WO2022184067A1 - Application of anti-tigit antibody in drug combination - Google Patents

Application of anti-tigit antibody in drug combination Download PDF

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WO2022184067A1
WO2022184067A1 PCT/CN2022/078682 CN2022078682W WO2022184067A1 WO 2022184067 A1 WO2022184067 A1 WO 2022184067A1 CN 2022078682 W CN2022078682 W CN 2022078682W WO 2022184067 A1 WO2022184067 A1 WO 2022184067A1
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Prior art keywords
amino acid
seq
antibody
antigen
binding fragment
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PCT/CN2022/078682
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French (fr)
Chinese (zh)
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黄俊杰
徐振前
符子艺
黄贤明
俞金泉
宋述强
李胜峰
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百奥泰生物制药股份有限公司
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Publication of WO2022184067A1 publication Critical patent/WO2022184067A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to the application of an anti-TIGIT antibody in combined medicine.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • Ig immunoglobulin
  • ITIM tyrosine inhibitor motif
  • TIGIT is part of a co-stimulatory network consisting mainly of the activating receptor CD226 and the inhibitory receptor TIGIT on T cells, and the ligand CD155 (also known as the ligand CD155 expressed on the surface of APCs, tumor cells, infected cells) PVR, a poliovirus receptor protein encoded in humans by the PVR gene) and CD112. Binding of TIGIT to PVR or CD112 will lead to the phosphorylation of Tyr225 in the cytoplasm of TIGIT, and the binding of TIGIT to cell-adaptive growth factor receptor binding protein 2 (GRB2).
  • ligand CD155 also known as the ligand CD155 expressed on the surface of APCs, tumor cells, infected cells
  • PVR a poliovirus receptor protein encoded in humans by the PVR gene
  • GRB2 can recruit SHIP1 to inhibit phosphatidylinositol tri-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling.
  • PI3K phosphatidylinositol tri-kinase
  • MAPK mitogen-activated protein kinase
  • phosphorylated TIGIT recruits SHIP1 via beta arrestin 2 ( ⁇ -arrestin2) and by blocking autoubiquitination of TNF receptor-associated factor 6 (TRAF6) and disrupts nuclear factor KB (NF-KB) activation , a series of signal transduction eventually lead to the inhibition of T cell or NK cell function and the inhibition of cytokine production.
  • PVR is both a ligand of TIGIT and a ligand of CD226 molecule.
  • Ser329 and Tyr322 of the intracellular domain of CD226 are phosphorylated; Ser329 phosphorylation promotes the activation of protein kinase (PKC) and the mutual binding of CD226 to lymphocyte-associated antigen 1 (LFA1). LFA1 is then used for TYN-mediated phosphorylation of Tyr322 and CD226-mediated downstream signaling. A series of signal transduction finally leads to the activation of T cell or NK cell function, which promotes the production of cytokines.
  • PDC protein kinase
  • LFA1 lymphocyte-associated antigen 1
  • TIGIT molecules can directly disrupt the formation of normal dimers of CD226, thereby destroying the normal physiological function of CD226.
  • TIGIT and CD226 are like two ends of the balance, through the pivot point of PVR, they skillfully regulate the immune function of the body through the transduction of co-stimulatory and co-inhibitory signals.
  • the present invention discloses a combination drug comprising an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the present invention provides a combination drug comprising a therapeutically effective amount of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the present invention discloses methods or uses of anti-TIGIT antibodies or antigen-binding fragments for combined treatment of tumors or cancers.
  • the method or use comprises administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the present invention discloses the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment in the preparation of a medicament for the treatment of tumors or cancer in combination with another therapeutic agent.
  • the present invention discloses the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and another therapeutic agent in the manufacture of a medicament for the treatment of tumor or cancer.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • another therapeutic agent in the manufacture of a medicament for the treatment of tumor or cancer.
  • the present invention also discloses a kit, which comprises an anti-TIGIT antibody or antigen-binding fragment (or preparation) and is used to instruct a patient in need to administer the anti-TIGIT antibody or antigen-binding fragment (or preparation) and another Instructions for a therapeutic agent (or formulation).
  • the present invention also discloses a kit comprising an anti-TIGIT antibody or antigen-binding fragment (or preparation), another therapeutic agent (or preparation), and an anti-TIGIT antibody for guiding the administration of a patient in need thereof or an antigen-binding fragment (or formulation) and another therapeutic agent (or formulation).
  • the present invention also discloses a kit comprising a composition (or formulation) of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent and for instructing a patient in need to administer anti-TIGIT Instructions for a composition (or formulation) of an antibody or 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-TIGIT 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-TIGIT antibody or an antigen-binding fragment and another therapeutic agent.
  • the pharmaceutical composition comprises at least 0.1% anti-TIGIT antibody or antigen-binding fragment and 0.1% another therapeutic agent.
  • the percentages of antibody and another therapeutic agent can vary and are between about 2% and about 90% by weight of a given dosage form.
  • the amount of anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent in such a therapeutically useful pharmaceutical composition can be an effective amount for administration.
