WO2023001118A1 - Application d'anticorps anti-ox40 dans un médicament combiné - Google Patents

Application d'anticorps anti-ox40 dans un médicament combiné Download PDF

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WO2023001118A1
WO2023001118A1 PCT/CN2022/106326 CN2022106326W WO2023001118A1 WO 2023001118 A1 WO2023001118 A1 WO 2023001118A1 CN 2022106326 W CN2022106326 W CN 2022106326W WO 2023001118 A1 WO2023001118 A1 WO 2023001118A1
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antibody
seq
sequence
antigen
amino acid
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PCT/CN2022/106326
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Chinese (zh)
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梁世忠
符子艺
宋述强
俞金泉
李胜峰
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百奥泰生物制药股份有限公司
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    • 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
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the invention belongs to the field of biomedicine, in particular to the application of anti-OX40 antibody in combined medicine.
  • T cells in the immune system There are two types of checkpoints in the immune system, one is inhibitory, such as PD-1, and the other is activating, such as OX40.
  • Adequate activation of T cells in the immune system requires two levels of signaling. The first signal is generated by T cell antigen receptor recognition of antigen, and the activation signal is transferred into the cell through the CD3 molecule; while the second signal is called costimulatory signal, which is generated by costimulatory molecules on the surface of antigen-presenting cells or target cells and activated Produced by the interaction of co-stimulatory molecule receptors on the surface of T cells.
  • Costimulatory signals promote the proliferation and differentiation of antigen-specific T cells into effector T cells (Lindsay K et al. Immunity 2016,44(5):1005-1019).
  • OX40 also known as TNFRSF4, ACT35, CD134, etc., belongs to the tumor necrosis factor receptor superfamily (TNFRSF), which is a type I transmembrane glycoprotein.
  • TNFRSF tumor necrosis factor receptor superfamily
  • OX40 is not expressed on resting T cells, but on activated CD4 + T cells, CD8 + T cells, NK cells and NKT cells (Paterson DJ et al. Mol. Immunol. 1987; 24:1281-1290). After T cells are activated by antigens, they will highly express OX40 molecules within 1-3 days. The activation of OX40 signal will further enhance the activation signal of T cells to enhance the response of the immune system (Gramaglia I et al. J. Immunol. 2000; 165:3043-3050).
  • anti-OX40 antibodies mainly activate the immune system and inhibit tumors through the following three cellular physiological mechanisms.
  • One is to directly activate CD4 + and CD8 + effector T cells, promote their proliferation and survival, and secrete related inflammatory factors; the other is to weaken the suppression of the immune system by inhibiting the signal and activity of Treg
  • the third is to deplete Treg cells through ADCC or ADCP, etc., to reduce their suppression of effector T cells (J. Willoughby et al. Molecular Immunology 83, 2017, 13-22).
  • OX40 is a very potential activating target in tumor immunotherapy, which can provide a new means for tumor immunotherapy.
  • the invention discloses a method or application of anti-OX40 antibody or antigen-binding fragment for combined treatment of tumor or cancer.
  • the method or use comprises: administering to a patient in need thereof an effective amount of an anti-OX40 antibody or antigen-binding fragment and another therapeutic agent.
  • the present invention discloses the use of an anti-OX40 antibody (such as antibody M or M-KF) or an antigen-binding fragment and another therapeutic agent in the preparation of a medicament for treating tumor or cancer.
  • the present invention discloses the use of an anti-OX40 antibody (such as Antibody M or Antibody M-KF) or an antigen-binding fragment for the preparation of a medicament for use in combination with another therapeutic agent.
  • an anti-OX40 antibody such as Antibody M or Antibody M-KF
  • an antigen-binding fragment for the preparation of a medicament for use in combination with another therapeutic agent.
  • the present invention discloses the use of an anti-OX40 antibody (such as antibody M or antibody M-KF) or an antigen-binding fragment in combination with another therapeutic agent in the treatment of tumor or cancer.
  • an anti-OX40 antibody such as antibody M or antibody M-KF
  • an antigen-binding fragment in combination with another therapeutic agent in the treatment of tumor or cancer.
  • the present invention also discloses a kit, which comprises an anti-OX40 antibody or an antigen-binding fragment (or preparation), another therapeutic agent (or preparation), and an anti-OX40 antibody for guiding patients in need thereof. or instructions for an antigen-binding fragment (or formulation) and another therapeutic agent (or formulation).
  • the present invention also discloses a kit comprising a composition (or preparation) of an anti-OX40 antibody or an antigen-binding fragment and another therapeutic agent and a method for guiding administration of an anti-OX40 antibody to a patient in need thereof. or instructions for a composition (or formulation) of an antigen-binding fragment and another therapeutic agent.
  • the present invention also discloses a pharmaceutical composition suitable for injection, such as a bolus injection type pharmaceutical composition or an infusion (drip) type pharmaceutical composition, comprising an anti-OX40 antibody or an antigen-binding fragment and another therapeutic agent.
  • a pharmaceutical composition suitable for injection such as a bolus injection type pharmaceutical composition or an infusion (drip) type pharmaceutical composition, comprising an anti-OX40 antibody or an antigen-binding fragment and another therapeutic agent.
  • the pharmaceutical composition comprises at least 0.1% of an anti-OX40 antibody or antigen-binding fragment and 0.1% of another therapeutic agent.
  • the percentage of antibody or antigen-binding fragment and another therapeutic agent can vary and can be between about 2% and about 90% by weight of a given dosage form.
  • the amount of anti-OX40 antibody or antigen-binding fragment and another therapeutic agent in such therapeutically useful pharmaceutical compositions can be an effective amount for administration.
  • the present invention also discloses a preparation method of the above-mentioned pharmaceutical composition: separately combining the anti-OX40 antibody or antigen-binding fragment described herein and another therapeutic agent (or the anti-OX40 antibody or antigen-binding fragment and another therapeutic agent) Composition) mixed with a pharmaceutically acceptable carrier suitable for injection (such as water for injection, physiological saline, etc.).
  • a pharmaceutically acceptable carrier suitable for injection such as water for injection, physiological saline, etc.
  • an anti-OX40 antibody or antigen-binding fragment is used in combination with another therapeutic agent to treat a tumor or cancer.
  • anti-OX40 antibody or antigen-binding fragment (or preparation) and another therapeutic agent (or preparation) are used in the treatment of tumor or cancer, which can relieve symptoms.
  • the other therapeutic agent is an antibody or antigen-binding fragment or an antibody drug conjugate (ADC).
  • ADC antibody drug conjugate
  • an anti-OX40 antibody or antigen-binding fragment (or formulation), another therapeutic agent (or formulation) is used in combination with other therapeutic methods to treat tumors or cancer, such as chemotherapy, radiotherapy, and surgical treatment, among others.
  • the anti-OX40 antibody or antigen-binding fragment at least comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, SEQ ID NO One or more of LCDR1 shown in :4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the anti-OX40 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, SEQ ID NO: LCDR1 shown in 4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the heavy chain variable region of the anti-OX40 antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO:7, which is at least 80% identical to the sequence set forth in SEQ ID NO:7 sequence, or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:7; and/or
  • the light chain variable region of the anti-OX40 antibody or antigen-binding fragment comprises the sequence shown in SEQ ID NO: 8, a sequence having at least 80% identity compared with the sequence shown in SEQ ID NO: 8, or a sequence with SEQ ID NO: 8 Compared with the sequence shown in NO:8, there are one or more amino acid sequences with conservative amino acid substitutions.
  • the heavy chain variable region of the anti-OX40 antibody or antigen-binding fragment comprises the sequence shown in SEQ ID NO: 7
  • the light chain variable region of the anti-OX40 antibody or antigen-binding fragment comprises SEQ ID The sequence shown in NO:8.
  • the heavy chain of the anti-OX40 antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO:9, a sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:9, or An amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 9; and/or
  • the light chain of the anti-OX40 antibody or antigen-binding fragment comprises the sequence shown in SEQ ID NO: 10, a sequence having at least 80% identity to the sequence shown in SEQ ID NO: 10, or a sequence shown in SEQ ID NO: 10
  • the sequences are compared to amino acid sequences having one or more conservative amino acid substitutions.
