytokine inhibitor significantly impairs the efficacy of an anti-T cell antigen-binding molecule (eg, TDCC (T cell-dependent cellular cytotoxicity; T cell-dependent cytotoxicity) or antitumor effect). Instead, it prevents or reduces the occurrence of CRS associated with the administration of the anti-T cell antigen-binding molecule.
  • an anti-T cell antigen-binding molecule eg, TDCC (T cell-dependent cellular cytotoxicity; T cell-dependent cytotoxicity) or antitumor effect.
  • the cytokine inhibitor when administered after the administration of the anti-T cell antigen-binding molecule and before the development of CRS, it has the effect of preventing or reducing the CRS that may occur thereafter.
  • a cytokine inhibitor when administered after administration of an anti-T cell antigen-binding molecule and after the occurrence of signs of CRS or CRS, it has the effect of treating CRS and alleviating the symptoms.
  • the anti-T cell antigen-binding molecule used in the combination therapy comprises a "domain comprising an antibody variable region having T cell receptor complex binding activity" and a "antibody variable region having cancer antigen binding activity". It is a bispecific antigen-binding molecule containing a "domain", preferably a bispecific antibody.
  • the bispecific antibody may have the structure of a single chain antibody, eg, a structure in which an antibody variable region is linked with a linker.
  • the anti-T cell antigen binding molecule further comprises an Fc region with reduced binding activity to the Fc ⁇ receptor.
  • the anti-T cell antigen-binding molecule is (1) a domain containing an antibody variable region having a gripican 3-binding activity, (2) a domain containing an antibody variable region having a T cell receptor complex binding activity, and ( 3) A bispecific antibody containing a domain containing an Fc region in which the binding activity to the Fc ⁇ receptor is reduced.
  • the cytokine inhibitor used in the combination therapy is an IL-6 inhibitor, preferably an anti-IL-6 receptor antibody, and most preferably tocilizumab.
  • tosirizumab when tosirizumab is administered before or at the same time as the anti-T cell antigen binding molecule, tosirizumab is administered to human adults and children, for example, from 5 mg / kg to 100 mg / kg, for example, from 5 mg / kg.
  • the dose is administered as a single dose.
  • 8 mg / kg or less 0.5 to 8 mg / kg, 1 to 8 mg / kg, 2 to 8 mg for a patient weighing 30 kg or more per dose.
  • / kg, 3-8 mg / kg, 4-8 mg / kg, preferably 4-8 mg / kg of tosirizumab is administered.
  • the anti-T cell antigen-binding molecule before administration of the anti-T cell antigen-binding molecule, at the same time, for patients weighing less than 30 kg, 12 mg / kg or less, 0.5 to 12 mg / kg, 1 to 12 mg / kg, 3 to 12 mg / kg, 5-12 mg / kg, 6-12 mg / kg, preferably 6-12 kg / kg of tosirizumab is administered.
  • the combination therapies of the present disclosure may further include administration of corticosteroids.
  • the anti-T cell antigen-binding molecule is administered 2 days, 1 day, or 0 days (the day) before the administration date.
  • corticosteroids Prior to administration of the T cell antigen-binding molecule, corticosteroids are administered to the individual orally or intravenously.
  • the corticosteroid is orally or intravenously administered to the individual at the same time as the administration of the anti-T cell antigen-binding molecule (these are referred to as "premedication of corticosteroid" or "premedication of steroid". There is.).
  • the premedication of the corticosteroid is in addition to the premedication of the cytokine inhibitor (in combination with the premedication of the cytokine inhibitor).
  • preferred corticosteroids include dexamethasone, hydrocortisone, and methylprednisolone.
  • the corticosteroid is dexamethasone, a pharmaceutically acceptable salt thereof, or a derivative thereof, which is administered by oral or intravenous administration. It will be understood by those skilled in the art that the dose of dexamethasone is not limited to the above, and may be appropriately changed depending on the condition of the individual, the occurrence of CRS, and the like.
  • the combination therapy consists of (1) pre-administration of corticosteroid, (2) pre-administration of cytokine inhibitor, and (3) administration of anti-T cell antigen-binding molecule on the day of administration of the anti-T cell antigen-binding molecule. , In this order. In this case, for example, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, or 5 hours or more, preferably 2 hours or more before the start of administration of the cytokine inhibitor, to the individual corticosteroid.
  • Cytokine inhibition 1 hour or longer, 2 hours or longer, 3 hours or longer, 4 hours or longer, or 5 hours or longer, preferably 2 hours or longer, before the end of administration and the start of administration of the anti-T cell antigen-binding molecule.
  • Administration of the drug to the individual is completed.
  • administration is performed on the day of administration of the anti-T cell antigen-binding molecule: (1) pre-administration of a cytokine inhibitor, (2) pre-administration of corticosteroid, (3) pre-administration of the anti-T cell antigen-binding molecule. Administration is performed in this order.
  • Corticosteroids that have been administered are 1 hour or longer, 2 hours or longer, 3 hours or longer, 4 hours or longer, or 5 hours or longer, preferably 2 hours or longer before the start of administration of the anti-T cell antigen-binding molecule.
  • Administration to the individual is completed.
  • the combination therapies of the present disclosure do not include premedication of corticosteroids.
  • Premedication of cytokine inhibitors prevents or reduces the occurrence of CRS associated with the administration of anti-T cell antigen-binding molecules, and does not require the administration of corticosteroids for the purpose of preventing or reducing CRS, although not limited to this. Become.
  • any of the anti-T cell antigen-binding molecules, cytokine inhibitors, and / or other agents in the present disclosure may be accompanied by a certain "tolerance" for each of the timing of administration, the interval of administration, and the dose. It is naturally understood by those skilled in the art, and those skilled in the art can appropriately determine the permissible range. For example, based on the individual's symptoms, etc., the administration interval of the anti-T cell antigen-binding molecule, cytokine inhibitor, and / or other drug may be increased or decreased in a timely manner, or the dose may be increased or decreased as appropriate, at the discretion of the doctor. It is within the above "allowable range”.
  • the present disclosure provides a pharmaceutical composition comprising an anti-T cell antigen-binding molecule for use in combination therapy with a cytokine inhibitor. To do.
  • the disclosure provides a pharmaceutical composition comprising a cytokine inhibitor for use in combination therapy with an anti-T cell antigen binding molecule.
  • the cytokine inhibitor is administered to the individual before or at the same time as the administration of the anti-T cell antigen binding molecule.
  • the cytokine inhibitor when administered before or at the same time as the administration of the anti-T cell antigen-binding molecule, it has the effect of preventing or reducing the occurrence of CRS associated with the administration of the anti-T cell antigen-binding molecule. ..
  • the cytokine inhibitor is administered of the anti-T cell antigen binding molecule 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or day before administration of the bispecific antibody. Will be done.
  • the cytokine inhibitor is administered at the same time as the anti-T cell antigen-binding molecule on the day of administration of the anti-T cell antigen-binding molecule.
  • pre-administration of a cytokine inhibitor significantly impairs the efficacy of an anti-T cell antigen-binding molecule (eg, T cell-dependent cellular cytotoxicity (TDCC), antitumor effect, etc.). Instead, it prevents or reduces the occurrence of CRS associated with the administration of the anti-T cell antigen-binding molecule.
  • an anti-T cell antigen-binding molecule eg, T cell-dependent cellular cytotoxicity (TDCC), antitumor effect, etc.
  • the combination therapies of the present disclosure include the pre-administration of the cytokine inhibitor, as well as the cytokine inhibition at 1, 2, 3, 4, or 5 days after administration of the anti-T cell antigen binding molecule. Includes that the agent is administered to an individual.
  • the combination therapies of the present disclosure include, in addition to pre-administration of the cytokine inhibitor, when signs of CRS or CRS occur after administration of the anti-T cell antigen-binding molecule, the cytokine inhibitor is further administered to the individual. Including being administered to. At this time, even if the individual had been (i) pre-administered the cytokine inhibitor, (ii) the pre-administration of the cytokine inhibitor and the administration of the cytokine inhibitor after the administration of the anti-T cell antigen-binding molecule. It may be an individual in which both of the above have been performed. In one aspect, the CRS is Grade 2 or higher or Grade 3 or higher.
  • the combination therapy of the present disclosure includes a step of administering an anti-T cell antigen-binding molecule to a subject, a step of selecting a subject who develops CRS or signs of CRS after administration of the anti-T cell antigen-binding molecule, and a selected subject. Includes the step of administering a cytokine inhibitor to the cell.
  • an anti-T cell antigen-binding molecule is administered repeatedly, and (ii) a cytokine inhibitor is administered before or at the same time as each administration of the repeated administration.
  • the anti-T cell antigen binding molecule is repeatedly administered at the same dose.
  • the anti-T cell antigen-binding molecule is administered repeatedly at weekly intervals, and (ii) 6 days, 5 days, and 4 days before each administration of the repeated administration. , 3 days, 2 days, 1 day, or the day before administration of the anti-T cell antigen-binding molecule, the cytokine inhibitor is administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and (ii) on the day of each administration of the repeated administration, the cytokine inhibitor is simultaneously administered with the anti-T cell antigen-binding molecule. Is administered.
  • the combination therapies of the present disclosure are provided on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen binding molecule, in addition to the pretreatment of the cytokine inhibitor.
  • the cytokine inhibitor may be administered to an individual.
  • the pre-administration of the cytokine inhibitor is performed 6 days before the administration of the anti-T cell antigen-binding molecule, on the day of administration of the anti-T cell antigen-binding molecule, -If the pre-administration of the cytokine inhibitor is performed 5 days before the administration of the anti-T cell antigen-binding molecule, the day or 1 day after the administration of the anti-T cell antigen-binding molecule.
  • the pre-administration of the cytokine inhibitor is performed 4 days before the administration of the anti-T cell antigen-binding molecule, the day, 1 day or 2 days after the administration of the anti-T cell antigen-binding molecule, -If the pre-administration of the cytokine inhibitor is performed 3 days before the administration of the anti-T cell antigen-binding molecule, the day, 1 day, 2 days or 3 days after the administration of the anti-T cell antigen-binding molecule, -If the pre-administration of the cytokine inhibitor is performed 2 days before the administration of the anti-T cell antigen-binding molecule, the day, 1 day, 2 days, 3 days or 4 days after the administration of the anti-T cell antigen-binding molecule, -If the pre-administration of the cytokine inhibitor is performed 1 day before the administration of the anti-T cell antigen-binding molecule, the day, 1 day, 2 days, 3 days, 4 days or 5 days after the administration of the T cell antigen-binding molecule
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (ii) 6 days, 5 days, and 4 before each administration of the repeated administration.