  • the present invention also discloses a preparation method of the above-mentioned pharmaceutical composition: respectively combining the anti-TIGIT antibody and another therapeutic agent (or the composition of the anti-TIGIT antibody and another therapeutic agent) described herein with a pharmaceutically
  • An acceptable carrier suitable for injection eg, water for injection, physiological saline, etc.
  • Methods for admixing the above-described anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent with a pharmaceutically acceptable carrier are generally known in the art.
  • the anti-TIGIT antibody or antigen-binding fragment is used in combination with another therapeutic agent to treat a tumor or cancer.
  • the present invention uses an anti-TIGIT antibody or antigen-binding fragment (or preparation) and another therapeutic agent (or preparation) in tumor or cancer treatment, which can alleviate symptoms.
  • the other therapeutic agent is an antibody or antigen-binding fragment or an antibody drug conjugate (ADC).
  • ADC antibody drug conjugate
  • an anti-TIGIT antibody or antigen-binding fragment (or formulation), another therapeutic agent (or formulation) is used in combination with other therapeutic methods for the treatment of tumors or cancers, such as chemotherapy, radiotherapy, surgery, and the like.
  • the anti-TIGIT antibody or antigen-binding fragment comprises at least HCDR1 set forth in SEQ ID NO:1, HCDR2 set forth in SEQ ID NO:2, HCDR3 set forth in SEQ ID NO:3, : one or more of LCDR1 shown in SEQ ID NO: 5, LCDR2 shown in SEQ ID NO: 6, and LCDR3 shown in SEQ ID NO: 6.
  • the anti-TIGIT antibody or antigen-binding fragment comprises HCDR1 set forth in SEQ ID NO:1, HCDR2 set forth in SEQ ID NO:2, HCDR3 set forth in SEQ ID NO:3, SEQ ID NO:3 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-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7, or is at least 80% identical to the sequence set forth in SEQ ID NO:7
  • the amino acid sequence of SEQ ID NO: 7 has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 7.
  • the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:8, or is at least 80% identical to the sequence set forth in SEQ ID NO:8
  • the amino acid sequence of SEQ ID NO: 8 has one or more conservative amino acid substitutions.
  • the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7, or is at least 80% identical to the sequence set forth in SEQ ID NO:7
  • the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises SEQ ID NO: 8
  • the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7
  • the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises SEQ ID NO: 7 The amino acid sequence shown in ID NO:8.
  • the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO:9, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:9, or The sequence shown in SEQ ID NO: 9 is compared to an amino acid sequence with one or more conservative amino acid substitutions.
  • the light chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 10, or is The sequence shown in SEQ ID NO: 10 is compared to an amino acid sequence with one or more conservative amino acid substitutions.
  • the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO:9, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:9, or The amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:9;
  • the light chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:10, or the amino acid sequence shown in SEQ ID NO:10.
  • the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF
  • the heavy chains of antibodies h10D8OF and h10D8OFKF comprise the amino acid sequence as set forth in SEQ ID NO: 9
  • the light chains of antibodies h10D8OF and h10D8OFKF comprise as shown in SEQ ID The amino acid sequence shown in NO:10.
  • antibodies h10D8OF and h10D8OFKF contain two heavy chains with identical sequences and two light chains with identical sequences, respectively.
  • Antibody protein can be expressed in CHO cells or HEK293 cells by genetic engineering and obtained by purification; purification can be carried out by conventional methods, such as centrifuging the cell suspension and collecting the supernatant, and centrifuging again to further remove impurities. Methods such as ProteinA affinity columns and ion exchange columns can be used to purify antibody proteins.
  • the anti-TIGIT antibody eg, antibody h10D8OFKF
  • antigen-binding fragment has a fucosylation level of 0-10%. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has a fucosylation level of 0-5%.
  • the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has a fucosylation level of 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 (including the endpoints) or any value therein.
  • the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment does not bind fucose.
  • the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has an enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
  • the hypofucosylated or afucosylated anti-TIGIT antibody or antigen-binding fragment is expressed by an alpha-(1,6)-fucosyltransferase knockout cell line.
  • the antibody h10D8OFKF is expressed by an ⁇ -(1,6)-fucosyltransferase knockout cell line, eg, an ⁇ -(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-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at about 0.05 mg to 1200 mg, about 0.05 mg to 1000 mg, about 0.05 mg to 500 mg, about 0.05 mg to 100 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, About 0.1 mg to 30 mg, about 0.1 mg to 10 mg, about 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 900 mg, about 10
  • the anti-TIGIT antibody or antigen-binding fragment is administered at about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg to 1 mg/kg, about 0.005 mg/kg to Doses are administered at 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.05 mg to 1000 mg, about 0.05 mg to 500 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, about 0.1 mg to 30 mg, about 0.1 mg to 10 mg, 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 300 mg, about 10 mg to 100 mg, about 10 mg to 30 mg, about Each treatment cycle.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg to 1 mg/kg, about 0.005 mg /kg to 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg 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 of its values.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks Dosing once or every 7 weeks.