  • the anti-OX40 antibody is antibody M or M-KF
  • the heavy chain of antibody M or M-KF comprises the sequence shown in SEQ ID NO: 9
  • the light chain of antibody M or M-KF Comprising the sequence shown in SEQ ID NO: 10
  • antibody M or M-KF respectively contains two heavy chains with the same sequence and two light chains with the same sequence.
  • Antibody proteins can be expressed in CHO cells or 293 cells through genetic engineering, and obtained by purification; purification can be performed by conventional methods, such as centrifuging the cell suspension first and collecting the supernatant, and centrifuging again to further remove impurities. Methods such as ProteinA affinity column and ion exchange column can be used to further purify antibody protein.
  • the fucosylation level of the anti-OX40 antibody (eg, antibody M-KF) or antigen-binding fragment is 0-10%. In some embodiments, the fucosylation level of the anti-OX40 antibody (eg, antibody M-KF) or antigen-binding fragment is 0-5%.
  • the fucosylation level of the anti-OX40 antibody (eg, antibody M-KF) or antigen-binding fragment is about 0, about 0.1%, about 0.5%, about 0.8%, about 1%, about 1.3%, about 1.6%, about 2.1%, 2.9%, about 3%, about 3.3%, 3.8%, about 4%, about 4.2%, 4.3%, about 4.6%, about 5%, or any two of these values range between values (inclusive) or any value therein.
  • the anti-OX40 antibody (eg, antibody M-KF) or antigen-binding fragment does not bind fucose.
  • the anti-OX40 antibody (such as antibody M-KF) or antigen-binding fragment has enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
  • hypofucosylated or afucosylated anti-OX40 antibody or antigen-binding fragment is expressed by an alpha-(1,6)-fucosyltransferase knockout cell line.
  • antibody M-KF is expressed by ⁇ -(1,6)-fucosyltransferase knockout CHO cells.
  • the present invention discloses a method for treating a tumor or cancer in a patient in need thereof, comprising administering an effective amount of an anti-OX40 antibody and another therapeutic agent, wherein the effective amount of the anti-OX40 antibody administered is about 0.6 mg to 900 mg per cycle of treatment.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the anti-OX40 antibody is antibody M or M-KF.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • another therapeutic agent or a combination of an anti-OX40 antibody and another therapeutic agent
  • a pharmaceutical composition respectively, and formulated in a suitable
  • Various forms of the chosen route of administration are administered to the patient, for example by parenteral, intravenous (iv), intramuscular, topical or subcutaneous routes.
  • the anti-OX40 antibody and another therapeutic agent can be infused intravenously separately.
  • anti-OX40 antibody and another therapeutic agent will depend on the nature of the drug, the extent to which the cell surface triggers internalization, transport and release of the drug, the disease being treated, and the condition of the patient (eg, age, sex, weight, etc.).
  • the anti-OX40 antibody (eg, Antibody M or M-KF) is about 0.01 mg/kg to 25 mg/kg per administration or formulations containing such doses of anti-OX40 antibody.
  • Preparations containing anti-OX40 antibodies may be those suitable for injectable use including sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include solvents or dispersion media of physiological saline, bacteriostatic water, or phosphate buffered saline (PBS), ethanol, polyalcohols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixture.
  • PBS phosphate buffered saline
  • the formulation comprises at least 0.1% anti-OX40 antibody.
  • the percentage of antibody can vary and can range from about 2% to 90% by weight of a given dosage form.
  • the anti-OX40 antibody per administration is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.06 mg/kg, about 0.08 mg/kg, about 0.1 mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.5mg/kg, about 0.9mg/kg, about 1mg/kg, about 2mg/kg, about 2.5mg/kg, about 3mg/kg, about 4mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 11mg/kg, about 12mg/kg, about 13mg/kg, about 14mg/kg, about 15mg/kg, about 16mg/kg, about 17mg/kg, about 18mg/kg, about 19mg/kg, about 20mg/kg, about 21mg/kg, about 22mg/kg, about 23mg/kg, about
  • an anti-OX40 antibody (eg, antibody M or M-KF) is administered at an effective dose of about 0.6 mg to 900 mg per dose. In some embodiments, the anti-OX40 antibody is administered at an effective dose of about 0.6 mg to 600 mg per dose. In some embodiments, the effective amount of anti-OX40 antibody (eg, antibody M or M-KF) administered is 0.6 mg to 900 mg once every 2, 3 or 4 weeks. In some embodiments, an effective amount of an anti-OX40 antibody administered is about 0.6 mg, about 1.8 mg, about 6 mg, about 18 mg, about 60 mg, about 100 mg, about 180 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600mg every 2, 3 or 4 weeks.
  • the effective amount of anti-OX40 antibody administered is about 0.6 mg, about 1.8 mg, about 6 mg, about 18 mg, about 60 mg, about 180 mg, about 360 mg, or about 600 mg once every 2, 3, or 4 weeks. In some embodiments, the effective amount of anti-OX40 antibody administered is about 600 mg to 900 mg once every 2, 3 or 4 weeks. In some embodiments, the effective amount of anti-OX40 antibody administered is about 700 mg, about 750 mg, about 800 mg, about 830 mg, or about 900 mg once every 2, 3, or 4 weeks.
  • therapeutically effective amounts of the other therapeutic agent and the anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the other therapeutic agent and the anti-OX40 antibody may be administered for the same or different periods.
  • the anti-OX40 antibody and another therapeutic agent are administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intraarterial injection, or intravenous (i.v.) injection.
  • the anti-OX40 antibody and the other therapeutic agent can be administered by the same or different means.
  • the anti-OX40 antibody is administered by intravenous (i.v.) infusion or bolus injection.
  • the second therapeutic agent is administered by intravenous (i.v.) infusion or bolus injection.
  • the anti-OX40 antibody (such as antibody M or M-KF) and the other therapeutic agent are independent dosage units and used in combination. In some embodiments, the anti-OX40 antibody can be administered before, after, or simultaneously with the other therapeutic agent. .
  • the anti-OX40 antibody (such as antibody M or M-KF) and the other therapeutic agent simultaneously form a combined administration unit and are administered in combination.
  • the patient has a tumor or cancer.
  • tumors and cancers include, but are not limited to, hematological cancers, solid tumors.
  • hematological cancers include, but are not limited to, leukemias, lymphomas, and myelomas.
  • leukemia includes acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myeloproliferative disorders/neoplastics (MPDS) ).
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MPDS myeloproliferative disorders/neoplastics
  • lymphoma includes Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small and large cell).
  • the myeloma includes multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bens-Jones myeloma.
  • solid tumors include breast cancer, ovarian cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, and kidney cancer.
  • the tumors and cancers are pathologically confirmed locally advanced or metastatic malignant solid tumors for which there is no effective treatment.
  • the other therapeutic agent is selected from the following antibody or antigen-binding fragment or antibody drug conjugate (ADC) against the target: EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor) , VEGFR2 (vascular endothelial growth factor receptor 2), CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed death receptor-1), PD-L1 (programmed death ligand-1 ), HER2 (human epidermal growth factor receptor 2), CD20 (cluster of differentiation 20), TROP2 (human trophoblast surface antigen 2), LAG3 (lymphocyte activation gene-3 molecule), CD27 (cluster of differentiation 27), ICOS (inducible costimulator), BTLA (B and T lymphocyte weakening factor), TIM3 (T cell immunoglobulin mucin 3), BCMA (B cell maturation antigen), c-MET (mesenchymal transition factor), TAA (tumor related antigen), GITR (ADC) against
  • the another therapeutic agent is selected from the group consisting of anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-GITR antibodies, anti-TIGIT antibodies, anti-CD19 antibodies, and anti- 4-1BB antibody.
  • the other therapeutic agent is an antibody (anti-CTLA-4 antibody) or antigen-binding fragment targeting T-lymphocyte-associated antigen 4 (CTLA-4), such as ipilimumab (Yervoy TM or its biological analogs) or defucosylated ipilimumab, as described in WO2014089113.
  • CTLA-4 T-lymphocyte-associated antigen 4
  • the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence shown in SEQ ID NO:23
  • the light chain of the anti-CTLA-4 antibody comprises the amino acid sequence shown in SEQ ID NO:24
  • the anti-CTLA -4 antibodies contain two sequence-identical heavy chains and two sequence-identical light chains.
  • the anti-CTLA-4 antibody or antigen-binding fragment is expressed by CHO cells. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment is expressed by an ⁇ -(1,6)-fucosyltransferase knockout cell line (eg, CHO cells).