  • Cytokine inhibitors are administered 1 day before, 3 days before, 2 days before, 1 day before or on the day before administration of the anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (ii) on the day of each administration of the repeated administration, cytokine inhibition is performed at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the drug is administered.
  • the combination therapies of the present disclosure are provided on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen binding molecule, in addition to the pretreatment of the cytokine inhibitor.
  • the cytokine inhibitor may be administered to an individual.
  • cytokine inhibitor is 6 days before administration of anti-T cell antigen-binding molecule, 5 days, 4 days, 3 days, 2 days or 1 day before), or ⁇ 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen-binding molecule (when pre-administration of cytokine inhibitor is performed on the day of administration of anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (ii) 6 days, 5 days, and 4 before each administration of the repeated administration.
  • Cytokine inhibitors are administered 1 day before, 3 days before, 2 days before, 1 day before, or on the day before administration of the anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (ii) on the day of each administration of the repeated administration, cytokine inhibition is performed at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the drug is administered.
  • the combination therapies of the present disclosure are provided on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen binding molecule, in addition to the pretreatment of the cytokine inhibitor.
  • the cytokine inhibitor may be administered to an individual.
  • cytokine inhibitor is 6 days before administration of anti-T cell antigen-binding molecule, 5 days, 4 days, 3 days, 2 days or 1 day before), or ⁇ 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen-binding molecule (when pre-administration of cytokine inhibitor is performed on the day of administration of anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (ii) 6 days, 5 days, and 4 before each administration of the repeated administration.
  • Cytokine inhibitors are administered 1 day before, 3 days before, 2 days before, 1 day before or on the day before administration of the anti-T cell antigen-binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (ii) on the day of each administration of the repeated administration, cytokine inhibition is performed at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the drug is administered.
  • the combination therapies of the present disclosure are provided on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen binding molecule, in addition to the pretreatment of the cytokine inhibitor.
  • the cytokine inhibitor may be administered to an individual.
  • cytokine inhibitor is 6 days before administration of anti-T cell antigen-binding molecule, 5 days, 4 days, 3 days, 2 days or 1 day before), or ⁇ 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen-binding molecule (when pre-administration of cytokine inhibitor is performed on the day of administration of anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (ii) 6 days, 5 days, and 4 before each administration of the repeated administration. Cytokine inhibitors are administered 1 day, 3 days, 2 days, 1 day, or the day before administration of the anti-T cell antigen binding molecule.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (ii) on the day of each administration of the repeated administration, cytokine inhibition is performed at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the drug is administered.
  • the combination therapies of the present disclosure are provided on the day, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen binding molecule, in addition to the pretreatment of the cytokine inhibitor.
  • the cytokine inhibitor may be administered to an individual.
  • cytokine inhibitor is 6 days before administration of anti-T cell antigen-binding molecule, 5 days, 4 days, 3 days, 2 days or 1 day before), or ⁇ 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen-binding molecule (when pre-administration of cytokine inhibitor is performed on the day of administration of anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is administered repeatedly at weekly intervals, with the first or more of the repeated administrations being pre-administered with a cytokine inhibitor. It is said.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the cytokine inhibitor is pre-administered in the following embodiment.
  • Inhibitors are administered, -Cytokines 5 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, -Cytokines 4 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule. Inhibitors are administered, -Cytokines before the administration of the anti-T cell antigen-binding molecule 3 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Inhibitors are administered, -Cytokines before administration of the anti-T cell antigen-binding molecule 2 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration. Inhibitors are administered, ⁇ Cytokines 1 day before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, and before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, ⁇ Cytokine inhibition before administration of anti-T cell antigen-binding molecule on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Anti-T cell antigen-binding molecule on the day of administration of the drug, or on the day of the first, first, second, first to third, first to fourth, or first to fifth doses of the repeated dose.
  • the cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the pre-dose is given 4 days before the first, 1-2, 1-3, 1-4, or 1-5 doses of the anti-T cell antigen-binding molecule
  • the pre-administration of the cytokine inhibitor is given 3 days before the first, 1-2, 1-3, 1-4, or 1-5 doses of the anti-T cell antigen-binding molecule.
  • the pre-administration of the cytokine inhibitor is 2 days before each administration of the first, 1-2, 1-3, 1-4, or 1-5 anti-T cell antigen-binding molecules.
  • cytokine inhibitor is the first, 1-2, 1-3, 1-4, or 1-5 doses of the anti-T cell antigen-binding molecule, respectively. If it is done on the day), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every two weeks, and the first one or more of the repeated administrations are preceded by a cytokine inhibitor. Will be done. Specifically, the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and the cytokine inhibitor is pre-administered in the following embodiment.
  • Inhibitors are administered, -Cytokines 5 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, -Cytokines 4 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule. Inhibitors are administered, -Cytokines before the administration of the anti-T cell antigen-binding molecule 3 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Inhibitors are administered, -Cytokines before administration of the anti-T cell antigen-binding molecule 2 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration. Inhibitors are administered, ⁇ Cytokines 1 day before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, and before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, ⁇ Cytokine inhibition before administration of anti-T cell antigen-binding molecule on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Anti-T cell antigen-binding molecule on the day of administration of the drug, or on the day of the first, first, second, first to third, first to fourth, or first to fifth doses of the repeated dose.
  • the cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor is the first, 1-2, 1-3, 1-4, or 1-5 of anti-T cell antigen-binding molecules, respectively. 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before administration of the anti-T cell antigen-binding molecule), or ⁇ The first, 1-2, 1-3 times of the anti-T cell antigen-binding molecule.
  • cytokine inhibitor is the first of anti-T cell antigen-binding molecule When performed on the day of each administration of the 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th doses),
  • the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every three weeks, and the first one or more of the repeated administrations are preceded by a cytokine inhibitor. Will be done. Specifically, the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and the cytokine inhibitor is pre-administered in the following embodiment.
  • Inhibitors are administered, -Cytokines 5 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, -Cytokines 4 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule. Inhibitors are administered, -Cytokines before the administration of the anti-T cell antigen-binding molecule 3 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Inhibitors are administered, -Cytokines before administration of the anti-T cell antigen-binding molecule 2 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration. Inhibitors are administered, ⁇ Cytokines 1 day before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, and before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, ⁇ Cytokine inhibition before administration of anti-T cell antigen-binding molecule on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Anti-T cell antigen-binding molecule on the day of administration of the drug, or on the day of the first, first, second, first to third, first to fourth, or first to fifth doses of the repeated dose.
  • the cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor is the first, 1-2, 1-3, 1-4, or 1-5 of anti-T cell antigen-binding molecules, respectively. 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before administration of the anti-T cell antigen-binding molecule), or ⁇ The first, 1-2, 1-3 times of the anti-T cell antigen-binding molecule.
  • cytokine inhibitor is the first of anti-T cell antigen-binding molecule When performed on the day of each administration of the 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th doses),
  • the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every four weeks, and the first one or more of the repeated administrations are pre-administered with a cytokine inhibitor. Will be done. Specifically, the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and the cytokine inhibitor is pre-administered in the following embodiment.
  • Inhibitors are administered, -Cytokines 5 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, -Cytokines 4 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule. Inhibitors are administered, -Cytokines before the administration of the anti-T cell antigen-binding molecule 3 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Inhibitors are administered, -Cytokines before administration of the anti-T cell antigen-binding molecule 2 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration. Inhibitors are administered, ⁇ Cytokines 1 day before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, and before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, ⁇ Cytokine inhibition before administration of anti-T cell antigen-binding molecule on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Anti-T cell antigen-binding molecule on the day of administration of the drug, or on the day of the first, first, second, first to third, first to fourth, or first to fifth doses of the repeated dose.
  • the cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor is the first, 1-2, 1-3, 1-4, or 1-5 of anti-T cell antigen-binding molecules, respectively. 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before administration of the anti-T cell antigen-binding molecule), or ⁇ The first, 1-2, 1-3 times of the anti-T cell antigen-binding molecule.
  • cytokine inhibitor is the first of anti-T cell antigen-binding molecule When performed on the day of each administration of the 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th doses),
  • the cytokine inhibitor may be further administered.
  • the anti-T cell antigen binding molecule is administered repeatedly at intervals of once every five weeks, with the first or more doses of the repeated dose being premedicated with a cytokine inhibitor. Will be done.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and the cytokine inhibitor is pre-administered in the following embodiment.
  • Inhibitors are administered, -Cytokines 5 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, -Cytokines 4 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, before administration of the anti-T cell antigen-binding molecule. Inhibitors are administered, -Cytokines before the administration of the anti-T cell antigen-binding molecule 3 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Inhibitors are administered, -Cytokines before administration of the anti-T cell antigen-binding molecule 2 days before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration. Inhibitors are administered, ⁇ Cytokines 1 day before the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration, and before administration of the anti-T cell antigen-binding molecule.
  • Inhibitors are administered, ⁇ Cytokine inhibition before administration of anti-T cell antigen-binding molecule on the day of the first, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the repeated administration.
  • Anti-T cell antigen-binding molecule on the day of administration of the drug, or on the day of the first, first, second, first to third, first to fourth, or first to fifth doses of the repeated dose.
  • the cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor is the first, 1-2, 1-3, 1-4, or 1-5 of anti-T cell antigen-binding molecules, respectively. 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before administration of the anti-T cell antigen-binding molecule), or ⁇ The first, 1-2, 1-3 times of the anti-T cell antigen-binding molecule.
  • cytokine inhibitor is the first of anti-T cell antigen-binding molecule When performed on the day of each administration of the 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, or 1st to 5th doses),
  • the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (ii).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once a week, and (iii) a pre-administration of the cytokine inhibitor is performed for the first dose of the anti-T cell antigen-binding molecule in each dosing cycle.
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once a week, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments.