  • the anti-TIGIT antibody is the antibody h10D8OF or h10D8OFKF.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • antigen-binding fragment and another therapeutic agent or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent
  • Pharmaceutical compositions can be formulated as Pharmaceutical compositions, and are administered to patients in a variety of forms suitable for the chosen route of administration, eg, by parenteral, intravenous (iv), intramuscular, topical or subcutaneous routes.
  • an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent may be administered intravenously, respectively.
  • anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent will depend on the nature of the drug, the extent to which internalization, transport and release of the drug is triggered on the cell surface, the disease being treated, and the condition of the patient (eg, age, gender, weight, etc.).
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • antigen-binding fragment or formulation containing this dose is about 0.001 mg/kg to 20 mg/kg per administration. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment or formulation containing this dose is about 0.01 mg/kg to 20 mg/kg per administration.
  • the preparations containing the anti-TIGIT antibody or antigen-binding fragment can be those suitable for injectable use including sterile aqueous solutions (herein water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic or phosphate buffered saline (PBS), ethanol, solvents or dispersion media of polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and the like, and suitable mixture.
  • the formulation comprises at least 0.1% anti-TIGIT antibody or antigen-binding fragment.
  • the percentage of antibody can vary and can be between about 2% and 90% by weight for a given dosage form.
  • the anti-TIGIT antibody or antigen-binding fragment is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg per administration mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.012mg/kg, about 0.015mg/kg, about 0.018mg/kg, about 0.02mg/ kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.1mg/kg, about 0.3mg/kg, About 0.5mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 2mg/kg, about 3mg/kg, about 4m
  • the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment per administration is about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg kg to 1 mg/kg, about 0.005 mg/kg to 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg once daily to once every 7 weeks; or weekly Dosing once, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks or once every 7 weeks; or every 2, Administer once every 3 or 4 weeks.
  • anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment per administration is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, About 0.005mg/kg, about 0.006mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.012mg/kg, about 0.015mg/kg, about 0.018 mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.1mg/kg kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg per dose.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the antigen-binding fragment is administered at a dose of about 9 mg to 1200 mg per dose.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1 mg to 600 mg per dose.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 50 mg to 600 mg per dose.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.05 mg to 500 mg, about 0.05 mg to 100 mg, about 0.1 mg to 100 mg, About 0.1 mg to 50 mg, about 0.1 mg to 30 mg, about 0.1 mg to 10 mg, about 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 300 mg, about 10 mg to 100 mg, about 10 mg to 30 mg, about 30 mg to 900 mg, about 30 mg to 600 mg, about 30 mg, about 3
  • the dose of anti-TIGIT antibody or antigen-binding fragment per administration is about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg , about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg are administered every 2, 3 or 4 weeks.
  • the dose of anti-TIGIT antibody or antigen-binding fragment per administration is about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg , about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 300 mg, about 600 mg, or about 900 mg are administered every 2, 3 or 4 weeks.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 600 mg to 1200 mg per administration once every 2, 3, or 4 weeks. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 700 mg, about 800 mg, 900 mg, or about 1200 mg per administration every 2, 3, or 4 weeks.
  • a therapeutically effective amount of another therapeutic agent and an anti-TIGTI antibody or antigen-binding fragment are administered to a patient separately or simultaneously.
  • the period of administration of the other therapeutic agent and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
  • the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intraarterial injection, or intravenous (i.v.) injection or infusion Dosing in other ways.
  • the anti-TIGIT antibody or antigen-binding fragment and the other therapeutic agent can be administered by the same or different means.
  • the anti-TIGIT antibody or antigen-binding fragment is administered by intravenous (i.v.) infusion.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the antigen-binding fragment and the another therapeutic agent are separate administration units, administered in combination.
  • the anti-TIGIT antibody or antigen-binding fragment may be administered prior to administration of the other therapeutic agent, may be administered after administration of the other therapeutic agent, or may be administered with the other therapeutic agent A therapeutic agent is administered concurrently.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the other therapeutic agent form a combined administration unit simultaneously, 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, leukemia, lymphoma, and myeloma.
  • the leukemia includes acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myeloproliferative disorders/neoplastics (MPDS) ).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MPDS myeloproliferative disorders/neoplastics
  • lymphomas include Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell).
  • the myeloma includes multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma.
  • solid tumors include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, and kidney cancer.
  • the tumor and cancer are pathologically confirmed locally advanced or metastatic malignant solid tumors for which there is no effective treatment.
  • the additional therapeutic agent is selected from the following antibodies or antigen-binding fragments or antibody drug conjugates (ADCs) directed against a 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 cell surface antigen 2), Lag3 (lymphocyte activation gene-3 molecule), CD27 (cluster of differentiation 27), OX40 (tumor necrosis factor receptor superfamily member 4), ICOS (inducible costimulator), BTLA (B and T lymphocyte attenuating factor), TIM3 (T cell immunoglobulin mucin 3), BCMA (B cell maturation
  • the another therapeutic agent is selected from the group consisting of anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR2 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-HER2 antibody, anti- CD20 antibody, anti-Trop2 antibody, anti-OX40 antibody and anti-ICOS antibody.
  • the other therapeutic agent is an antibody targeting T lymphocyte-associated antigen 4 (CTLA-4) (anti-CTLA-4 antibody) or an antigen-binding fragment, such as ipilimumab (Yervoy TM or its biosimilar) or defucosylated ipilimumab as described in WO2014089113.