  • the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-10%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-5%. In some embodiments, the fucosylation level of the anti-CTLA-4 antibody or antigen-binding fragment is about 0, about 0.1%, about 0.3%, about 0.4%, about 0.6%, about 1.3%, about 1.9 %, about 2.2%, about 2.8%, about 3.3%, about 3.7%, about 4.1%, about 4.5%, about 5%, or a range between any two of these values (inclusive) or any value therein .
  • the anti-CTLA-4 antibody or antigen-binding fragment has ⁇ 5% total high mannose glycoforms and/or ⁇ 3% total sialylated glycoforms.
  • the total amount of high mannose glycoforms of the anti-CTLA-4 antibody or antigen-binding fragment is about 0.1%, about 0.3%, about 0.9%, about 1.18%, about 1.7%, about 2.6%, about 3.3% %, about 4.1%, about 4.9%, about 4.99%, or a range between any two of these values (inclusive), or any value therein.
  • the total amount of sialylated glycoforms of the anti-CTLA-4 antibody or antigen-binding fragment is about 0.1%, about 0.2%, about 0.36%, about 0.8%, about 1.5%, about 2.2%, about 2.7%, about 2.9%, about 2.99%, or a range between any two of these values, inclusive, or any value therein.
  • the anti-CTLA-4 antibody or antigen-binding fragment has ⁇ 2% total high mannose glycoforms and/or ⁇ 1% total sialylated glycoforms.
  • the anti-CTLA-4 antibody is ipilimumab and the effective amount administered is about 30 mg to 300 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of ipilimumab administered is about 1 mg/kg, about 3 mg/kg, or about 10 mg/kg once every 3 weeks, 6 weeks, or 12 weeks.
  • the effective amount of ipilimumab administered is about 1 mg/kg every 3 or 6 weeks.
  • the effective amount of ipilimumab administered is about 3 mg/kg every 3 or 6 weeks.
  • the effective amount of ipilimumab administered is about 10 mg/kg every 3 weeks or every 12 weeks.
  • the amount of ipilimumab per administration is about 0.5 mg/kg to 10 mg/kg or formulations containing such doses of ipilimumab.
  • the ipilimumab per administration is about 0.5 mg/kg, about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4mg/kg, about 4.8mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 6.9mg/kg, about 7mg/kg, about 8.4mg/kg, about 9mg /kg, about 10 mg/kg, or a range between any two of these values (inclusive), or any value therein, or a formulation containing this dose of ipilimumab.
  • therapeutically effective amounts of ipilimumab and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration cycles of ipilimumab and anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is an anti-PD-1 antibody or antigen-binding fragment.
  • the anti-PD-1 antibody is nivolumab, pembrolizumab, camrelizumab, sintilimab , toripalimab or tislelizumab, or an anti-PD-1 antibody or antigen-binding fragment described in WO2020207432.
  • Anti-PD-1 antibodies or antigen-binding fragments can be expressed in cells (such as CHO) by genetic engineering and obtained by purification.
  • the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:25, HCDR2 shown in SEQ ID NO:26, HCDR3 shown in SEQ ID NO:27, SEQ ID LCDR1 shown in NO:28, LCDR2 shown in SEQ ID NO:29 and LCDR3 shown in SEQ ID NO:30.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO:31, which is at least 80% identical to the sequence set forth in SEQ ID NO:31 or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:31; and/or the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises SEQ ID NO:31
  • the sequence shown in ID NO:32 a sequence having at least 80% identity compared to the sequence shown in SEQ ID NO:32, or having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:32 amino acid sequence.
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:33, and the light chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:34.
  • the effective amount of anti-PD-1 antibody administered is about 50 mg to 600 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of anti-PD-1 antibody administered is about 1 mg/kg to 10 mg/kg every 2 weeks or every 3 weeks.
  • the effective amount of anti-PD-1 antibody administered is about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg , about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg (or a range between any two of these values (inclusive) or any value therein) every 2 weeks or every 3 weeks.
  • the effective amount of anti-PD-1 antibody administered is about 100 mg to about 600 mg once every 2, 3 or 4 weeks.
  • the effective amount of the anti-PD-1 antibody administered is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg (or the range between any two of these values (inclusive). ) or any value therein) every 2, 3, or 4 weeks.
  • the anti-PD-1 antibody is about 1 mg/kg to 10 mg/kg per administration, or a formulation containing such a dose of anti-PD-1 antibody.
  • the anti-PD-1 antibody per administration is about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 7 mg/kg, about 10 mg/kg, or a range (including endpoints) between any two of these values or any value, or preparations containing this dose of anti-PD-1 antibody.
  • therapeutically effective amounts of anti-PD-1 antibody and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration cycles of the anti-PD-1 antibody and the anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is an antibody targeting PD-L1 (anti-PD-L1 antibody) or an antigen-binding fragment, such as Atezolizumab, or Durvalumab (Durvalumab).
  • Anti-PD-L1 antibodies or antigen-binding fragments can be expressed in cells (such as CHO) through genetic engineering, and obtained by purification; purification can be performed by conventional methods.
  • the other therapeutic agent is atezolizumab, including Tecentriq TM , a biosimilar thereof, or an ADCC effect enhancing mAb or an afucosylated mAb.
  • the effective amount of atezolizumab administered is about 60 mg to 1200 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of atezolizumab administered is about 60 mg, 70 mg, 80 mg, 120 mg, 160 mg, 220 mg, 300 mg, 420 mg, 600 mg, 700 mg, 800 mg, 1000 mg, 1120 mg, about 1200 mg once every 3 weeks .
  • each administration of atezolizumab is about 1 mg/kg to 20 mg/kg or a formulation containing such doses of atezolizumab.
  • atezolizumab is about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4mg/kg, about 4.8mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 9mg/kg, about 12mg/kg, about 15mg/kg, about 18mg/kg, about 20mg/kg , or the range (inclusive) between any two of these values, or any value therein, or a formulation containing this dose of atezolizumab.
  • the other therapeutic agent is Durvalumab, including IMFINZI TM , biosimilars thereof, or ADCC effect enhancing mAbs or afucosylated mAbs.
  • the effective amount of Durvalumab administered is about 60 mg to 900 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of Durvalumab administered is about 5 mg/kg to 15 mg/kg every 2 weeks or every 3 weeks.
  • the effective amount of Durvalumab administered is about 10 mg/kg every 2 weeks.
  • the amount of Durvalumab per administration is from about 1 mg/kg to 10 mg/kg or formulations containing such doses of Durvalumab.
  • each administration of Durvalumab is about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4 mg/kg, About 4.8 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 9 mg/kg, about 10 mg/kg, or a range between any two of these values (inclusive) or where Any value, or formulations containing this dose of Durvalumab.
  • therapeutically effective amounts of the anti-PD-L1 antibody and the anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration cycles of the anti-PD-L1 antibody and the anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is an anti-TIGIT antibody or antigen-binding fragment.
  • the anti-TIGIT antibody is Tiragolumab (tireliumab) or its biosimilar or ADCC effect-enhancing monoclonal antibody or defucosylated monoclonal antibody, or the anti-TIGIT antibody described in WO2021043206 or antigen-binding fragments.
  • the anti-TIGIT antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:13, HCDR2 shown in SEQ ID NO:14, HCDR3 shown in SEQ ID NO:15, SEQ ID NO: LCDR1 shown in 16, LCDR2 shown in SEQ ID NO:17, and LCDR3 shown in SEQ ID NO:18.
  • the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO: 19, which is at least 80% identical to the sequence set forth in SEQ ID NO: 19 sequence, or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 19; and/or the light chain variable region of the anti-TIGTI antibody or antigen-binding fragment comprises SEQ ID NO: 20
  • the sequence shown is a sequence having at least 80% identity compared to the sequence shown in SEQ ID NO:20, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:20.
  • the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF
  • the heavy chain of antibody h10D8OF and h10D8OFKF comprises the sequence shown in SEQ ID NO: 21
  • the light chain of antibody h10D8OF and h10D8OFKF comprises the sequence shown in SEQ ID NO: 22
  • the sequences are shown; antibodies h10D8OF and h10D8OFKF contain two identical heavy chains and two identical light chains, respectively.