  • Cytokine inhibitors are administered 6 days prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule.
  • Cytokine inhibitors are administered 5 days prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule.
  • Cytokine inhibitors are administered 4 days prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule. Cytokine inhibitors are administered 3 days prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule. Cytokine inhibitors are administered 2 days prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule. Cytokine inhibitors are administered 1 day prior to the first administration of each dosing cycle and prior to administration of the anti-T cell antigen binding molecule.
  • a cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or-On the day of the first administration of each dosing cycle, with the administration of the anti-T cell antigen-binding molecule. At the same time, a cytokine inhibitor is administered.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after the first administration of each administration cycle of the anti-T cell antigen-binding molecule is twice, three times).
  • the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (1).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once a week, and (iii) (a) in the first dosing cycle, for each (every) dose of the anti-T cell antigen-binding molecule, (iii) b) In the second and subsequent dosing cycles, a pre-administration of the cytokine inhibitor is performed for the first dosing of each dosing cycle.
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once a week, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments. • (a) 6 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 6 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 5 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 5 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 3 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 3 days before the first dosing in each subsequent dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 2 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 1 day before the first administration in each administration cycle in the second and subsequent administration cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) In the first administration cycle, on the day of each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, on the day of the first administration of each administration cycle.
  • Cytokine inhibitors are administered prior to administration of the T cell antigen-binding molecule, or (a) on the day of each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 In the subsequent administration cycles, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule on the first administration day of each administration cycle.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the pre-administration of the cytokine inhibitor is (a) anti-dose in the first dosing cycle. 6 days before each (each) administration of the T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, 6 days before the first administration of each administration cycle), -(A) On the day or one day after each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, (b) On the first administration day or one day after each administration cycle in the second and subsequent administration cycles.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the pre-administration of the cytokine inhibitor is (a) the first time.
  • the dosing cycle 5 days before each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent dosing cycles, 5 days before the first dosing of each dosing cycle), -(A) In the first administration cycle, on the day, 1 day or 2 days after each administration of the anti-T cell antigen-binding molecule (each time), (b) In the second and subsequent administration cycles, the first of each administration cycle.
  • anti-T cell antigen-binding molecule On the day of administration, 1 day or 2 days later (anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of 2, 3, 4, or 5 administrations, and the cytokine inhibitor is pre-administered. , (A) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles. If done), ⁇ (A) In the first administration cycle, each administration cycle of the anti-T cell antigen-binding molecule (each time), 1 day, 2 days or 3 days later, and (b) in the second and subsequent administration cycles, each administration cycle.
  • anti-T cell antigen-binding molecule On the day of the first administration, 1 day, 2 days or 3 days (anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of 2, 3, 4, or 5 administrations, and cytokines are administered. Pre-administration of the inhibitor is (a) 3 days before each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) in each administration cycle in the second and subsequent administration cycles. If done 3 days before the first dose), ⁇ (A) In the first administration cycle, on the day, 1 day, 2 days, 3 days or 4 days after each (every) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles.
  • each dosing cycle On the day of the first administration of each dosing cycle, 1 day, 2 days, 3 days, 4 days or 5 days (anti-T cell antigen-binding molecule is administered 2, 3, 4, or 5 times). It is repeatedly administered in one administration cycle, and the pre-administration of the cytokine inhibitor is (a) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 2 In the subsequent dosing cycles, if given 1 day before the first dosing of each dosing cycle), ⁇ (A) In the first administration cycle, each administration of the anti-T cell antigen-binding molecule (each time) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days, and (b) the second and subsequent administrations.
  • cytokine inhibitor In the cycle, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle (anti-T cell antigen-binding molecule is 2, 3, 4, or 5 times). It is repeatedly administered in a single administration cycle, and pre-administration of the cytokine inhibitor is performed (a) on the day of each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b). In the second and subsequent dosing cycles, if performed on the day of the first dosing of each dosing cycle), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (ii).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every two weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for the first dose of the anti-T cell antigen-binding molecule in each dosing cycle. ..
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every two weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments.
  • -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 6 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 5 days before the first dose of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 4 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 3 days before the first administration of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 2 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and one day before the first dosing of each dosing cycle, the anti-T cell antigen Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle, and anti-T cell antigen binding is performed on the first administration day of each dosing cycle.
  • a cytokine inhibitor Prior to administration of the molecule, a cytokine inhibitor is administered, or the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses. On the day of the first administration of each dosing cycle, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the day 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle of the anti-T cell antigen-binding molecule (the anti-T cell antigen-binding molecule is 2 times, 3 times, A dosing cycle consisting of 4 or 5 doses, repeated every 2 weeks, with pre-administration of cytokine inhibitor being the first dose of each dosing cycle of anti-T cell antigen-binding molecule.
  • cytokine inhibitor 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before), or ⁇ 1 day, 2 days, 3 days after the first administration of each dosing cycle of the anti-T cell antigen binding molecule, After 4, 5 or 6 days (anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every two weeks in a dosing cycle consisting of two, three, four, or five doses. If pre-administration of the cytokine inhibitor is performed on the day of the first administration of each anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (1).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every two weeks, and (iii) (a) in the first dosing cycle, for each (every) dose of the anti-T cell antigen-binding molecule.
  • a pre-administration of the cytokine inhibitor is performed for the first dosing of each dosing cycle.
  • an anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and (ii) an anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every two weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments. • (a) 6 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 6 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 5 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 5 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 3 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 3 days before the first dosing in each subsequent dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 2 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 1 day before the first administration in each administration cycle in the second and subsequent administration cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) In the first administration cycle, on the day of each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, on the day of the first administration of each administration cycle.
  • Cytokine inhibitors are administered prior to administration of the T cell antigen-binding molecule, or (a) on the day of each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 In the subsequent administration cycles, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule on the first administration day of each administration cycle.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • a dosing cycle consisting of one or five doses, repeated every two weeks, with pre-administration of the cytokine inhibitor (a) anti-T cell antigen in the first dosing cycle.
  • anti-T cell antigen-binding molecule is repeatedly administered once every two weeks in a dosing cycle consisting of two, three, four, or five doses, and cytokines.
  • Pre-administration of the inhibitor is (a) on the day of each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) the beginning of each administration cycle in the second and subsequent administration cycles. If performed on the day of administration), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (ii).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every three weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for the first dose of the anti-T cell antigen-binding molecule in each dosing cycle. ..
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every three weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments.
  • -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 6 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 5 days before the first dose of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 4 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 3 days before the first administration of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 2 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and one day before the first dosing of each dosing cycle, the anti-T cell antigen Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle, and anti-T cell antigen binding is performed on the first administration day of each dosing cycle.
  • a cytokine inhibitor Prior to administration of the molecule, a cytokine inhibitor is administered, or the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses. On the day of the first administration of each dosing cycle, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the day 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle of the anti-T cell antigen-binding molecule (the anti-T cell antigen-binding molecule is 2 times, 3 times, A dosing cycle consisting of 4 or 5 doses, repeated at intervals of once every 3 weeks, with pre-administration of the cytokine inhibitor being the first dose of each dosing cycle of the anti-T cell antigen-binding molecule.
  • cytokine inhibitor 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before), or ⁇ 1 day, 2 days, 3 days after the first administration of each dosing cycle of the anti-T cell antigen binding molecule, After 4, 5 or 6 days (anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every 3 weeks in a administration cycle consisting of 2, 3, 4, or 5 administrations as one cycle. If pre-administration of the cytokine inhibitor is performed on the day of the first administration of each anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (1).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every three weeks, and (iii) (a) in the first dosing cycle, for each (every) dose of the anti-T cell antigen-binding molecule.
  • a pre-administration of the cytokine inhibitor is performed for the first dosing of each dosing cycle.
  • an anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and (ii) an anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every three weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments. • (a) 6 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 6 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 5 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 5 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 3 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 3 days before the first dosing in each subsequent dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 2 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 1 day before the first administration in each administration cycle in the second and subsequent administration cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) In the first administration cycle, on the day of each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, on the day of the first administration of each administration cycle.
  • Cytokine inhibitors are administered prior to administration of the T cell antigen-binding molecule, or (a) on the day of each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 In the subsequent administration cycles, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule on the first administration day of each administration cycle.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • anti-T cell antigen-binding molecule is repeatedly administered once every 3 weeks in a dosing cycle consisting of 2, 3, 4, or 5 doses of cytokines.
  • Pre-administration of the inhibitor is (a) on the day of each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) the beginning of each administration cycle in the second and subsequent administration cycles. If performed on the day of administration), in addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (ii).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every four weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for the first dose of the anti-T cell antigen-binding molecule in each dosing cycle. ..
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every 4 weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments.
  • -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 6 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 5 days before the first dose of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 4 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 3 days before the first administration of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 2 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and one day before the first dosing of each dosing cycle, the anti-T cell antigen Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle, and anti-T cell antigen binding is performed on the first administration day of each dosing cycle.
  • a cytokine inhibitor Prior to administration of the molecule, a cytokine inhibitor is administered, or the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses. On the day of the first administration of each dosing cycle, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the day 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle of the anti-T cell antigen-binding molecule (the anti-T cell antigen-binding molecule is 2 times, 3 times, A dosing cycle consisting of 4 or 5 doses, repeated at intervals of once every 4 weeks, with pre-administration of cytokine inhibitor being the first dose of each dosing cycle of anti-T cell antigen-binding molecule.
  • cytokine inhibitor 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before), or ⁇ 1 day, 2 days, 3 days after the first administration of each dosing cycle of the anti-T cell antigen binding molecule, After 4, 5 or 6 days (anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every 4 weeks in a administration cycle consisting of 2, 3, 4, or 5 administrations as one cycle. If pre-administration of the cytokine inhibitor is performed on the day of the first administration of each anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (1).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every four weeks, and (iii) (a) in the first dosing cycle, for each (every) dose of the anti-T cell antigen-binding molecule.
  • a pre-administration of the cytokine inhibitor is performed for the first dosing of each dosing cycle.
  • an anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and (ii) an anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every 4 weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments. • (a) 6 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 6 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 5 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 5 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 3 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 3 days before the first dosing in each subsequent dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 2 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 1 day before the first administration in each administration cycle in the second and subsequent administration cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) In the first administration cycle, on the day of each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, on the day of the first administration of each administration cycle.