  • CTLA-4 T lymphocyte-associated antigen 4
  • antigen-binding fragment such as ipilimumab (Yervoy TM or its biosimilar) or defucosylated ipilimumab as described in WO2014089113.
  • the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 17 and the light chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 18; anti-CTLA The -4 antibody contains two heavy chains with identical sequences and two light chains with identical sequences.
  • 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 alpha-(1,6)-fucosyltransferase knockout cell line (eg, CHO cells).
  • an alpha-(1,6)-fucosyltransferase knockout cell line eg, CHO cells.
  • 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 (including endpoints) between any two of these values or any value therein.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a total amount of sialylated glycoforms of about 0.1%, 0.2%, about 0.36%, about 0.8%, about 1.5%, about 2.2%, about 2.7% %, about 2.9%, 2.99%, or a range (including endpoints) between any two of these values, 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 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 anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 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 (including endpoints) between any two of these values or any value therein .
  • the dose of ipilimumab 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 of its values.
  • ipilimumab is administered at a dose of 1 mg/kg, 3 mg/kg, or 10 mg/kg administered every 3, 6, or 12 weeks.
  • ipilimumab is administered at a dose of 1 mg/kg administered every 3 or 6 weeks.
  • ipilimumab is administered at a dose of 3 mg/kg administered every 3 or 6 weeks.
  • ipilimumab is administered at a dose of 10 mg/kg administered every 3 weeks or every 12 weeks.
  • each administration of ipilimumab is about 0.5 mg/kg to 10 mg/kg or a formulation containing such dose of ipilimumab.
  • the ipilimumab 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 per administration 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 (including the endpoints) or any value therein, or a formulation containing ipilimumab at this dose.
  • therapeutically effective amounts of ipilimumab and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously.
  • the period of administration of ipilimumab and the anti-TIGIT antibody or antigen-binding fragment 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 (eg Opdivo or OPDIVO or a biosimilar thereof), pembrolizumab (eg Keytruda or Keytruda or its biosimilars) biosimilars), camrelizumab (such as Erica or its biosimilars), sintilimab (such as or its biosimilars), toripalimab (toripalimab; such as Tuoyi or its biosimilars), or tislelizumab (tislelizumab; such as or its biological analogs).
  • nivolumab eg Opdivo or OPDIVO or a biosimilar thereof
  • pembrolizumab eg Keytruda or Keytruda or its biosimilars
  • camrelizumab such as Erica or its biosimilars
  • sintilimab such as or its biosimilars
  • toripalimab such
  • the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 set forth in SEQ ID NO:21, HCDR2 set forth in SEQ ID NO:22, HCDR3 set forth in SEQ ID NO:23, SEQ ID NO:23 LCDR1 shown in NO:24, LCDR2 shown in SEQ ID NO:25 and LCDR3 shown in SEQ ID NO:26.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 ⁇ compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 27.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:28, or has at least 80 ⁇ compared to the sequence set forth in SEQ ID NO:28 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 28.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 ⁇ compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO: 27;
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises SEQ ID NO: 27
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:19 and the light chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:20.
  • it can be expressed in cells (eg, CHO) by genetic engineering and obtained by purification.
  • the anti-PD-1 antibody is tislelizumab.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at about 1 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg, about 15 to 35 mg, Doses of about 50 mg to 600 mg are administered. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at about 0.01 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 1 mg/kg, Doses of about 1 mg/kg to 10 mg/kg are administered.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1 to 600 mg, about 50 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg, about 15mg to 35mg per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg to 10 mg/kg, about 1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, about 0.1 mg/kg mg/kg to 1 mg/kg 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 of its values.
  • the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 1 to 600 mg, about 50 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg , about 15 mg to 35 mg once daily to once every 7 weeks, or once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks Dosing once, every 6 weeks, or every 7 weeks; or every 2 weeks or every 3 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 0.01 mg/kg to 10 mg/kg, about 1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, About 0.1 mg/kg to 1 mg/kg once daily to once every 7 weeks, or once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, every Dosing every 5 weeks, every 6 weeks, or every 7 weeks; or every 2 weeks or every 3 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg , about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, 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, about 10 mg/kg (or a range (including endpoints) between any two of these values, or any value therein ) every 2 weeks or every 3 weeks.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 10 mg to about 600 mg per administration once every 2, 3, or 4 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg , about 20 mg, about 30 mg, about 33 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg (or any of these values)
  • the range between any two values of (including endpoints) or any value therein) is administered every 2, 3 or 4 weeks.
  • the anti-PD-1 antibody or antigen-binding fragment per administration is about 0.1 mg/kg to 10 mg/kg or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment per administration is about 1 mg/kg to 10 mg/kg or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment.
  • the anti-PD-1 antibody or antigen-binding fragment per administration is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, About 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.2mg/kg, about 2mg/kg, about 2.4mg/kg, about 3mg/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 between any two of these values range (including endpoints) or any value therein, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment.