  • the level of fucosylation of the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment is 0-10%. In some embodiments, the level of fucosylation of the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment is 0-5%.
  • the fucosylation level of the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment is about 0, about 0.1%, about 0.5%, about 0.8%, about 1%, about 1.3% , about 1.6%, about 2.1%, 2.9%, about 3%, about 3.3%, 3.8%, about 4%, about 4.2%, about 4.3%, about 4.6%, about 5%, or any two of these values A range between values (inclusive) or any value in it.
  • the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment does not bind fucose.
  • the anti-TIGIT antibody (such as antibody h10D8OFKF) or antigen-binding fragment has enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
  • the anti-TIGIT antibody or antigen-binding fragment can be expressed in CHO cells or 293 cells by genetic engineering, and obtained by purification; purification can be performed by conventional methods, such as centrifuging the cell suspension first and collecting the supernatant, Centrifuge again to further remove impurities. Methods such as ProteinA affinity column and ion exchange column can be used to purify antibody protein.
  • hypofucosylated or afucosylated anti-TIGIT antibody or antigen-binding fragment is expressed by an alpha-(1,6)-fucosyltransferase knockout cell line.
  • antibody h10D8OFKF is expressed by ⁇ -(1,6)-fucosyltransferase knockout CHO cells.
  • the effective amount of anti-TIGIT antibody administered is about 9 mg to 1200 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of anti-TIGIT antibody administered is about 0.01 mg/kg to 20 mg/kg once every 2 weeks or every 3 weeks.
  • the effective amount of anti-TIGIT antibody administered is about 0.01 mg/kg, about 0.03 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg , about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, about 10mg/kg, about 11mg/kg, about 12mg/kg, about 13mg/kg, about 14mg/kg, about 15mg/kg , about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg (or the range (including endpoints) between any two of these values or any value therein) per 2 Weekly or every 3 weeks.
  • an effective amount of an anti-TIGIT antibody administered is about 10 mg to about 900 mg once every 2, 3, or 4 weeks. In some embodiments, an effective amount of an anti-TIGIT antibody administered is about 10 mg, about 30 mg, about 100 mg, about 160 mg, about 200 mg, about 242 mg, about 300 mg, about 346 mg, about 400 mg, about 500 mg, about 600 mg (or these values The range between any two values in (inclusive) or any value therein) every 2, 3, or 4 weeks.
  • therapeutically effective amounts of anti-TIGIT antibody and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration periods of the anti-TIGIT antibody and the anti-OX40 antibody may be the same or different.
  • the other therapeutic agent is an anti-GITR antibody or antigen-binding fragment.
  • the anti-GITR antibody or antigen-binding fragment such as the antibody or antigen-binding fragment described in CN111918878A.
  • the effective amount of anti-GITR antibody administered is about 0.01 mg/kg to 20 mg/kg every 2 weeks, every 3 weeks, or every 4 weeks.
  • therapeutically effective amounts of anti-GITR antibody and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration cycles of the anti-GITR antibody and the anti-OX40 antibody may be the same or different.
  • the other therapeutic agent is a monoclonal antibody that specifically binds to the extracellular dimerization domain (subdomain II) of epidermal growth factor receptor 2 (HER2) (anti-HER2 antibody) Or antigen-binding fragments such as Pertuzumab.
  • Pertuzumab can be expressed in cells (such as CHO) by genetic engineering and obtained by purification.
  • the other therapeutic agent is Pertuzumab, including Perjeta TM or a biosimilar thereof or an ADCC effect enhancing mAb or an afucosylated mAb.
  • the effective amount of pertuzumab administered is about 40 mg to 900 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of Pertuzumab administered is about an initial 840 mg followed by 420 mg every 3 weeks thereafter.
  • the amount of Pertuzumab per administration is about 1 mg/kg to 12 mg/kg or a formulation containing such doses of Pertuzumab.
  • pertuzumab is about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.9 mg/kg, about 7 mg/kg, about 8.4 mg/kg, about 9 mg/kg, about 11 mg/kg, about 12 mg/kg, or a range between any two of these values (inclusive), or any value therein, or a formulation containing such a dose of Pertuzumab.
  • therapeutically effective amounts of pertuzumab and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration periods of Pertuzumab and anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds VEGF-A and inhibits its binding to VEGF receptor-2 (VEGFR2) (anti- VEGF antibody), such as bevacizumab.
  • IgG1 humanized immunoglobulin G1
  • VEGFR2 VEGF receptor-2
  • Bevacizumab can be expressed in cells (such as CHO) by genetic engineering and obtained by purification.
  • the other therapeutic agent is bevacizumab, bevacizumab comprising or its biosimilars, such as BAT1706, or ADCC effect enhancing mAb or defucosylated mAb.
  • the effective amount of bevacizumab administered is about 50 mg to 400 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of bevacizumab administered is about 5 mg/kg to 15 mg/kg every 2 weeks or every 3 weeks.
  • the effective amount of bevacizumab administered is about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, or about 15 mg/kg every 2 weeks or every 3 weeks.
  • the effective amount of bevacizumab administered is about 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks, 15 mg/kg every 3 weeks 1 time a week.
  • the amount of bevacizumab per administration is about 1 mg/kg to 9 mg/kg or a formulation containing such doses of bevacizumab.
  • each administration of bevacizumab is about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6 mg/kg, about 4 mg/kg, about 4.8 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.9 mg/kg, about 7 mg/kg, about 8.4 mg/kg, about 9 mg/kg, or these
  • therapeutically effective amounts of bevacizumab and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration cycles of bevacizumab and anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is an antibody targeting CD20 (anti-CD20 antibody), such as ofatumumab, obinutuzumab, BAT4306F described in CN109096399A or BAT4406F described in CN109096399A.
  • Anti-CD20 antibody anti-CD20 antibody
  • Ofatumumab and obinutuzumab can be expressed in cells (such as CHO) through genetic engineering and obtained through purification.
  • the other therapeutic agent is ofatumumab, ofatumumab including Arzerra TM or Its biosimilar or ADCC effect enhancing mAb or afucosylated mAb.
  • ofatumumab is administered in an effective amount of about 10 mg to 2000 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount ofatumumab administered is about 20 mg weekly or monthly.
  • the effective amount ofatumumab administered is about 300 mg initially, 1000 mg after 1 week, and 1000 mg every 4 weeks or every 8 weeks thereafter. In some embodiments, the effective amount ofatumumab administered is about 300 mg initially, 2000 mg after 1 week, and 2000 mg every 1 week or every 4 weeks thereafter.
  • each administration of ofatumumab is about 0.5 mg/kg to 18 mg/kg or a formulation containing such a dose of ofatumumab.
  • ofatumumab per administration is about 0.5 mg/kg, about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6mg/kg, about 4mg/kg, about 4.8mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 6.9mg/kg, about 7mg/kg, about 8.4mg/kg, about 9 mg/kg, about 11 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 17 mg/kg, about 18 mg/kg, or the range between any two of these values (inclusive) or any value therein, or a formulation containing this dose of ofatumumab.
  • therapeutically effective amounts of ofatumumab and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the administration periods of ofatumumab and anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is obinutuzumab, comprising Its biosimilar, or ADCC effect enhancing monoclonal antibody or defucosylated monoclonal antibody.
  • obinutuzumab is administered in an effective amount of about 10 mg to 2000 mg per treatment cycle.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (including endpoint) or any value in it.
  • the effective amount of obinutuzumab administered is 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, day 15, and 1000 mg per cycle thereafter.
  • the effective amount of obinutuzumab administered is 1000 mg each on Day 1, Day 8, and Day 15, and 1000 mg per course thereafter. Each course of treatment can be 1 month or 2 months.
  • the amount of obinutuzumab per administration is from about 0.5 mg/kg to 15 mg/kg or a formulation containing such doses of ofatumumab.
  • ofatumumab per administration is about 0.5 mg/kg, about 1 mg/kg, about 1.2 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 3 mg/kg, about 3.6mg/kg, about 4mg/kg, about 4.8mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 6.9mg/kg, about 7mg/kg, about 8.4mg/kg, about 9 mg/kg, about 11 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, or the range between any two of these values (including the endpoints) or any value therein, or a dose containing Formulations of falimumab.
  • therapeutically effective amounts of obinutuzumab and anti-OX40 antibody are administered to the patient separately or simultaneously.