  • Cytokine inhibitors are administered prior to administration of the T cell antigen-binding molecule, or (a) on the day of each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 In the subsequent administration cycles, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule on the first administration day of each administration cycle.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 4 weeks in a dosing cycle consisting of 2, 3, 4, or 5 doses of cytokines.
  • Pre-administration of the inhibitor is (a) on the day of each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) the beginning of each administration cycle in the second and subsequent administration cycles. If performed on the day of administration), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (ii).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every 5 weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for the first dose of the anti-T cell antigen-binding molecule in each dosing cycle. ..
  • anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every 5 weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments.
  • -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 6 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 5 days before the first dose of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 4 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 3 days before the first administration of each dosing cycle. Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and the anti-T cell antigen is administered 2 days before the first administration of each dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses, and one day before the first dosing of each dosing cycle, the anti-T cell antigen Cytokine inhibitors are administered prior to administration of the binding molecule, -Anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses as one cycle, and anti-T cell antigen binding is performed on the first administration day of each dosing cycle.
  • a cytokine inhibitor Prior to administration of the molecule, a cytokine inhibitor is administered, or the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses. On the day of the first administration of each dosing cycle, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the day 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle of the anti-T cell antigen-binding molecule (the anti-T cell antigen-binding molecule is 2 times, 3 times, A dosing cycle consisting of 4 or 5 doses, repeated every 5 weeks, with pre-administration of the cytokine inhibitor being the first dose of each dosing cycle of anti-T cell antigen-binding molecule.
  • cytokine inhibitor 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before), or ⁇ 1 day, 2 days, 3 days after the first administration of each dosing cycle of the anti-T cell antigen binding molecule, After 4, 5 or 6 days (anti-T cell antigen-binding molecule is administered repeatedly at intervals of once every 5 weeks in a administration cycle consisting of 2, 3, 4, or 5 administrations as one cycle. If pre-administration of the cytokine inhibitor is performed on the day of the first administration of each anti-T cell antigen-binding molecule), In addition, the cytokine inhibitor may be further administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered in a dosing cycle consisting of two, three, four, or five doses (1).
  • the interval between repeated doses of the anti-T cell antigen-binding molecule is once every 5 weeks, and (iii) (a) in the first dosing cycle, for each (every) dose of the anti-T cell antigen-binding molecule.
  • a pre-administration of the cytokine inhibitor is performed for the first dosing of each dosing cycle.
  • an anti-T cell antigen-binding molecule is repeatedly administered in an administration cycle consisting of two, three, four, or five administration cycles, and (ii) an anti-T cell antigen-binding molecule.
  • the interval between repeated doses is once every 5 weeks, and (iii) the premedication of the cytokine inhibitor is carried out in the following embodiments. • (a) 6 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 6 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 5 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 5 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 4 days before each (each) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 4 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 3 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 3 days before the first dosing in each subsequent dosing cycle.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, • (a) 2 days before each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 days before the first dosing of each dosing cycle in the second and subsequent dosing cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) 1 day before each (every) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) 1 day before the first administration in each administration cycle in the second and subsequent administration cycles.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen binding molecule, -(A) In the first administration cycle, on the day of each (each) administration of the anti-T cell antigen-binding molecule, and (b) in the second and subsequent administration cycles, on the day of the first administration of each administration cycle.
  • Cytokine inhibitors are administered prior to administration of the T cell antigen-binding molecule, or (a) on the day of each (every) administration of the anti-T cell antigen-binding molecule in the first dosing cycle, and (b) 2 In the subsequent administration cycles, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule on the first administration day of each administration cycle.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • a dosing cycle consisting of one or five doses, repeated at intervals of once every five weeks, with pre-administration of the cytokine inhibitor (a) anti-T cell antigen in the first dosing cycle.
  • anti-T cell antigen-binding molecule is repeatedly administered once every 5 weeks in a dosing cycle consisting of 2, 3, 4, or 5 doses of cytokines.
  • Pre-administration of the inhibitor is (a) on the day of each (each) administration of the anti-T cell antigen-binding molecule in the first administration cycle, and (b) the beginning of each administration cycle in the second and subsequent administration cycles. If performed on the day of administration), in addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) prior to each dose of the incremental dose and maintenance dose period. Or at the same time, a cytokine inhibitor is administered.
  • the dose of the anti-T cell antigen-binding molecule is gradually increased during the incremental administration period.
  • the dose is “gradually increased”, it means that the n + 1th dose is larger than the nth dose.
  • the second dose is larger than the first dose.
  • the second dose is larger than the first dose and the third dose is larger than the second dose.
  • the anti-T cell antigen-binding molecule is administered four times during the escalation period, the second dose is larger than the first dose, the third dose is larger than the second dose, and the third dose.
  • the fourth dose is greater than the dose of.
  • the anti-T cell antigen-binding molecule is administered 5 times during the escalation period, the 2nd dose is larger than the 1st dose, the 3rd dose is larger than the 2nd dose, and the 3rd dose.
  • the fourth dose is larger than the dose of, and the fifth dose is larger than the fourth dose.
  • the anti-T cell antigen-binding molecule is administered 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during the incremental dose period.
  • the anti-T cell antigen-binding molecule is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every five weeks. Will be done.
  • the anti-T cell antigen-binding molecule is repeatedly administered at the same dose during the maintenance administration period. In one embodiment, during the maintenance dosing period, the anti-T cell antigen-binding molecule is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every five weeks. Will be done. In a further embodiment, the dosing interval of the anti-T cell antigen-binding molecule during the maintenance dosing period is the same as the dosing interval of the anti-T cell antigen binding molecule during the incremental dosing period.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at weekly intervals, and (iii) a pre-administration of the cytokine inhibitor is performed for each administration during the incremental administration period and the maintenance administration period.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at weekly intervals, and (iii) the cytokine inhibitor is pre-administered in the following embodiments.
  • -A cytokine inhibitor is administered 6 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered or a cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the pre-administration of the cytokine inhibitor is administered each time during the incremental administration period and the maintenance administration period 6).
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the pre-administration of the cytokine inhibitor is performed each time during the incremental administration period and the maintenance administration period. If done 5 days before administration), -On the day of administration of the anti-T cell antigen-binding molecule, 1 day or 2 days later (the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the pre-administration of the cytokine inhibitor is an incremental administration period and maintenance administration.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the pre-administration of the cytokine inhibitor is a gradual increase administration period.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week, and the cytokine inhibitor is pre-administered.
  • the anti-T cell antigen-binding molecule is repeatedly administered once a week and before the cytokine inhibitor. If administration is performed 1 day before each administration in the escalation period and maintenance administration period), or ⁇ 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the anti-T cell antigen-binding molecule. (When the anti-T cell antigen-binding molecule is repeatedly administered once a week and the cytokine inhibitor is pre-administered on the day of each administration during the incremental and maintenance periods), In addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for each administration during the incremental administration period and the maintenance administration period.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered or a cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days the anti-T cell antigen-binding molecule is repeatedly administered once every two weeks).
  • pre-administration of the cytokine inhibitor is performed 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before each administration in the incremental administration period and maintenance administration period), or the anti-T cell antigen binding. 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the molecule (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and the pre-administration of cytokine inhibitor is gradually increased.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for each administration during the incremental administration period and the maintenance administration period.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered or a cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days the anti-T cell antigen-binding molecule is repeatedly administered once every 3 weeks).
  • pre-administration of the cytokine inhibitor is performed 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before each administration during the escalation period and maintenance administration period), or the anti-T cell antigen binding. 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the molecule (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 3 weeks, and the pre-administration of cytokine inhibitor is gradually increased.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for each administration during the incremental administration period and the maintenance administration period.
  • the combination therapies of the present disclosure include (i) a period of incremental administration of an anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) an anti-T cell during the incremental administration period and the maintenance administration period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered or a cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days the anti-T cell antigen-binding molecule is repeatedly administered once every 4 weeks).
  • pre-administration of the cytokine inhibitor is performed 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before each administration in the incremental administration period and maintenance administration period), or the anti-T cell antigen binding. 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the molecule (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 4 weeks, and the pre-administration of cytokine inhibitor is gradually increased.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (iii) a pre-administration of the cytokine inhibitor is performed for each administration during the incremental administration period and the maintenance administration period.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration in the incremental administration period and the maintenance administration period, and before the administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered or a cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days the anti-T cell antigen-binding molecule is repeatedly administered once every 5 weeks).
  • pre-administration of the cytokine inhibitor is performed 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before each administration in the incremental administration period and maintenance administration period), or the anti-T cell antigen binding. 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration of the molecule (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and the pre-administration of cytokine inhibitor is gradually increased.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered once a week, (iii) (a) during the incremental dose period, pre-administration of the cytokine inhibitor for each dose, and (b) during the maintenance dose period. Is not pre-administered with cytokine inhibitors.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at weekly intervals, and (iii) the cytokine inhibitor is pre-administered in the following embodiments.
  • -A cytokine inhibitor is administered 6 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule on the day of each administration of the escalating administration period, or-On the day of each administration of the escalating administration period, the anti-T cell antigen-binding molecule A cytokine inhibitor is administered at the same time as the administration of.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • -On the day of each administration during the escalation period when the anti-T cell antigen-binding molecule is repeatedly administered once a week and the cytokine inhibitor is pre-administered 6 days before each administration during the escalation period.