  • tislelizumab is 100 mg-300 mg per administration. In some embodiments, tislelizumab is about 200 mg per administration. In some embodiments, tislelizumab is administered every 2-4 weeks. In some embodiments, tislelizumab is administered about every 3 weeks.
  • therapeutically effective amounts of the anti-PD-1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously.
  • the period of administration of the anti-PD-1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment may be the same or different.
  • the other therapeutic agent is an antibody that targets PD-L1 (anti-PD-L1 antibody) or an antigen-binding fragment, such as Atezolizumab, such as or its biosimilar), or durvalumab (Durvalumab, such as or its biological analogs).
  • Atezolizumab and Durvalumab can be expressed in cells (such as CHO) through genetic engineering and obtained through purification; the purification can be performed by conventional methods.
  • the other therapeutic agent is atezolizumab, which includes Tecentriq TM , its biosimilar, or ADCC effect-enhancing mAb or defucosylated mAb.
  • atezolizumab is administered at a dose of 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 of its values.
  • atezolizumab is administered at a dose of about 1200 mg administered every 3 weeks.
  • each administration of atezolizumab is about 1 mg/kg to 20 mg/kg or a formulation containing such doses of atezolizumab.
  • the atezolizumab 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 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 a range (including endpoints) between any two of these values, or any value therein, or a formulation containing atezolizumab at this dose.
  • the other therapeutic agent is Durvalumab, including IMFINZI TM , a biosimilar thereof, or an ADCC effect-enhancing mAb or a defucosylated mAb.
  • Durvalumab is administered at a dose of 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 of its values.
  • Durvalumab is administered at a dose of about 5 mg/kg to 15 mg/kg administered every 2 weeks or every 3 weeks.
  • Durvalumab is administered at a dose of about 10 mg/kg administered every 2 weeks.
  • the Durvalumab per administration is about 1 mg/kg to 10 mg/kg or a formulation containing such dose of Durvalumab. In some embodiments, the Durvalumab 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 6 mg/kg, about 9 mg/kg, about 10 mg/kg, or a range (including endpoints) between any two of these values or in which any value, or formulation containing this dose of Durvalumab.
  • therapeutically effective amounts of the anti-PD-L1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously.
  • the period of administration of the anti-PD-L1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment may be the same or different.
  • the other therapeutic agent is a monoclonal antibody (anti-HER2 antibody) that specifically binds to the extracellular dimerization domain (subdomain II) of epidermal growth factor receptor 2 (HER2). ), 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, which includes perjeta TM or a biosimilar thereof or an ADCC effect-enhancing mAb or a defucosylated mAb.
  • the dose 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 of its values.
  • Pertuzumab is administered at a dose of about 840 mg initially, followed by 420 mg administered every 3 weeks.
  • the Pertuzumab per administration is about 1 mg/kg to 12 mg/kg or a formulation containing this dose of Pertuzumab. In some embodiments, the Pertuzumab 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 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 11mg /kg, about 12 mg/kg, or a range between any two of these values (including the endpoints) or any value therein, or a formulation containing Pertuzumab at this dose.
  • therapeutically effective amounts of Pertuzumab and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously.
  • the period of administration of Pertuzumab and the anti-TIGIT antibody or antigen-binding fragment 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 interaction with VEGF receptor-2 (VEGFR-2) Binding (anti-VEGF antibody) such as bevacizumab.
  • IgG1 humanized immunoglobulin G1
  • VEGFR-2 VEGF receptor-2
  • Bevacizumab can be expressed in cells (eg, CHO) by genetic engineering and obtained by purification.
  • the other therapeutic agent is bevacizumab
  • bevacizumab includes Avastin TM or a biosimilar thereof, such as or BAT1706 (or or ), or ADCC effect-enhancing mAb or defucosylated mAb.
  • the dose 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 of its values.
  • bevacizumab is administered at a dose of about 5 mg/kg to 15 mg/kg administered every 2 weeks or every 3 weeks.
  • bevacizumab is administered at a dose of about 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg administered every 2 weeks or every 3 weeks.
  • bevacizumab is administered at a dose of about 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks, 15 mg/kg Dosing every 3 weeks.
  • the bevacizumab per administration is about 1 mg/kg to 9 mg/kg or a formulation containing bevacizumab at this dose. In some embodiments, the bevacizumab 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 6 mg/kg, about 6.9 mg/kg, about 7 mg/kg, about 8.4 mg/kg, about 9 mg/kg, or A range (including endpoints) between any two of these values, or any value therein, or a formulation containing bevacizumab at this dose.
  • a therapeutically effective amount of bevacizumab and an anti-TIGIT antibody or antigen-binding fragment is administered to the patient separately or simultaneously.
  • the period of administration of bevacizumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
  • the other therapeutic agent is an antibody that targets CD20 (anti-CD20 antibody), such as ofatumumab, or obinutuzumab.
  • anti-CD20 antibody such as ofatumumab, or obinutuzumab.
  • Ofatumumab and obinutuzumab can be expressed in cells (such as CHO) through genetic engineering and obtained through purification.