  • the dosing cycles of obinutuzumab and anti-OX40 antibody can be the same or different.
  • the other therapeutic agent is an anti-HER2 antibody drug conjugate (HER2-ADC) or an anti-Trop2 antibody drug conjugate (Trop2-ADC), such as ado-trastuzumab emtansine (T-DM1), Trastuzumab deruxtecan (DS-8201), the antibody drug conjugate described in CN103333246B and CN109078181A.
  • HER2-ADC anti-HER2 antibody drug conjugate
  • Trop2-ADC anti-Trop2 antibody drug conjugate
  • T-DM1 ado-trastuzumab emtansine
  • DS-8201 Trastuzumab deruxtecan
  • the present invention discloses a method of treating a tumor or cancer comprising administering to a patient in need thereof an effective amount of an anti-OX40 antibody or antigen-binding fragment (or formulation) and another therapeutic agent (or formulation) ;
  • the effective dose of anti-OX40 antibody or antigen-binding fragment is about 0.6 mg to 900 mg in a single administration (or a preparation containing this dose of anti-OX40 antibody).
  • the other therapeutic agent is an anti-PD-1 antibody or antigen-binding fragment.
  • the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:25, HCDR2 shown in SEQ ID NO:26, HCDR3 shown in SEQ ID NO:27, SEQ ID LCDR1 shown in NO:28, LCDR2 shown in SEQ ID NO:29 and LCDR3 shown in SEQ ID NO:30.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO:31, which is at least 80% identical to the sequence set forth in SEQ ID NO:31 or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:31; and/or the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises SEQ ID NO:31
  • the sequence shown in ID NO:32 a sequence having at least 80% identity compared to the sequence shown in SEQ ID NO:32, or having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:32 amino acid sequence.
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:33, and the light chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:34.
  • the effective amount of anti-PD-1 antibody is about 50 mg to 600 mg in a single administration (or a preparation containing such dose of anti-PD-1 antibody). Dosage schedule and mode of administration depend on the benefit-risk assessment of anti-PD-1 antibody (or formulation), anti-OX40 (or formulation) in certain patient populations and general clinical practice guidelines.
  • the anti-OX40 antibody (such as antibody M or M-KF) is administered to the patient in an effective amount of about 0.6 mg to 900 mg of anti-OX40 antibody (or a preparation containing such a dose of anti-OX40 antibody) per treatment cycle,
  • the effective amount of anti-PD-1 antibody administered to the patient in each treatment cycle is about 50 mg to 600 mg (or a preparation containing this dose of anti-PD-1 antibody).
  • the effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) administered to a patient per treatment cycle is about 0.6 mg, about 1.8 mg, about 6 mg, about 9 mg, about 10 mg, about 12 mg, about 18mg, about 20mg, about 30mg, about 50mg, about 60mg, about 80mg, about 120mg, about 180mg, about 200mg, about 250mg, about 290mg, about 300mg, about 330mg, about 360mg, about 380mg, about 400mg, about 434mg, About 480 mg, about 500 mg, about 567 mg, about 580 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or a range (including endpoints) between any two of these values or any value therein, or containing this dose of anti Preparations of OX40 Antibodies.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • a treatment cycle is administered once from 1 week to 7 weeks.
  • the effective amount of the anti-OX40 antibody administered in each treatment cycle is 0.6 mg to 100 mg, or a preparation containing this dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, about 3 weeks weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or a range between any two of these values (inclusive) or any value therein.
  • one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an effective amount of anti-OX40 antibody of about 100 mg to about 300 mg in each treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, About 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of anti-OX40 antibody of about 300 mg to about 600 mg in each treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, About 3 weeks, or about 4 weeks.
  • the patient is administered an effective amount of anti-OX40 antibody of about 600 mg to about 900 mg per treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, About 3 weeks or about 4 weeks.
  • the effective amount of the anti-OX40 antibody administered to the patient per treatment cycle is about 6 mg, about 18 mg, about 50 mg, about 60 mg, about 100 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 260 mg, about 300 mg, about 360 mg, about 400 mg, about 430 mg, about 460 mg, about 520 mg, about 600 mg, about 900 mg, or any of these values
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 5 mg to 16 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 6 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 6 mg per treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (eg, antibody M or M-KF) of about 15 mg to 40 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 18 mg is administered 1 Second-rate.
  • an anti-OX40 antibody eg, antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 18 mg per treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, or about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 100 mg to 190 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 180 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 180 mg per treatment cycle, or a preparation containing this dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, about 3 weeks week or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 167 mg to 250 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 210 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 210 mg per treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks, or about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 267 mg to 354 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 312 mg, or a preparation containing such a dose of anti-OX40 antibody, in each treatment cycle; wherein, a treatment cycle is about 1 week, about 2 weeks, or about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 380 mg to 450 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 400 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered with an effective amount of anti-OX40 antibody of about 400 mg in each treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks, about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 542 mg to 643 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 620 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 620 mg, or a preparation containing such a dose of anti-OX40 antibody, in each treatment cycle; wherein, a treatment cycle is about 1 week, about 2 weeks, or about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of an anti-OX40 antibody (e.g., antibody M or M-KF) of about 827 mg to 940 mg per treatment cycle, or a formulation containing such an anti-OX40 antibody; for example, about 900 mg is administered 1 Second-rate.
  • an anti-OX40 antibody e.g., antibody M or M-KF
  • the patient is administered an effective amount of anti-OX40 antibody of about 900 mg per treatment cycle, or a preparation containing such a dose of anti-OX40 antibody; wherein, one treatment cycle is about 1 week, about 2 weeks, or about 3 weeks or about 4 weeks.
  • the effective amount of an anti-OX40 antibody is about 0.6 mg to 900 mg once every 3 weeks. In some embodiments, the effective amount of an anti-OX40 antibody is about 0.6 mg, about 1.8 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 180 mg, about 200 mg, about 300 mg, about 360 mg, about 400 mg, about 500 mg , about 600 mg, about 700 mg, about 800 mg, or about 900 mg every 3 weeks. In some embodiments, the effective amount of an anti-OX40 antibody is about 6 mg, about 18 mg, about 60 mg, about 180 mg, about 360 mg, about 600 mg, or about 900 mg once every 3 weeks.
  • the effective amount of the anti-PD-1 antibody administered to the patient per treatment cycle is about 50 mg, about 60 mg, about 80 mg, about 120 mg, about 200 mg, about 250 mg, about 290 mg, about 300 mg, about 330 mg, about 380 mg, about 400 mg, about 434 mg, about 480 mg, about 500 mg, about 567 mg, about 580 mg, about 600 mg, or a range between any two of these values (including endpoints) or any value therein, or containing this dose of anti-PD -1 Preparation of antibodies.
  • a treatment cycle is administered once from 1 week to 7 weeks.
  • the effective amount of anti-PD-1 antibody administered in each treatment cycle is 100 mg to 200 mg, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or a range (including endpoints) between any two of these values, or any value therein. In some embodiments, one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 200 mg to about 300 mg in each treatment cycle, or a preparation containing such a dose of anti-PD-1 antibody; wherein, one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the effective amount of the anti-PD-1 antibody administered to the patient per treatment cycle is about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 300 mg, or the range between any two of these values (including the endpoints) or any value therein, or a preparation containing this dose of anti-PD-1 antibody; wherein, one treatment cycle is about 1 weeks, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 45 mg to 80 mg per treatment cycle, or a preparation containing such a dose of anti-PD-1 antibody; for example, about 50 mg is administered once.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 50 mg in each treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 87 mg to 130 mg per treatment cycle, or a preparation containing such a dose of anti-PD-1 antibody; for example, about 100 mg is administered once.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 100 mg in each treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 180 mg to 230 mg per treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; for example, about 200 mg is administered once.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 200 mg in each treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks or about 4 weeks.
  • the effective amount of anti-PD-1 antibody administered to the patient is about 267 mg to 343 mg, or a preparation containing this dose of anti-PD-1 antibody; for example, about 300 mg is administered once in each treatment cycle.
  • the patient is administered with an effective amount of anti-PD-1 antibody of about 300 mg in each treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks or about 4 weeks.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 300 mg to 700 mg per treatment cycle, or a preparation containing such a dose of anti-PD-1 antibody; for example, about 600 mg is administered once.