  • anti-T cell antigen-binding molecule is repeatedly administered once a week, and the pre-administration of the cytokine inhibitor is 5 days before each administration during the escalation period. If done), -On the day of each dose during the escalation period, 1 day or 2 days later (anti-T cell antigen-binding molecule is repeatedly administered at weekly intervals, and premedication with a cytokine inhibitor is performed at each dose during the escalation period.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, (iii) (a) during the escalation period, a cytokine inhibitor is pre-administered for each administration, and (b) the maintenance administration period. In, no pre-administration of cytokine inhibitors is given.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule on the day of each administration of the escalating administration period, or-On the day of each administration of the escalating administration period, the anti-T cell antigen-binding molecule A cytokine inhibitor is administered at the same time as the administration of.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor As a specific example -On the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after each administration in the escalating administration period (anti-T cell antigen-binding molecule is repeatedly administered once every two weeks, cytokine inhibitor If the pre-administration of is performed 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before each administration of the escalating administration period), or ⁇ 1 day, 2 days after each administration of the escalating administration period , 3 days, 4 days, 5 days or 6 days (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and pre-administration of cytokine inhibitor is performed on the day of each administration of the incremental administration period. If done), In addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, the anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, (iii) (a) during the escalation period, a cytokine inhibitor is pre-administered for each administration, and (b) the maintenance administration period. In, no pre-administration of cytokine inhibitors is given.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule on the day of each administration of the escalating administration period, or-On the day of each administration of the escalating administration period, the anti-T cell antigen-binding molecule A cytokine inhibitor is administered at the same time as the administration of.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor As a specific example -On the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after each administration in the escalating administration period (anti-T cell antigen-binding molecule is repeatedly administered once every 3 weeks, cytokine inhibitor If the pre-administration of is performed 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before each administration of the escalating administration period), or ⁇ 1 day, 2 days after each administration of the escalating administration period , 3 days, 4 days, 5 days or 6 days (anti-T cell antigen-binding molecule is repeatedly administered once every 3 weeks, and pre-administration of cytokine inhibitor is performed on the day of each administration of the incremental administration period. If done), In addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, (iii) (a) during the escalation period, a cytokine inhibitor is pre-administered for each administration, and (b) the maintenance administration period. In, no pre-administration of cytokine inhibitors is given.
  • the combination therapies of the present disclosure include (i) a period of incremental administration of an anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) an anti-T cell during the incremental administration period and the maintenance administration period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule on the day of each administration of the escalating administration period, or-On the day of each administration of the escalating administration period, the anti-T cell antigen-binding molecule A cytokine inhibitor is administered at the same time as the administration of.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor As a specific example -On the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after each administration in the escalating administration period (anti-T cell antigen-binding molecule is repeatedly administered once every 4 weeks, cytokine inhibitor If the pre-administration of is performed 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before each administration of the escalating administration period), or ⁇ 1 day, 2 days after each administration of the escalating administration period , 3 days, 4 days, 5 days or 6 days (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 4 weeks, and pre-administration of cytokine inhibitor is performed on the day of each administration of the incremental administration period. If done), In addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, the anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, (iii) (a) during the incremental administration period, a cytokine inhibitor is pre-administered for each administration, and (b) the maintenance administration period. In, no pre-administration of cytokine inhibitors is given.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment.
  • -A cytokine inhibitor is administered 6 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 5 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 4 days before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 3 days before each administration of the escalating administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 2 days before each administration of the escalating administration period and before the administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered 1 day before each administration of the incremental administration period and before administration of the anti-T cell antigen-binding molecule.
  • -A cytokine inhibitor is administered before administration of the anti-T cell antigen-binding molecule on the day of each administration of the escalating administration period, or-On the day of each administration of the escalating administration period, the anti-T cell antigen-binding molecule A cytokine inhibitor is administered at the same time as the administration of.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • cytokine inhibitor As a specific example -On the day, 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after each administration in the escalating administration period (anti-T cell antigen-binding molecule is repeatedly administered once every 5 weeks, cytokine inhibitor If the pre-administration of is performed 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before each administration of the escalating administration period), or ⁇ 1 day, 2 days after each administration of the escalating administration period , 3 days, 4 days, 5 days or 6 days (anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and pre-administration of cytokine inhibitor is performed on the day of each administration of the incremental administration period. If done), In addition, the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at weekly intervals, (iii) (a) for each dose during the incremental dose period, and (b) for the first of the maintenance dose period during the maintenance dose period.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at weekly intervals, and (iii) the cytokine inhibitor is pre-administered in the following embodiments.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • ⁇ (A) 5 days before each administration in the escalating administration period and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period. Cytokine inhibitors are administered 5 days prior to administration of the anti-T cell antigen binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor On the day, the cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or: (a) the day of each dose during the escalation period, and (b) the first first of the maintenance dose periods, 1 On the day of each of the 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • anti-T cell antigen-binding molecule is repeatedly administered once a week, and pre-administration of cytokine inhibitor is (a) 6 days before each administration in the incremental administration period, and (b) the beginning of the maintenance administration period. 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administration 6 days before each administration), ⁇ (A) On the day or 1 day after each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th maintenance administration periods.
  • Anti-T cell antigen-binding molecules are repeatedly administered once a week, with pre-administration of cytokine inhibitors being (a) on the day of each dose during the incremental dose period and (b) the first 1 of the maintenance dose period.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, (iii) (a) for each dose during the incremental dose period, and (b) at the beginning of the maintenance dose period for the maintenance dose period.
  • Pre-administration of the cytokine inhibitor is performed for 1 time, 1 to 2 times, 1 to 3 times, 1 to 4 times, or 1 to 5 times of administration.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment. ⁇ (A) 6 days before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • Cytokine inhibitors are administered 5 days prior to administration of the anti-T cell antigen binding molecule.
  • ⁇ (A) 4 days before each administration in the escalating administration period and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • Cytokine inhibitors are administered 4 days prior to administration of the anti-T cell antigen-binding molecule.
  • Three days before administration, a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • A 1 day before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor On the day, the cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or: (a) the day of each dose during the escalation period, and (b) the first first of the maintenance dose periods, 1 On the day of each of the 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) an incremental dose period of the anti-T cell antigen binding molecule and a subsequent maintenance dose period, and (ii) the anti-T cell during the incremental dose and maintenance dose period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, (iii) (a) for each dose during the incremental dose period, and (b) at the beginning of the maintenance dose period for the maintenance dose period.
  • Pre-administration of the cytokine inhibitor is performed for 1 time, 1 to 2 times, 1 to 3 times, 1 to 4 times, or 1 to 5 times of administration.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every three weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment. ⁇ (A) 6 days before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • Cytokine inhibitors are administered 5 days prior to administration of the anti-T cell antigen binding molecule.
  • ⁇ (A) 4 days before each administration in the escalating administration period and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • Cytokine inhibitors are administered 4 days prior to administration of the anti-T cell antigen-binding molecule.
  • Three days before administration, a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • A 1 day before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor On the day, the cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or: (a) the day of each dose during the escalation period, and (b) the first first of the maintenance dose periods, 1 On the day of each of the 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a escalating period of the anti-T cell antigen binding molecule and a subsequent maintenance administration period, and (ii) during the escalating and maintenance administration period
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, (iii) (a) for each dose during the incremental dose period, and (b) at the beginning of the maintenance dose period for the maintenance dose period.
  • Pre-administration of the cytokine inhibitor is performed for 1 time, 1 to 2 times, 1 to 3 times, 1 to 4 times, or 1 to 5 times of administration.
  • the combination therapies of the present disclosure include (i) a period of incremental administration of an anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) an anti-T cell during the incremental administration period and the maintenance administration period.
  • the antigen-binding molecule is repeatedly administered at intervals of once every four weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment. ⁇ (A) 6 days before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • Cytokine inhibitors are administered 5 days prior to administration of the anti-T cell antigen binding molecule.
  • ⁇ (A) 4 days before each administration in the escalating administration period and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • Cytokine inhibitors are administered 4 days prior to administration of the anti-T cell antigen-binding molecule.
  • Three days before administration, a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • A 1 day before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor On the day, the cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or: (a) the day of each dose during the escalation period, and (b) the first first of the maintenance dose periods, 1 On the day of each of the 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the cytokine inhibitor may be further administered.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, the anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, (iii) (a) for each dose during the incremental dose period, and (b) at the beginning of the maintenance dose period for the maintenance dose period.
  • Pre-administration of the cytokine inhibitor is performed for 1 time, 1 to 2 times, 1 to 3 times, 1 to 4 times, or 1 to 5 times of administration.
  • the combination therapies of the present disclosure include (i) a escalating period of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalating administration period and the maintenance administration period, anti-T cells.
  • the antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, and (iii) the cytokine inhibitor is pre-administered in the following embodiment. ⁇ (A) 6 days before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • Cytokine inhibitors are administered 5 days prior to administration of the anti-T cell antigen binding molecule.
  • ⁇ (A) 4 days before each administration in the escalating administration period and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • Cytokine inhibitors are administered 4 days prior to administration of the anti-T cell antigen-binding molecule.
  • Three days before administration, a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • A 1 day before each administration in the escalating administration period, and (b) the first 1st, 1st, 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations of the maintenance administration period.
  • a cytokine inhibitor is administered prior to administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor On the day, the cytokine inhibitor is administered prior to the administration of the anti-T cell antigen-binding molecule, or: (a) the day of each dose during the escalation period, and (b) the first first of the maintenance dose periods, 1 On the day of each of the 2nd, 1st to 3rd, 1st to 4th, and 1st to 5th administrations, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a period of incremental administration of the anti-T cell antigen-binding molecule, followed by a maintenance administration period, and (ii) during the period of incremental administration of the anti-T cell antigen-binding molecule. Repeatedly administered once a week (iii) During the maintenance period, the anti-T cell antigen-binding molecule was administered twice, three, four, or five times at weekly intervals.
  • the combination therapies of the present disclosure include (i) a period of escalation of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalation period, the anti-T cell antigen-binding molecule Repeatedly administered once a week (iii) During the maintenance period, the anti-T cell antigen-binding molecule was administered twice, three, four, or five times at weekly intervals.
  • Cytokine inhibitors are administered (a) 6 days prior to each dose and (b) 6 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru • Cytokine inhibitors are administered 5 days prior to each dose and (b) 5 days prior to the first dose of each dosing cycle during the maintenance regime, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 4 days prior to each dose and (b) 4 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 3 days prior to each dose and (b) 3 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 2 days prior to each dose and (b) 2 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 1 day prior to each dose and (b) 1 day prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen-binding molecule on the day of (a) incremental administration and (b) on the day of the first administration of each administration cycle during the maintenance administration period.