  • the other therapeutic agent is ofatumumab, and ofatumumab comprises Arzerra TM or Its biosimilar or ADCC effect-enhancing monoclonal antibody or defucosylated monoclonal antibody, such as BAT4406F disclosed in CN109096399A.
  • ofatumumab is administered at a dose 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 of its values.
  • ofatumumab is administered at a dose of about 20 mg administered weekly or monthly.
  • ofatumumab is administered at a dose of about 300 mg initially, 1000 mg after 1 week, and then 1000 mg administered every 4 weeks or every 8 weeks. In some embodiments, ofatumumab is administered at a dose of about 300 mg initially, 2000 mg after 1 week, and then 2000 mg administered every 1 week or every 4 weeks.
  • ofatumumab per administration is about 0.5 mg/kg to 18 mg/kg or a formulation containing such dose of ofatumumab. In some embodiments, 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 a range between any two of these values (including endpoints) or any of these values, or a formulation containing this dose of ofatumumab.
  • a therapeutically effective amount of ofatumumab and an anti-TIGIT antibody or antigen-binding fragment is administered to a patient separately or simultaneously.
  • the period of administration of ofatumumab and the anti-TIGIT antibody or antigen-binding fragment 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, such as BAT4306F described in CN109096399A.
  • the dose of obinutuzumab administered is 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 of its values.
  • obinutuzumab is administered at a dose of 100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8, 15, and 1,000 mg per course thereafter.
  • the effective amount of obinutuzumab administered is 1,000 mg each on day 1, day 8, day 15, and then 1,000 mg per course of treatment thereafter. Each course of treatment can be 1 month or 2 months.
  • the obinutuzumab per administration is about 0.5 mg/kg to 15 mg/kg or a formulation containing such dose of obinutuzumab.
  • the obinutuzumab 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 per administration , 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 11 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, or a range between any two of these values (including endpoints) or any value therein, or a formulation containing obinutuzumab at this dose.
  • a therapeutically effective amount of obinutuzumab and an anti-TIGIT antibody or antigen-binding fragment is administered to the patient separately or simultaneously.
  • the period of administration of obinutuzumab and the anti-TIGIT antibody or antigen-binding fragment 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), eg, 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-TIGIT antibody or antigen-binding fragment (or formulation) and another therapeutic agent (or formulation) ).
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg.
  • the effective amount of the anti-TIGIT antibody or antigen-binding fragment is about 9 mg to 1200 mg (or a formulation containing such a dose of the anti-TIGIT antibody) in a single administration.
  • the other therapeutic agent is an anti-PD-1 antibody or antigen-binding fragment.
  • the anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, HCDR3 shown in SEQ ID NO:23, HCDR3 shown in SEQ ID NO:24 LCDR1 shown in SEQ ID NO: 25, LCDR2 shown in SEQ ID NO: 25, and LCDR3 shown in SEQ ID NO: 26.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 ⁇ compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO: 27; and/or the light chain variable of the anti-PD-1 antibody or antigen-binding fragment
  • the region comprises the amino acid sequence shown in SEQ ID NO: 28, or an amino acid sequence that is at least 80% identical to the sequence shown in SEQ ID NO: 28, or has one or more identities compared to the sequence shown in SEQ ID NO: 28. Amino acid sequence of multiple conservative amino acid substitutions.
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:19 and the light chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:20.
  • the effective amount of the anti-PD-1 antibody or antigen-binding fragment is about 1 mg to 600 mg (or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment) in a single administration. Dosage schedule and mode of administration depend on benefit-risk assessment of anti-PD-1 antibody or antigen-binding fragment (or preparation), anti-TIGIT antibody or antigen-binding fragment (or preparation) in certain patient populations and general clinical practice guidelines .
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.05 mg to 1200 mg per treatment cycle (or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment)
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered to patients per treatment cycle is about 1 mg to 600 mg (or a preparation containing this dose of anti-PD-1 antibody or antigen-binding fragment).
  • the patient is administered an anti-TIGIT antibody (e.g., antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 9 mg to 1200 mg (or a formulation containing such a dose of anti-TIGIT antibody or antigen-binding fragment) per treatment cycle
  • an anti-TIGIT antibody e.g., antibody h10D8OF or h10D8OFKF
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered to a patient per treatment cycle is about 50 mg to 600 mg (or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment).
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, About 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg , about 10 mg, about 12 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 80 mg, about 100 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, about 700 mg, about 800 mg, about 900 mg, about 1000 mg,
  • one treatment cycle is administered once every 1 week to 7 weeks.
  • the dose of anti-TIGIT antibody or antigen-binding fragment administered per treatment cycle is about 0.05 mg to 1200 mg, or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one 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.