  • the patient is administered an effective amount of anti-PD-1 antibody of about 600 mg in each treatment cycle, or a preparation containing this dose of anti-PD-1 antibody; wherein, a treatment cycle is about 1 week, about 2 weeks , about 3 weeks or about 4 weeks.
  • the patient is administered an anti-OX40 antibody and another therapeutic agent (or a combination of an anti-OX40 antibody and another therapeutic agent) once per treatment cycle.
  • the anti-OX40 antibody and another therapeutic agent or a combination of an anti-OX40 antibody and another therapeutic agent
  • the patient can only be dosed 1 or 4 times per treatment cycle.
  • the patient is treated for one treatment cycle. In some embodiments, the patient receives multiple (e.g., 2, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16 or 17) treatment cycles. In some embodiments, the patient is treated until the condition is in remission and no longer requires treatment.
  • the present invention discloses a method for treating tumor or cancer, said method comprising: administering about 0.6 mg to 100 mg, about 100 mg to 300 mg, about 300 mg to 600 mg, or about 600 mg to a patient in need thereof Up to 900 mg, such as about 0.6 mg, about 1.8 mg, about 6 mg, about 10 mg, about 18 mg, about 20 mg, about 30 mg, about 100 mg, about 120 mg, about 180 mg, about 200 mg, about 300 mg, about 360 mg, about 600 mg, or about 900 mg
  • Anti-OX40 antibody (such as antibody M or M-KF), or preparations containing such doses of anti-OX40 antibody; also administer about 50 mg to 100 mg, about 100 mg to 200 mg, about 200 mg to 400 mg, or about 400 mg to 600 mg to patients in need , such as about 100 mg, about 120 mg, about 150 mg, about 200 mg or about 300 mg of anti-PD-1 antibody, or a preparation containing such a dose of anti-PD-1 antibody.
  • the patient is treated with a single dose of the anti-about 200 mg antibody, and a single dose of the anti-PD-1 antibody. In some embodiments, the patient is treated with a single dose of the anti-OX40 antibody and anti-PD-1 antibody composition.
  • the anti-OX40 antibody and the anti-PD-1 antibody are administered every 3 weeks.
  • the patient's symptoms are relieved. In some embodiments, after a single dose of administration, the patient's symptoms are not relieved as expected, and then about 0.6 mg to 900 mg of the anti-OX40 antibody and about 50 mg to 600 mg of the anti-PD-1 antibody are administered to the patient.
  • the anti-OX40 antibody is Antibody M or M-KF; the anti-PD-1 antibody is Antibody A.
  • the present invention discloses a method for treating a tumor or cancer, the method comprising administering 3 mg/kg to 10 mg/kg of the anti-OX40 antibody M-KF and 300mg to 600mg of anti-PD-1 antibody A.
  • the method comprises administering 3 mg/kg, 5 mg/kg, 6 mg/kg, or 10 mg/kg of Antibody M-KF and 300 mg of Antibody A to a patient in need thereof once every 3 weeks.
  • the method comprises administering 3 mg/kg, 5 mg/kg, 6 mg/kg, or 10 mg/kg of anti-OX40 antibody M-KF and 600 mg of anti-PD-1 once every 3 weeks to a patient in need thereof Antibody A.
  • the method comprises administering to the patient an equivalent amount of Antibody M-KF once 3 weeks prior to administering Antibody M-KF and Antibody A to the patient.
  • the anti-OX40 antibody (or formulation), anti-PD-1 antibody (or formulation) is injected subcutaneously (s.c.), intraperitoneally (i.p.), parenterally, intraarterially, or intravenously (i.v. ) administration by way of injection or the like.
  • the anti-OX40 antibody (or preparation) and anti-PD-1 antibody (or preparation) are administered by infusion.
  • the anti-OX40 antibody (or preparation) and anti-PD-1 antibody (or preparation) are administered by bolus injection.
  • the anti-OX40 antibody (or formulation), anti-PD-1 antibody (or formulation) is administered by intravenous (i.v.) infusion.
  • the duration of the intravenous infusion is about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 81 minutes, about 87 minutes, about 90 minutes, about 95 minutes minutes, or the range between any two of these values (inclusive), or any value therein.
  • Figure 1 shows that the anti-OX40 antibody M-KF inhibits the growth of tumor; the ordinate indicates the tumor volume.
  • an entity refers to one or more such entities, for example "an antibody” should be understood as one or more antibodies, therefore, the term “a” (or “an” ), “one or more” and “at least one” may be used interchangeably herein.
  • compositions, methods, etc. include the listed elements, such as components or steps, but not exclude others.
  • Consisting essentially of means that the compositions and methods exclude other elements that substantially affect the characteristics of the combination, but do not exclude elements that do not substantially affect the composition or method.
  • Consisting of means excluding elements not specifically recited.
  • polypeptide is intended to encompass the singular as well as the plural “polypeptides” and refers to a molecule composed of amino acid monomers linked linearly by amide bonds (also known as peptide bonds).
  • polypeptide refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product.
  • the definition of “polypeptide” includes peptide, dipeptide, tripeptide, oligopeptide, "protein”, “amino acid chain” or any other term used to refer to a chain of two or more amino acids, and the term “polypeptide” may Used in place of, or interchangeably with, any of the above terms.
  • polypeptide is also intended to refer to the products of post-expression modifications of the polypeptide, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or non-natural Amino acid modifications that occur.
  • a polypeptide may be derived from natural biological sources or produced by recombinant techniques, but it need not be translated from a specified nucleic acid sequence, it may be produced by any means including chemical synthesis.
  • amino acid refers to an organic compound containing both amino and carboxyl groups, such as an ⁇ -amino acid, which can be encoded by a nucleic acid directly or in the form of a precursor.
  • a single amino acid is encoded by a nucleic acid consisting of three nucleotides (so-called codons or base triplets). Each amino acid is encoded by at least one codon. The fact that the same amino acid is encoded by different codons is called “degeneracy of the genetic code”.
  • Amino acids include natural amino acids and unnatural amino acids.
  • Natural amino acids include alanine (three-letter code: ala, one-letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine amino acid (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I ), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y) and valine (val, V).
  • a “conservative amino acid substitution” refers to the replacement of one amino acid residue with another amino acid residue containing a side chain (R group) of similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions are unlikely to substantially alter the functional properties of a protein.
  • classes of amino acids that contain chemically similar side chains include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chains: serine and threonine 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, Arginine and histidine; 6) acidic side chains: aspartic acid and glutamic acid.
  • the number of amino acids in the "conservative amino acid substitution of VL, VH" can be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10, About 11, about 13, about 14, about 15 conservative amino acid substitutions, or a range between any two of these values (inclusive), or any value therein.
  • the number of amino acids for "conservative amino acid substitutions in the heavy or light chain” can be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10 about 11, about 13, about 14, about 15, about 18, about 19, about 22, about 24, about 25, about 29, about 31, about 35, About 38, about 41, about 45 conservative amino acid substitutions, or a range between any two of these values (inclusive), or any value therein.
  • encoding when applied to a polynucleotide refers to a polynucleotide which is said to "encode” a polypeptide which, in its native state or when manipulated by methods well known to those skilled in the art, is transcribed and/or Or translation may result in the polypeptide and/or fragments thereof.
  • Antibodies, antigen-binding fragments or derivatives disclosed in the present invention include but are not limited to polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies, epitope binding Fragments (eg Fab, Fab', F(ab') 2 and scFv).
  • polypeptides or polynucleotides refers to polypeptides or polynucleotides, meaning forms of polypeptides or polynucleotides that do not occur in nature, non-limiting examples may be produced by combination of polynucleotides or polynucleotides that do not normally exist or peptide.
  • Homology refers to the sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing the alignable positions in each sequence. When a position in the sequences being compared is occupied by the same base or amino acid, then the molecules are homologous at that position. The degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences.
  • At least 80% identity is about 80% identity, about 81% identity, about 82% identity, about 83% identity, about 85% identity, about 86% identity, about 87% identity, About 88% identity, about 90% identity, about 91% identity, about 92% identity, about 94% identity, about 95% identity, about 98% identity, about 99% identity, or these A range (inclusive) between any two values in Numeric or any value therein.
  • a polynucleotide or polynucleotide sequence has a certain percentage (eg, 90%, 95%, 98%, or 99%) of "identity” or “sequence identity” with another sequence.