  • -(A) Increasing administration period On the day of each administration and (b) On the day of the first administration of each administration cycle in the maintenance administration period, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • pre-administration of the cytokine inhibitor is (a) 5 days prior to each dose in the incremental dose period and (b) 5 days prior to the first dose in each dosing cycle during the maintenance dose period), • (a) day, 1 or 2 days after administration of the incremental dose period, and (b) day, 1 day or 2 days after the first dose of each dosing cycle during the maintenance dosing period (anti-T cell antigen-binding molecule in the week)
  • pre-administration of the cytokine inhibitor is given (a) 4 days before each dose in the incremental dose period and (b) 4 days before
  • the antigen-binding molecule is administered repeatedly at weekly intervals, with premedication of the cytokine inhibitor at the beginning of each dosing cycle, (a) 3 days prior to each dose and (b) maintenance period.
  • anti-T cell antigen-binding molecule is repeatedly administered once a week, and pre-administration of cytokine inhibitor is performed (a) 2 days before each administration period and (b) maintenance administration period. If given 2 days before the first dose of each dosing cycle), -(A) On the day of administration, 1 day, 2 days, 3 days, 4 days or 5 days after the incremental administration period, and (b) on the day of the first administration, 1 day, 2 days after the first administration cycle in the maintenance administration period.
  • anti-T cell antigen-binding molecule After 3 days, 4 days or 5 days (anti-T cell antigen-binding molecule is repeatedly administered once a week, pre-administration of cytokine inhibitor is (a) 1 day before each administration, and (b) ) During the maintenance dosing period, if given 1 day before the first dosing of each dosing cycle), or (a) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after dosing in the incremental dose period, and (b) During the maintenance period, 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the first administration of each administration cycle (anti-T cell antigen-binding molecule is repeatedly administered once a week).
  • the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a period of incremental administration of the anti-T cell antigen-binding molecule, followed by a maintenance administration period, and (ii) during the period of incremental administration of the anti-T cell antigen-binding molecule. Repeatedly administered at intervals of once every two weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every two weeks.
  • the combination therapies of the present disclosure include (i) a period of escalation of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalation period, the anti-T cell antigen-binding molecule Repeatedly administered at intervals of once every two weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every two weeks.
  • Cytokine inhibitors are administered (a) 6 days prior to each dose and (b) 6 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru • Cytokine inhibitors are administered 5 days prior to each dose and (b) 5 days prior to the first dose of each dosing cycle during the maintenance regime, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 4 days prior to each dose and (b) 4 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 3 days prior to each dose and (b) 3 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 2 days prior to each dose and (b) 2 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 1 day prior to each dose and (b) 1 day prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen-binding molecule on the day of (a) incremental administration and (b) on the day of the first administration of each administration cycle during the maintenance administration period.
  • -(A) Increasing administration period On the day of each administration and (b) On the day of the first administration of each administration cycle in the maintenance administration period, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • On the day of administration 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the incremental administration period, and (b) on the day of the first administration, 1 day after the first administration cycle in the maintenance administration period.
  • the anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every two weeks, and the pre-administration of the cytokine inhibitor is (a) for each incremental administration period. 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before administration, and (b) 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, or (b) the first administration of each administration cycle in the maintenance administration period. (If given 1 day before), or: (a) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the incremental dose period, and (b) the beginning of each dosing cycle during the maintenance dosing period.
  • cytokine inhibitor 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days after administration (anti-T cell antigen-binding molecule is repeatedly administered once every two weeks, and pre-administration of cytokine inhibitor is performed in (a). Increasing dose period On the day of each dose, and (b) on the day of the first dose of each dosing cycle during the maintenance dosing period), In addition, the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a period of incremental administration of the anti-T cell antigen-binding molecule, followed by a maintenance administration period, and (ii) during the period of incremental administration of the anti-T cell antigen-binding molecule. Repeatedly administered at intervals of once every three weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule was administered twice, three times, four times, or five times at intervals of once every three weeks.
  • the combination therapies of the present disclosure include (i) a period of escalation of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalation period, the anti-T cell antigen-binding molecule Repeatedly administered at intervals of once every three weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule was administered twice, three times, four times, or five times at intervals of once every three weeks.
  • Cytokine inhibitors are administered (a) 6 days prior to each dose and (b) 6 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru • Cytokine inhibitors are administered 5 days prior to each dose and (b) 5 days prior to the first dose of each dosing cycle during the maintenance regime, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 4 days prior to each dose and (b) 4 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 3 days prior to each dose and (b) 3 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 2 days prior to each dose and (b) 2 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 1 day prior to each dose and (b) 1 day prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen-binding molecule on the day of (a) incremental administration and (b) on the day of the first administration of each administration cycle during the maintenance administration period.
  • -(A) Increasing administration period On the day of each administration and (b) On the day of the first administration of each administration cycle in the maintenance administration period, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • On the day of administration 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the incremental administration period, and (b) on the day of the first administration, 1 day after the first administration cycle in the maintenance administration period.
  • anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 3 weeks, and pre-administration of cytokine inhibitor is performed (a) for each incremental administration period. 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before administration, and (b) 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, or (b) the first administration of each administration cycle in the maintenance administration period. (If given 1 day before), or: (a) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the incremental dose period, and (b) the beginning of each dosing cycle during the maintenance dosing period.
  • cytokine inhibitor 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration (anti-T cell antigen-binding molecule is repeatedly administered once every 3 weeks, and pre-administration of cytokine inhibitor is performed (a). Increasing Dosing Period On the day of each dose, and (b) On the day of the first dosing of each dosing cycle during the maintenance dosing period), In addition, the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a period of incremental administration of the anti-T cell antigen-binding molecule, followed by a maintenance administration period, and (ii) during the period of incremental administration of the anti-T cell antigen-binding molecule. Repeatedly administered once every four weeks (iii) During the maintenance period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every four weeks. Repeatedly administered in one administration cycle, (iv) (a) for each dose during the incremental dose period, and (b) for the first dose in each dose cycle during the maintenance dose period.
  • the combination therapy of the present disclosure includes (i) a period of incremental administration of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the period of incremental administration, the anti-T cell antigen-binding molecule is contained. Repeatedly administered once every four weeks (iii) During the maintenance period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every four weeks. Is repeatedly administered in an administration cycle in which the administration of the above is one cycle, and (iv) the pre-administration of the cytokine inhibitor is performed in the following embodiment.
  • Cytokine inhibitors are administered (a) 6 days prior to each dose and (b) 6 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered 5 days prior to each dose and (b) 5 days prior to the first dose of each dosing cycle during the maintenance regime, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 4 days prior to each dose and (b) 4 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 3 days prior to each dose and (b) 3 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 2 days prior to each dose and (b) 2 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 1 day prior to each dose and (b) 1 day prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen-binding molecule on the day of (a) incremental administration and (b) on the day of the first administration of each administration cycle during the maintenance administration period. Or, -(A) Increasing administration period On the day of each administration and (b) On the day of the first administration of each administration cycle in the maintenance administration period, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • On the day of administration 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after the incremental administration period, and (b) on the day of the first administration, 1 day after the first administration cycle in the maintenance administration period.
  • cytokine inhibitor is (a) each time of increasing dose period. 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before administration, and (b) 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, or (b) the first administration of each administration cycle in the maintenance administration period. (If given 1 day before), or: (a) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the incremental dose period, and (b) the beginning of each dosing cycle during the maintenance dosing period.
  • cytokine inhibitor 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration (anti-T cell antigen-binding molecule is repeatedly administered once every 4 weeks, and pre-administration of cytokine inhibitor is performed in (a). Increasing Dosing Period On the day of each dose, and (b) On the day of the first dosing of each dosing cycle during the maintenance dosing period), In addition, the cytokine inhibitor may be further administered.
  • the combination therapy of the present disclosure comprises (i) a period of incremental administration of the anti-T cell antigen-binding molecule, followed by a maintenance administration period, and (ii) during the period of incremental administration of the anti-T cell antigen-binding molecule. Repeatedly administered at intervals of once every 5 weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every five weeks.
  • the combination therapies of the present disclosure include (i) a period of escalation of the anti-T cell antigen-binding molecule and a subsequent maintenance administration period, and (ii) during the escalation period, the anti-T cell antigen-binding molecule Repeatedly administered at intervals of once every 5 weeks (iii) During the maintenance administration period, the anti-T cell antigen-binding molecule is administered twice, three times, four times, or five times at intervals of once every five weeks.
  • Cytokine inhibitors are administered (a) 6 days prior to each dose and (b) 6 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru • Cytokine inhibitors are administered 5 days prior to each dose and (b) 5 days prior to the first dose of each dosing cycle during the maintenance regime, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 4 days prior to each dose and (b) 4 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 3 days prior to each dose and (b) 3 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 2 days prior to each dose and (b) 2 days prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered (a) 1 day prior to each dose and (b) 1 day prior to the first dose of each dosing cycle during the maintenance duration, prior to the administration of the anti-T cell antigen-binding molecule.
  • Ru, • Cytokine inhibitors are administered prior to administration of the anti-T cell antigen-binding molecule on the day of (a) incremental administration and (b) on the day of the first administration of each administration cycle during the maintenance administration period.
  • -(A) Increasing administration period On the day of each administration and (b) On the day of the first administration of each administration cycle in the maintenance administration period, the cytokine inhibitor is administered at the same time as the administration of the anti-T cell antigen-binding molecule.
  • the combination therapy of the present disclosure comprises pre-administration of the cytokine inhibitor according to the above-mentioned embodiment, and on the day, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the anti-T cell antigen-binding molecule.
  • the cytokine inhibitor may be further administered to the individual.
  • anti-T cell antigen-binding molecule is repeatedly administered at intervals of once every 5 weeks, pre-administration of cytokine inhibitor, (a) incremental administration period each time. 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before administration, and (b) 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, or (b) the first administration of each administration cycle in the maintenance administration period. (If given 1 day before), or: (a) 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration of the incremental dose period, and (b) the beginning of each dosing cycle during the maintenance dosing period.
  • cytokine inhibitor 1 day, 2 days, 3 days, 4 days, 5 days or 6 days after administration (anti-T cell antigen-binding molecule is repeatedly administered once every 5 weeks, and pre-administration of cytokine inhibitor is performed (a). Increasing dose period On the day of each dose, and (b) on the day of the first dose of each dosing cycle during the maintenance dosing period), In addition, the cytokine inhibitor may be further administered.