  • one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 1 mg to 30 mg per treatment cycle, or a formulation containing such dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one 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 dose of anti-TIGIT antibody or antigen-binding fragment administered in each treatment cycle is 9 mg to 100 mg, or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one 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 anti-TIGIT antibody or antigen-binding fragment at a dose of about 100 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 300 mg to about 600 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 600 mg to about 900 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the dose of the anti-TIGIT antibody or antigen-binding fragment administered to the patient per treatment cycle is about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 50 mg, about 74 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 350 mg, about 400 mg, about 430 mg, about 460 mg, about 520 mg, about 600 mg, about 900 mg, or any two of these values A range between values (including endpoints) or any value therein, or a formulation comprising such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.8 mg to 2 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; For example, about 1 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 1 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 2 mg to 5 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 3 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 3 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 7 mg to 20 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 10 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 10 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 23 mg to 50 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 30 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 30 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 75 mg to 150 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 100 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 100 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 167 mg to 250 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 200 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 200 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 267 mg to 354 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 300 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 300 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 347 mg to 430 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 400 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 400 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 557 mg to 650 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 600 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 600 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 877 mg to 950 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 900 mg is administered once.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 900 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
  • the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 0.05 mg to 1200 mg administered once every 3 weeks. In some embodiments, the dose of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 1 mg to 900 mg administered every 3 weeks. In some embodiments, the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 10 mg to 900 mg administered once every 3 weeks.
  • the dose of anti-TIGIT antibody or antigen-binding fragment is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, About 600 mg, about 700 mg, about 800 mg, or about 900 mg are administered every 3 weeks.
  • the dose of anti-TIGIT antibody or antigen-binding fragment is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 300 mg, about 600 mg, or about 900 mg are administered every 3 weeks.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 33 mg, about 40 mg, 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 any of these values A range between, inclusive of the endpoints, or any value therein, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment.
  • one treatment cycle is administered once every 1 week to 7 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered per treatment cycle is 15 mg to 35 mg, 10 mg to 50 mg, 10 mg to 100 mg, 1 mg to 100 mg, 50 mg to 600 mg, or containing such dose of anti-PD -1 A preparation of an antibody or antigen-binding fragment; wherein one 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 any of these values A range between two values (including the endpoints) or any value within it.
  • one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered in each treatment cycle is 10 mg to 200 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one 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 anti-PD-1 antibody or antigen-binding fragment at a dose of about 10 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one of The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered in each treatment cycle is 100 mg to 200 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one 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 anti-PD-1 antibody or antigen-binding fragment at a dose of about 200 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one of The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 33 mg, about 40 mg, about 50 mg, about 60 mg, about 80 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, or a range between any two of these values (including endpoints) or any value therein, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 10 mg to 20 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; such as about 16 mg given medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 16 mg per treatment cycle, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 20 mg to 45 mg per treatment cycle, or a formulation containing such a dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 33 mg administered medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 33 mg per treatment cycle, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 45 mg to 80 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 50 mg given medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 50 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 87 mg to 130 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; such as about 100 mg administered medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 100 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 180 mg to 230 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 200 mg given medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 200 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 267 mg to 343 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 300 mg given medicine once.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 300 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 300 mg to 700 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 600 mg given medicine once.
  • the dose of anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 600 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent (or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent once per treatment cycle) ).
  • the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered separately multiple times per treatment cycle, eg 2, 3, 4 or 5 times.
  • the patient is only dosed once or four times per treatment cycle.
  • the patient is treated with one treatment cycle. In some embodiments, the patient is treated with multiple (eg, 2, 3, or 4) treatment cycles. In some embodiments, the patient receives treatment until the condition resolves and no longer requires treatment.
  • the present invention discloses a method for treating a tumor or cancer, the method comprising: administering to a patient in need thereof about 0.05 mg to 10 mg, about 10 mg to 100 mg, about 100 mg to 300 mg, about 300 mg to 600 mg or about 600 mg to 1200 mg, such as about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 100 mg, about 120 mg, about 200 mg, about 300 mg , about 600 mg or about 900 mg of an anti-TIGIT antibody (e.g., antibody h10D8OF or h10D8OFKF) or antigen-binding fragment, a formulation containing this dose of an anti-TIGIT antibody (
  • the patient is treated with a single dose of an anti-TIGIT antibody or antigen-binding fragment, and a single dose of an anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the patient is treated with a single dose of a combination of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment are administered every 3 weeks.
  • the patient's symptoms are relieved after a single dose is administered. In some embodiments, after a single dose is administered and the patient's symptoms are not relieved as expected, the patient is administered about 0.05 mg to 1200 mg of anti-TIGIT antibody or antigen-binding fragment and about 1 mg to 600 mg of anti-PD-1 antibody or antigen, respectively Combine fragments. In some embodiments, the patient's symptoms are relieved after a single dose is administered. In some embodiments, after a single dose is administered and the patient's symptoms are not relieved as expected, the patient is administered about 9 mg to 1200 mg of anti-TIGIT antibody or antigen-binding fragment and about 50 mg to 600 mg of anti-PD-1 antibody or antigen-binding fragment, respectively. Fragment.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, Administration by intra-arterial injection or intravenous (i.v.) injection.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered by infusion.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered as a bolus injection.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (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 (including the endpoints) between any two of these values, or any value therein.
  • administration of the anti-PD-1 antibody or antigen-binding fragment (or formulation) occurs after administration of the anti-TIGIT antibody or antigen-binding fragment (or formulation). In some embodiments, administration of the anti-PD-1 antibody or antigen-binding fragment (or formulation) occurs about 15-60 minutes (eg, about 30 minutes) after administration of the anti-TIGIT antibody or antigen-binding fragment (or formulation).