  • “Sex” means that when the sequences are aligned, the percentage of bases (or amino acids) in the two sequences being compared are identical. This alignment percent identity or sequence identity can be determined using visual inspection or software programs known in the art, such as those described by Ausubel et al.eds. (2007) in Current Protocols in Molecular Biology. It is preferred to use the default parameters for the alignment.
  • Biologically equivalent polynucleotides are polynucleotides that share the above indicated percentages of identity and encode a polypeptide having the same or similar biological activity.
  • Antibody and antigen-binding fragment refer to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen.
  • Antibodies can be whole antibodies and any antigen-binding fragments thereof or single chains thereof.
  • the term “antibody” thus includes any protein or peptide whose molecule contains at least a portion of an immunoglobulin molecule that has the biological activity to bind an antigen.
  • Antibodies and antigen-binding fragments include, but are not limited to, complementarity determining regions (CDRs), heavy chain variable regions (VH), light chain variable regions (VL), heavy chain constant regions of heavy or light chains or ligand-binding portions thereof (CH), light chain constant region (CL), framework region (FR) or any portion thereof, or at least a portion of a binding protein.
  • CDR regions include the CDR regions of the light chain (LCDR1-3) and the CDR regions of the heavy chain (HCDR1-3).
  • antibody includes a wide variety of polypeptides that can be distinguished biochemically.
  • classes of heavy chains include gamma, mu, alpha, delta or epsilon ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ ), with some subclasses (eg ⁇ 1- ⁇ 4).
  • the nature of this chain determines the "class” of the antibody as IgG, IgM, IgA, IgG or IgE, respectively.
  • the immunoglobulin subclasses (isotypes), eg, IgGl, IgG2, IgG3, IgG4, IgG5, etc., are well characterized and the functional specificities conferred are also known. All immunoglobulin classes are within the scope of the present disclosure. In some embodiments, the immunoglobulin molecule is of the IgG class.
  • Light chains can be classified as kappa ( ⁇ ) or lambda ( ⁇ ). Each heavy chain can be associated with a kappa or lambda light chain.
  • ⁇ kappa
  • lambda ⁇
  • Each heavy chain can be associated with a kappa or lambda light chain.
  • immunoglobulins are produced by hybridomas, B cells, or genetically engineered host cells, their light and heavy chains are joined by covalent bonds, and the "tail" portions of the two heavy chains are linked by covalent disulfide bonds or non-covalent bonding.
  • the amino acid sequence extends from the N-terminus at the forked end of the Y configuration to the C-terminus at the bottom of each chain.
  • the variable region of the immunoglobulin kappa light chain is V ⁇ ; the variable region of the immunoglobulin lambda light chain is V ⁇ .
  • variable light and variable heavy chains are divided into regions of structural and functional homology.
  • the terms "constant” and “variable” are used according to function.
  • the variable light (VL) and variable heavy (VH) chains determine antigen recognition and specificity.
  • the constant region (CL) of the light chain and the constant region (CH) of the heavy chain confer important biological properties such as secretion, transplacental movement, Fc receptor binding, complement fixation, etc.
  • the N-terminal portion is the variable region and the C-terminal portion is the constant region; the CH3 and CL domains actually comprise the carboxy-terminal ends of the heavy and light chains, respectively.
  • CDR complementarity determining regions
  • CDRs as defined by Kabat and Chothia include overlapping or subsets of amino acid residues when compared to each other. Nevertheless, it is within the scope of the invention to use either definition to refer to the CDRs of an antibody or variant thereof.
  • the exact residue numbers comprising a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can generally determine which specific residues are included in the CDRs based on the amino acid sequence of the variable region of the antibody.
  • Kabat et al. also defined a numbering system applicable to the variable region sequences of any antibody.
  • One of ordinary skill in the art can apply this "Kabat numbering" system to any variable region sequence independently of other experimental data other than the sequence itself.
  • “Kabat numbering” refers to the numbering system proposed by Kabat et al., U.S. Dept. of Health and Human Services in "Sequence of Proteins of Immunological Interest” (1983).
  • Antibodies can also use the EU or Chothia numbering system.
  • an antibody drug conjugate refers to an antibody or antigen-binding fragment thereof chemically linked to one or more chemical drugs (which may optionally be therapeutic or cytotoxic agents).
  • an ADC includes an antibody, a cytotoxic or therapeutic drug, and a linker that enables linking or conjugation of the drug to the antibody.
  • ADCs typically have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 drug conjugated to the antibody.
  • Drugs that can be included in ADCs are, but not limited to: mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, Hormones, antihormones, corticosteroids, photoactive therapeutics, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors, and radiosensitizers.
  • the drug included in the ADC may be a maytansinoid drug.
  • the drug included in the ADC may be a compound represented by formula I as described in this application or a pharmaceutically acceptable salt thereof.
  • the antibody in an ADC, is conjugated to the drug via a self-cysteine or a thiolated amino acid, such as a thiolated lysine, forming a disulfide bond.
  • Treatment means therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent, slow down, ameliorate and stop undesirable physiological changes or disorders, such as the progression of disease, including but not limited to the following whether detectable or undetectable Relief of symptoms, reduction of disease extent, stabilization of disease state (i.e. not worsening), delay or slowing of disease progression, improvement or palliation of disease state, alleviation or disappearance (whether partial or total), prolongation and Expected survival without treatment, etc.
  • Patients in need of treatment include those who already have a condition or disorder, are susceptible to a condition or disorder, or are in need of prevention of the condition or disorder, and can or are expected to benefit from the administration of an antibody or composition disclosed herein for detection, Patients who benefit from the diagnostic process and/or treatment.
  • Patient refers to any mammal in need of diagnosis, prognosis, or treatment, including humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and the like. In some embodiments, the patient is a human.
  • Effective amount means that amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual or human; an effective amount is sought by a researcher, veterinarian, physician or other clinician.
  • the phrase "in need thereof” means that a patient has been identified as being in need of a particular method or treatment. In some embodiments, identification may be by any diagnostic means. A patient may in need thereof during any of the methods and treatments described herein.
  • an antibody expression vector includes at least one promoter element, an antibody coding sequence, a transcription termination signal, and a polyA tail.
  • Other elements include enhancers, Kozak sequences, and donor and acceptor sites for RNA splicing flanking the inserted sequence.
  • High-efficiency transcription can be obtained through the early and late promoters of SV40, long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and early promoters of cytomegalovirus, and other cellular promoters such as muscle Kinetin promoter.
  • Suitable expression vectors may include pIRES1neo, pRetro-Off, pRetro-On, PLXSN, or pLNCX, pcDNA3.1(+/-), pcDNA/Zeo(+/-), pcDNA3.1/Hygro(+/-), PSVL, PMSG, pRSVcat, pSV2dhfr, pBC12MI and pCS2 etc.
  • Commonly used mammalian cells include 293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells and CHO cells, etc.
  • DNA sequences of the heavy chain and light chain according to the amino acid sequences of the heavy chain and light chain of the antibody, and modify the 5' and 3' ends of the DNA sequence with PCR primers, which include the kozak sequences of the heavy chain and the light chain and the Signal peptide DNA sequence.
  • the constructed sequence is then cloned into the existing recombinant antibody expression vector, and the correct construction of the recombinant plasmid is verified by sequencing analysis.
  • the above-mentioned recombinant plasmids were transfected into expression cells for expression, and the supernatant was collected and purified to obtain antibody protein samples, which were used in various examples below.
  • the expression vector used is pCDNA3.1TM(+) (Invitrogen Company, product number is V79020), and the expression cell used for antibody M-KF is ⁇ -(1,6)-fucus Glycosyltransferase gene knockout CHO cells (fucosylation level is about 0), the expression cells used for antibody M are CHO-S cells (purchased from Invitrogen); positive control antibody 11D4 (anti-OX40 antibody) heavy
  • the sequence of chain and light chain comes from patent US8236930B2
  • the expression vector used is pCHO1.0 plasmid (purchased from Invitrogen), and the expression cell is CHO-S cell (purchased from Invitrogen); the amino acid sequences of antibodies M and M-KF are shown in Table 1 , the nucleic acid sequences of antibodies M and M-KF are shown in Table 2, and the sequence of the leader peptide is in the box in Table 2;
  • the expression vector used was pCDNA3.1 TM (+)
  • the expression cell used for the antibody h10D8OF was CHO cells
  • the expression cell used for the antibody h10D8OFKF was ⁇ -(1,6)-fucose CHO cells with base transferase gene knockout (fucosylation level is about 0);
  • the amino acid sequences of antibodies h10D8OF and h10D8OFKF are shown in Table 3;
  • the expression vector used was pCDNA3.1 TM (+), and the expression cell was ⁇ -(1,6)-fucosyltransferase gene knockout CHO cells (Fucus The glycosylation level is about 0); the amino acid sequence of the anti-CTLA-4 antibody is shown in Table 4;
  • the expression vector used for antibody A is pCDNA3.1 TM (+), and the expression cell is CHO cells; the amino acid sequence of antibody A is shown in Table 5.