  • the present disclosure provides an anti-GPC3 / T cell receptor complex bispecific antibody.
  • a pharmaceutical composition comprising and for use in combination therapy with a cytokine inhibitor.
  • the disclosure provides a pharmaceutical composition comprising a cytokine inhibitor for use in combination therapy with an anti-glypican 3 (GPC3) / T cell receptor complex bispecific antibody.
  • the cytokine inhibitor is administered to the individual before, at the same time or after administration of the anti-GPC3 / T cell receptor complex bispecific antibody.
  • the cytokine inhibitor is an individual for the purpose of treating CRS or CRS when signs of CRS or CRS occur in the individual after administration of the anti-GPC3 / T cell receptor complex bispecific antibody. Is administered to.
  • the cytokine inhibitor When, but not limited to, the cytokine inhibitor is administered before or at the same time as the anti-GPC3 / T cell receptor complex bispecific antibody, the anti-GPC3 / T cell receptor complex bispecificity. It has the effect of preventing or reducing the occurrence of CRS associated with the administration of the antibody.
  • the cytokine inhibitor is the anti-GPC3 / T cell receptor complex bispecific antibody, said double, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or day before administration. It is administered before administration of the specific antibody.
  • the cytokine inhibitor is administered at the same time as the bispecific antibody on the day of administration of the anti-GPC3 / T cell receptor complex bispecific antibody (pre-administration of the cytokine inhibitor).
  • Specific Examples of Combination Therapy Including Premedication of Cytokine Inhibitors Refer to the various aspects described above.
  • the cytokine inhibitor is administered after the administration of the anti-GPC3 / T cell receptor complex bispecific antibody and before the development of CRS, it has the effect of preventing or reducing the CRS that may occur thereafter. ..
  • a cytokine inhibitor is given after administration of an anti-GPC3 / T cell receptor complex bispecific antibody and after the onset of CRS or signs of CRS, treat CRS and alleviate its symptoms. Has an effect.
  • pre-administration of a cytokine inhibitor provides the efficacy of an anti-GPC3 / T cell receptor complex bispecific antibody (eg, TDCC (T cell-dependent cellular cytotoxicity; T cell-dependent cytotoxicity)) or anti-GPC3 / T cell receptor complex bispecific antibody. Prevents or reduces the occurrence of CRS associated with the administration of the anti-GPC3 / T cell receptor complex bispecific antibody without significantly impairing the tumor effect).
  • the present invention also provides a kit for use in the method of the present invention, which comprises the multispecific antigen-binding molecule of the present invention or the multispecific antigen-binding molecule produced by the production method of the present invention. To do.
  • the kit may be packaged with a pharmaceutically acceptable carrier, medium, instructions describing the method of use, and the like.
  • the present invention also relates to a multispecific antigen-binding molecule of the present invention or a multispecific antigen-binding molecule produced by the production method of the present invention for use in the method of the present invention.
  • the present invention also relates to nucleic acids encoding these molecules, vectors into which the nucleic acids have been introduced, the nucleic acids or cells containing the vectors, methods for producing the molecules by culturing the cells, and methods. It also concerns the molecules produced.
  • the T-cell antigen-binding molecule is a multispecific antigen-binding molecule
  • a nucleic acid encoding the multispecific antigen-binding molecule, or a vector into which the nucleic acid has been introduced is introduced into an appropriate host cell, and the host cell is introduced.
  • the multispecific antigen-binding molecule can be produced by culturing.
  • the desired multispecific antigen-binding molecule can be recovered from the culture supernatant.
  • a method for purifying the desired multispecific antigen-binding molecule from the culture is also known.
  • the cytokine inhibitor is a protein component such as an antibody
  • the nucleic acid encoding the cytokine inhibitor molecule or the vector into which the nucleic acid is introduced is introduced into an appropriate host cell, and the host cell is introduced.
  • the T cell antigen-binding molecule and the cytokine inhibitor can be independently packaged with a pharmaceutically acceptable carrier, medium, instructions describing the usage method, and the like. Alternatively, both can be formulated and then combined to form a kit.
  • the kit can include, for example, a package containing a formulated T cell antigen-binding molecule and a package containing a formulated cytokine inhibitor. If each of the preparations constituting the kit is lyophilized or a liquid concentrated preparation, a liquid medium for dissolving or diluting the preparation can be combined with the kit.
  • the ERY101EG study is a phase I clinical study in patients with Glypican-3-positive advanced solid tumors and is the estimated minimum. Dose escalation was performed from the initial dose of 0.0031 ⁇ g / kg as determined by the Minimum Anticipated Biological Effect Level (MABEL) and NOAEL. In this study, the tolerability of ERY974 was evaluated in 1 to 3 subjects per cohort, and the dose (or target dose) was gradually increased as the cohort moved from one cohort to the next.
  • MABEL Minimum Anticipated Biological Effect Level
  • ERY974 was administered intravenously once a week. Intravenous administration of ERY974 was performed over 3 hours, followed by flushing with saline over 1 hour. If the investigator determined that there was no problem with the safety of the subjects, it was decided that the administration time of ERY974 could be shortened to a minimum of 2 hours.
  • the dose of dexamethasone given before the first and second doses of ERY974 and the afternoon before the day of ERY974 administration is 8 mg orally, and the dose of ERY974 is the first dose.
  • the dose of dexamethasone pre-administered 1 hour before the start of ERY974 administration was 8 mg intravenously.
  • the dose of dexamethasone pre-administered 1 hour before the start of ERY974 administration was increased to 20 mg.
  • the dose and schedule of dexamethasone in each cohort was recommended and sponsored by the Safety Monitoring Committee (SMC) at the time of dose escalation.
  • SMC Safety Monitoring Committee
  • ERY974 is repeatedly administered by intravenous drip in QW in the same manner as in cohorts 1 to 5, but the first, second, third, and so on. / Or the dose was increased sequentially with the 4th dose. That is, first, the subjects received a low dose of ERY974 in the first dose (Day 1) (0.081 ⁇ g / kg in cohort 6 and 0.12 ⁇ g / kg in cohort 7 and later). Then, in the second and subsequent doses, the dose to the subject was gradually increased until the dose reached the target dose determined in each cohort.
  • cohort 6 0.081 ⁇ g / kg was administered on Day 1, 0.24 ⁇ g / kg after Day 8, 0.12 ⁇ g / kg was administered in Cohort 7, and 0.24 ⁇ g / kg was administered after Day 8.
  • cohorts 8A, 9A, and 10A 0.12 ⁇ g / kg was administered in the first (Day 1) and the target dose determined in each cohort was administered in the second (Day 8) (this is called the Fixed Day 1 regimen).
  • cohorts 8B, 8B and 9B 0.12 ⁇ g / kg was determined in the first (Day 1) and second (Day 8), 0.24 ⁇ g / kg in the third (Day 15), and each cohort was determined in the fourth (Day 22).
  • the target dose was administered (this is called the Fixed Day 15 regimen).
  • the DLT evaluation period is from the first administration to the 7th day after the third administration (entering the administration day), and for the Fixed Day15 regimen, from the first administration to 7 after the fourth administration. DLT was evaluated with the DLT evaluation period up to the day (entering the administration date).
  • the target doses for cohorts 6 and 7 were 0.24 ⁇ g / kg
  • the target doses for cohorts 8A and 8B were 0.36 ⁇ g / kg
  • the target doses for cohorts 9A and 9B were 0.54 ⁇ g / kg
  • the target doses for cohort 10A were It was 0.81 ⁇ g / kg. From cohort 1 to cohort 10A, a total of 29 subjects received ERY974.
  • Example 2 Evaluation Items and Evaluation Results in the ERY101EG Study The ERY101EG mainly evaluated the occurrence of adverse events (AE) and the occurrence of dose limiting toxicity (DLT) at the dosage of each cohort.
  • AE adverse events
  • DLT dose limiting toxicity
  • DLT Dose Limiting Toxicity
  • DLT was not observed in cohorts 1-9. DLT was reported in 2 of 3 enrolled in Cohort 10A. Due to cytokine release syndrome (1 case of Grade 2 and 1 case of Grade 3) that occurred after administration of 0.81 ⁇ g / kg of ERY974 on the second (Day 8) of both patients, the third (Day 15) administration of ERY974 was postponed. Because it was necessary, it corresponded to the above-mentioned predetermined DLT standard and was judged to be DLT. In cohort 10A, one subject who did not have DLT also developed cytokine release syndrome (Grade 2) after administration of 0.81 ⁇ g / kg of ERY974 on the second (Day 8), and ERY974 on the third (Day 15). The dose was reduced. From this, it was concluded that the regimen / dose of cohort 10A was an unacceptable dosage under premedication with steroids.
  • the number of CRS expression was 1, 0, 3, 3 in cohorts 8A, 8B, 9A, and 9B (3 patients each), Grade 1 or 2, and between cohorts 8A and 8B, and with cohort 9A. No clear difference was observed between 9B. Since cohort 10B (Fixed Day 15 regimen, target dose 0.81 ⁇ g / kg) was not performed in the ERY101EG trial, DLT was not detected in the Fixed Day 15 regimen study, and therefore cohort 10B is intolerable usage. It cannot be concluded that it is a dose. However, there were no indications from the results up to Cohort 9B that the Fixed Day 15 regimen was superior to the Fixed Day 1 regimen in terms of CRS suppression.
  • Example 3 Analysis of Cytokine Release Syndrome (CRS) and Elevation of IL-6 and Use of Tocilizumab in ERY101EG Study (3-1) Cytokine level after administration of ERY974
  • CRS Cytokine release syndrome
  • Three subjects enrolled in Cohort 10A developed CRS requiring ERY974 withdrawal or dose reduction after the second (Day 8) administration of ERY974 (after the first target dose of 0.81 ⁇ g / kg). (2 cases of Grade 2 and 1 case of Grade 1), and in these 3 patients, IL-6, IL-8 and IL-10 increased within 24 hours after the end of the second (Day 8) study drug administration.
  • tocilizumab for the treatment of CRS
  • tocilizumab was used alone or in combination with steroids for the treatment of CRS in some patients at the discretion of the investigator. It was.
  • Table 11 The severity of CRS ranged from grade 1 to grade 3.
  • Tocilizumab was administered on the same day as the onset of CRS, with the exception of 2 patients (cohort 10A, 840010006, 840010007).
  • CRS recovered 4 days after the same day of tocilizumab administration.
  • the serum concentration of tocilizumab required to bind IL-6R of 80% or more from the K m value is theoretically 10.8 ⁇ g / mL or more, and the simulation results show that non-linear disappearance is observed below 10 ⁇ g / mL. (Fig. 5A).
  • Indirect response model shows the process of formation and elimination of IL-6R in serum (IL-6R has membrane-bound IL-6R and soluble IL-6R, and IL-6R in serum is the latter).
  • Gibiansky is a population pharmacokinetic model that incorporates binding to Tosilizumab for the disappearance of its unbound IL-6R (referring to IL-6R that does not form a complex with IL-6). Reported by (Gibiansky, L. and Frey, N., Linking interleukin-6 receptor blockade with tocilizumab and its hemotological effects using a modeling approach. J Pharmacokinet Pharmacaodyn. 2012 Feb; 39 (1) (Hereafter referred to as "Gibiansky et al.'S paper").
  • Tocilizumab Setting the dose and frequency of tocilizumab that can maintain the target concentration Tocilizumab is used by the US Food and Drug Administration (FDA) for the treatment of severe or life-threatening CRS associated with CAR-T cell therapy. It has been approved and is approved for administration of 8 mg / kg / 8h to patients weighing 30 kg or more. Therefore, 8 mg / kg was selected as the single dose of tocilizumab.
  • Simulation results (FIGS. 5A and 5B) show that 95% of patients have exceeded target levels of exposure between 7 and 14 days after dosing, and 50% of patients have exceeded target levels of exposure. It was between 14 and 21 days after administration.
  • the IL-6 / IL-6R complex concentration is 300, 1000 for IL-6 in the presence of unbound sIL-6R calculated from the Gibiansky model. , 3000, 5000 and 10000 pg / mL were assumed and calculated (it is understood that the higher the IL-6 / IL-6R complex concentration, the more IL-6 signaling occurs). The calculation was performed based on the following formula, assuming that the reactions of IL-6 and IL-6R were in equilibrium. The Kd value is the value reported by Baran et al. Baran P, Hansen S, Waetzig GH, et al.
  • interleukin (IL) -6 interleukin-6
  • sIL-6R IL-6 soluble IL-6 receptor
  • IL-6 sIL- 6R sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem. 2018; 293 (18): 6762-6775.) (Hereinafter referred to as "the paper of Baren et al.”), 22 nM was used.
  • tocilizumab serum concentration it is speculated that the higher the IL-6 concentration, the higher the IL-6 / IL-6R complex concentration, and the more likely it is to induce CRS (Fig. 11). Therefore, it is suggested that the target concentration estimated from patients with rheumatism may not be sufficient to suppress CRS after administration of ERY974. Thus, if the target concentration of tocilizumab estimated from rheumatoid patients is not sufficient to suppress CRS after ERY974 administration, tocilizumab may be administered multiple times to keep the IL-6 / IL-6R complex concentration low. An IL-6-mediated signal-suppressing effect can be expected (Figs. 9 and 10).
  • tocilizumab can suppress the increase in serum IL-6 associated with the administration of ERY974 by suppressing the secondary activation of immune cells in advance. It is inferred that. If pre-administration of tocilizumab can suppress the increase in serum IL-6 associated with the administration of ERY974, it is theoretically possible to reduce the concentration of tocilizumab required to suppress CRS.
  • tocilizumab in therapeutic applications for CRS (8 mg / kg for patients weighing 30 kg or more, see Example 4-3), premedication with tocilizumab CRS suppression effect can be expected.
  • the optimal single dose of tocilizumab was determined (for example, as a single dose, taking into account the serum concentration, IL-6 concentration, and AE report of tocilizumab obtained after the start of the study. It is assumed that the dose will be set lower than 8 mg / kg).
  • ERY102JP study is a phase I clinical study in patients with Glypican-3 (GPC3) -positive advanced solid tumors treated with a single agent of ERY974.
  • GPC3 Glypican-3
  • This study is a single-center, open-label, dose-escalation study that shows the safety, tolerability, pharmacokinetics, and antitumor effects of ERY974 as a single agent in patients with GPC3-positive advanced / recurrent solid tumors after pretreatment with tocilizumab. Designed for evaluation.
  • the number of subjects scheduled to participate in this clinical trial is 15 to 30 (3 to 6 in each cohort, 5 cohorts in total) at the initial stage of preparing the clinical trial protocol, but the results of this clinical trial and overseas clinical trials
  • the planned number of subjects may be changed, including changes in the administration method of ERY974 and / or tocilizumab, and studies on specific carcinomas.
  • the primary objective of this study is to pre-administer tocilizumab, an anti-IL-6 receptor antibody, in patients with GPC3-positive advanced / recurrent solid tumors, followed by a single dose (or dosage) of ERY974 for each cohort.
  • dose limiting toxicity (DLT) is evaluated, maximum tolerated dose (MTD) is determined, and safety, tolerability evaluation and pharmacokinetics are confirmed.
  • MTD maximum tolerated dose
  • ERY974 was judged to be ineffective or unacceptable harmful to the single dose shown in Table 12 below at weekly (QW) intervals. Administer intravenously until the event occurs. In this study, as a general rule, the dose of ERY974 per dose shall not be changed, but if clinically necessary due to the occurrence of adverse events, etc., the dose may be reduced at the discretion of the investigator.
  • Intravenous administration of ERY974 is performed for 3 hours, followed by flushing with saline for 1 hour. If the investigator determines that there is no problem with the safety of the subject, the administration time of ERY974 can be shortened to a minimum of 1 hour.
  • DLT evaluation In the ERY102JP study, one cycle was 7 days, and 28 days from the first administration of ERY974 (cycle 1 Day 1) to the fifth administration of ERY974 (cycle 5 Day 1) (cycle 5 Day 1). If the administration is postponed within the permissible range, +3 days) will be the DLT evaluation period. If the administration of ERY974 is postponed, the DLT evaluation period will be extended, but the maximum DLT evaluation period shall not exceed 42 days (+3 days if the administration is postponed within the permissible range). .. Among the adverse events that occurred during the DLT evaluation period, the events for which a causal relationship with the predetermined ERY974 cannot be ruled out are defined as DLT.
  • ERY974 3 to 6 subjects were enrolled in each cohort to perform a DLT evaluation, and the investigator and sponsor based on the DLT expression status observed during the DLT evaluation period. Will, in consultation, decide whether or not to move to the next ERY974 dose-stage cohort.
  • the maximum dose with a DLT expression rate of less than 33% is defined as MTD.
  • the pharmacokinetic parameters of ERY974 and tocilizumab (AUC, Cmax, Tmax, etc.) will be calculated, and the effects of anti-ERY974 antibody and anti-tocilizumab antibody on their respective pharmacokinetics will be evaluated.
  • ERY974 that is, the determination of tumor shrinkage effect
  • RECIST v1.1 the response rate (Overall Response Rate, ORR), disease control rate (DCR), and progression-free survival (Progression Free Survival).
  • PFS the duration of response (Duration of Response DoR) is determined.
  • ERY974 and tocilizumab after approval are used in combination with tocilizumab, and in the combination therapy, tocilizumab is administered to an individual before or at the same time as administration of ERY974.
  • tocilizumab is administered 6 days, 5 days, 4 days, 3 days, 2 days, 1 day or the day before administration of ERY974.
  • tocilizumab may be administered at the same time as ERY974 on the day of administration of ERY974.
  • the pharmaceutical composition containing ERY974 may further contain a document instructing it to be used in combination with a cytokine inhibitor.
  • the pharmaceutical composition containing tocilizumab may further contain a document instructing it to be used in combination with an anti-T cell antigen binding molecule.
  • Example 7 Effect of pre- and post-administration of anti-mouse IL6 receptor antibody (MR-16-1) on the efficacy of ERY974 surrogate antibody (GC33 / 2C11) (7-1) Pretreatment of anti-mouse IL6 receptor antibody (MR-16-1)
  • MR-16-1 Okazaki M
  • et al. characterization of anti-mouse interleukin-6 receptor antibody
  • Immunol Lett. 2002 Dec 3; 84 (3): 231-40 and Saito T, et al., Preparation of soluble murine IL-6 receptor and anti -Murine IL-6 receptor antibodies, J.
  • Hepa1-6 / hGPC3 cancer cells which highly expressed human GPC3 in the mouse cancer cell line Hepa1-6, were transplanted subcutaneously in C57BL / 6 mice. The day of transplantation was set to day 0. On Day 18, grouping was done according to tumor size and body weight. The group settings are as shown in Table 14.
  • MR-16-1 was administered intravenously at 30 mg / kg on day 18. On day 19, the day after MR-16-1, GC33 / 2C11 was administered intravenously at 0.2 and 5 mg / kg.
  • MR-16-1 was administered 6 times in total (day 18, 21, 25, 28, 32 and day 35).
  • GC33 / 2C11 was a single dose on day 19 only.
  • GC33 / 2C11 has an amino acid sequence of SEQ ID NO: 443 as a heavy chain on the GPC3 side, an amino acid sequence of SEQ ID NO: 444 as a light chain on the GPC3 side, an amino acid sequence of SEQ ID NO: 445 as a heavy chain on the CD3 side, and CD3. It was an antibody containing the amino acid sequence of SEQ ID NO: 446 as the light chain on the side.
  • GC33 / 2C11 On Day 17, GC33 / 2C11, 0.2, or 5 mg / kg was first administered intravenously, and two hours later, MR-16-1 was administered intravenously at 30 mg / kg. MR-16-1 was administered 6 times in total (day 17, 21, 24, 28, 31 and day 35). GC33 / 2C11 was a single dose on day 17 only.
  • the present disclosure is useful for the prevention, alleviation, or treatment of side effects caused by cytokine production associated with the administration of an anti-T cell antigen-binding molecule.
  • Anti-T cell antigen-binding molecules are attracting attention as a therapeutic means for cancer. Therefore, in some embodiments, the present disclosure is useful in the treatment of cancer with anti-T cell antigen binding molecules.

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