  • Embodiment 2 drug efficacy test in vivo
  • the anti-tumor efficacy of the antibody M-KF of the present invention was studied in the OX40 humanized mouse model (purchased from Biocytogen). MC38 tumor cells were inoculated subcutaneously on the right side of OX40 humanized female mice at a concentration of 5 ⁇ 10 5 cells/0.1 mL.
  • the tumor grew to 119mm 3 they were randomly divided into groups according to the tumor volume, with 6 rats in each group.
  • the grouping day was defined as D0 day, and the administration began on D0 day; the administration dates were: day 0, day 3, day 6, day 9, day 12, and day 15.
  • the administration route of the antibody was intraperitoneal administration (ip), according to the frequency of Q3D (once every 3 days), three dosage groups of 1 mg/kg, 0.2 mg/kg, and 0.04 mg/kg were administered 6 times in total.
  • the dosing regimen is shown in Table 6.
  • tumors and body weights were measured twice weekly throughout the study and mice were euthanized when tumors reached endpoint or when mice had 20% body weight loss.
  • the tumor volume (mm 3 ) was 0.5 ⁇ (tumor long diameter ⁇ tumor short diameter 2 ).
  • mice The experimental results such as tumor volume, mouse body weight, and tumor weight of mice in each group are expressed as mean ⁇ standard error (mean ⁇ SEM). Data were analyzed using SPSS. P ⁇ 0.05 means significant difference.
  • TGItv inhibition rate relative to tumor volume
  • TGItv (1-(mean RTV administration group )/(mean RTV control group )) ⁇ 100%; mean RTV administration group : RTV average value of administration group, mean RTV control group : control group RTV average value;
  • RTV n V nt /V n0 ;
  • V nt the tumor volume of the mouse numbered on day t,
  • V n0 the tumor volume of the mouse numbered on day 0
  • RTV n the tumor volume of the mouse numbered The relative volume of the tumor in the mice of n at day t.
  • N is the number of animals.
  • the medium and high doses of antibody M-KF can significantly inhibit the growth of tumors (P ⁇ 0.05), and the effect is significantly better than the high dose of antibody 11D4; Significant differences were found, indicating that the mice tolerated the drug well against antibody M-KF.
  • Example 3 MC38 colon cancer animal model experiment of B-hPD-1/hOX40 double humanized mice
  • MC38 colon cancer cells resuspended in PBS were inoculated into B-hPD-1/hOX40 humanized mice at a concentration of 5 ⁇ 105/0.1mL, 0.1mL/vessel (Beijing Biocytogen Biotechnology Co., Ltd.) Subcutaneous on the right side.
  • the average tumor volume reached about 105 mm 3 72 mice with appropriate individual tumor volumes were selected to enter the group, and the animals were randomly assigned to 9 groups according to the tumor volume, with 8 mice in each group, and the administration began on the day of the grouping.
  • Table 8 For the specific dosage regimen, see Table 8 below.
  • Drug evaluation indicators include: tumor volume inhibition rate (TGItv) and tumor weight inhibition rate (TGItw):
  • TGItv (%) [1-(Ti-T0)/(Vi-V0)] ⁇ 100%
  • Ti the mean value of the tumor volume of the treatment group on the i-th day of administration
  • T0 the treatment group on the 0th day of administration
  • Vi the mean value of the tumor volume of the negative control group on the i-th day of administration
  • V0 the mean value of the tumor volume of the negative control group on the day 0 of the administration
  • TGItw (%) (W negative control group ⁇ W treatment group)/W negative control group ⁇ 100%, W refers to tumor weight.
  • mice had good activity and eating status during the administration period, and their body weight increased to a certain extent, indicating that the mice had good tolerance to the test drug
  • This study is an evaluation of the safety, tolerability, and pharmacokinetics (PK) of antibody M-KF single administration and antibody M-KF combined with anti-PD-1 antibody A in patients with advanced malignant solid tumors.
  • MTD maximum tolerated dose
  • MAD maximum administered dose
  • Antibody M-KF is administered through intravenous infusion, the infusion time is 60 ⁇ 5min, and 21 days after administration is the DLT observation period; the dose of antibody M-KF is 0.1mg/kg, 0.3mg/kg, 1mg/kg kg, 3mg/kg, 6mg/kg and 10mg/kg every 3 weeks. After the first administration of antibody M-KF, antibody A was administered by intravenous infusion at a dose of 300 mg every 3 weeks, and the infusion time was 60 ⁇ 5 minutes. If DLT does not occur in the first cycle (course) of antibody M-KF monotherapy at each dose level, the combination therapy of 300 mg antibody A and antibody M-KF will start from the second cycle.
  • Antibody A was administered at intervals of once every 3 weeks after the injection of antibody M-KF.
  • a single subject will be enrolled at a starting dose level of 0.1 mg/kg antibody M-KF. If there is no grade 2 or higher toxicity that may be related to the study drug during the DLT observation period according to CTCAE v5.0, the dose of the single subject will be increased to 0.3 mg/kg; if a single subject is tested during the DLT observation period If any grade 2 or higher toxicity related to the study drug occurs, an additional 2 subjects will be enrolled at this dose level. In antibody M-KF monotherapy and combination therapy, the observation period of DLT was 3 weeks.
  • Antibody M-KF starts with a dose of 1 mg/kg and adopts a dose-escalation rule based on "3+3" to explore a safe dose range; the dose of antibody M-KF will be increased to 10 mg/kg until reaching the MTD or MAD.
  • the MTD was defined as the highest dose level at which no more than 1 of 6 subjects experienced a dose-limiting toxicity (DLT) during the first cycle of study treatment (21 days after the first dose of antibody M-KF). Dose escalation was based on observed toxicities during the first and second cycles of treatment.
  • DLT dose-limiting toxicity
  • the maximum duration of treatment is 1 year.
  • Subjects who continue to receive treatment for more than 1 year without disease progression can continue to receive the next cycle of drug treatment for more than 2 years. If the patient has an infusion-related reaction and can continue the treatment, diphenhydramine or acetaminophen can be used for prophylaxis based on the actual clinical situation.
  • Safety evaluation indicators involve: vital signs and physical examination, laboratory examination (blood routine, blood biochemistry, thyroid function, coagulation routine, urine routine, stool routine, pregnancy test), electrocardiogram, adverse events (including immune-related adverse events), etc. .
  • PK pharmacokinetic
  • Clinical effectiveness evaluation best overall response (Best overall response), objective response rate (Objective Response Rate, ORR), duration of response (Duration of Response, DOR), disease control rate (Disease control rate, DCR), no progression Survival (Progression-Free Survival, PFS), overall survival (Overall survival, OS).
  • DLT was defined as the toxicity that occurred during the DLT observation period (21-day first cycle of antibody M-KF monotherapy, and 21-day second cycle of antibody A combination therapy). Unless clearly related to the underlying disease, disease progression, concomitant drugs, or comorbidities, all AEs of the assigned grade should be counted as DLTs and considered at least possibly related to the study drug, as follows:
  • Grade 4 neutropenia lasting for any duration, or Grade 3 neutropenia lasting ⁇ 7 days or pre-existing infection

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Abstract

L'invention concerne une application d'un anticorps anti-OX40 dans un médicament combiné. Le procédé de traitement comprend l'administration d'une quantité efficace d'un anticorps anti-OX40 et d'un autre agent thérapeutique à un patient en ayant besoin.
PCT/CN2022/106326 2021-07-19 2022-07-18 Application d'anticorps anti-ox40 dans un médicament combiné WO2023001118A1 (fr)

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Citations (2)

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