  • Figure 1 shows that the antibody inhibits the growth of tumor body; the abscissa represents the days of administration, and the ordinate represents the tumor volume.
  • Figure 2 shows the effect of antibody on the body weight of mice; the abscissa represents the days of administration, and the ordinate represents the weight of mice.
  • an entity refers to one or more of such entities, eg "an antibody” should be understood to mean one or more antibodies, thus the term “an” (or “an” ), “one or more” and “at least one” are used interchangeably herein.
  • compositions, methods and the like include the recited elements, such as components or steps, but do not exclude others.
  • Consisting essentially of means that the compositions and methods exclude other elements that have an essential effect on the characteristics of the combination, but do not exclude elements that have no essential effect on the compositions or methods.
  • Consisting of means excluding elements not specifically recited.
  • polypeptide is intended to encompass the singular “polypeptide” as well as the plural “polypeptide”, and refers to a molecule composed of amino acid monomers linked linearly by amide bonds (also known as peptide bonds).
  • polypeptide refers to any single chain or chains of two or more amino acids, and does not refer to a particular length of the product.
  • the definition of “polypeptide” includes a peptide, dipeptide, tripeptide, oligopeptide, "protein”, “amino acid chain” or any other term used to refer to two or more amino acid chains, and the term “polypeptide” may Used in place of, or used interchangeably with, any of the above terms.
  • polypeptide is also intended to refer to the product 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-native Amino acid modifications that occur.
  • a polypeptide may be derived from a natural biological source or produced by recombinant techniques, but it need not be translated from a given nucleic acid sequence, and it may be produced by any means including chemical synthesis.
  • Amino acid refers to an organic compound containing both an amino group and a carboxyl group, such as an alpha-amino acid, which can be encoded by a nucleic acid directly or in a precursor form.
  • 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 same amino acid is encoded by different codons 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).
  • alanine three-letter code: ala, one-letter code: A
  • arginine arg, R
  • asparagine asparag
  • Constant amino acid substitution refers to the replacement of one amino acid residue by another amino acid residue containing a side chain (R group) of similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions will not substantially alter the functional properties of the protein.
  • amino acid classes containing 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 for "conservative amino acid substitutions of VL and 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 (including endpoints) between any two of these values, or any value therein.
  • the number of amino acids for a "conservative amino acid substitution of a 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 (including endpoints) between any two of these values, or any value therein.
  • encoding when applied to a polynucleotide refers to a polynucleotide referred to as “encoding” a polypeptide, transcribed and/or in its native state or when manipulated by methods well known to those skilled in the art Or translation can yield the polypeptide and/or fragments thereof.
  • Antibodies, antigen-binding fragments or derivatives disclosed herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies, epitope binding Fragments (eg, Fab-like, Fab'-like, and F(ab') 2 ), single-chain-like Fvs (scFv).
  • recombinant refers to a polypeptide or polynucleotide and means a form of the polypeptide or polynucleotide that does not occur in nature, non-limiting examples may be combined to produce 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 positions within each sequence that can be aligned. A molecule is homologous when a position in the sequences being compared is occupied by the same base or amino acid. The degree of homology between sequences is a function of the number of matches 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 (including endpoints) between any two values in a numerical value or any value therein.
  • a polynucleotide or polynucleotide sequence has a certain percentage (eg, 90%, 95%, 98% or 99%) "identity" or “sequence identity” to 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.
  • the percent alignment 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. The default parameters are preferably used for alignment.
  • Biologically equivalent polynucleotides are polynucleotides that have the above-specified percentages of identity and encode polypeptides having the same or similar biological activity.
  • Antibody refers to a polypeptide or polypeptide complex that specifically recognizes and binds 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 in the molecule that contains at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen.
  • Antibodies and antigen-binding fragments include, but are not limited to, the 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), a light chain constant region (CL), a framework region (FR), or any portion thereof, or at least a portion of a binding protein.
  • the 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 biochemically distinguishable polypeptides. Those of skill in the art will appreciate that classes of heavy chains include gamma, mu, alpha, delta, or epsilon (gamma, mu, alpha, delta, epsilon), with some subclasses (eg, gamma1-gamma4). The nature of this chain determines the "class” of the antibody as IgG, IgM, IgA, IgG or IgE, respectively. Immunoglobulin subclasses (isotypes), eg, IgGl, IgG2, IgG3, IgG4, IgG5, etc., are well characterized and the functional specificities conferred are known. All immunoglobulin species 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 bind to a kappa or lambda light chain.
  • ⁇ kappa
  • ⁇ lambda
  • Each heavy chain can bind to 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" portion of the two heavy chains is joined by a covalent disulfide bond or non-covalent bond.
  • the amino acid sequence extends from the N-terminus of the forked terminus in the Y configuration to the C-terminus at the bottom of each chain.
  • the variable region of immunoglobulin kappa light chain is V ⁇ ; the variable region of immunoglobulin lambda light chain is V ⁇ .
  • Both light and heavy chains are divided into regions of structural and functional homology.
  • the terms "constant” and “variable” are used according to function.
  • the light chain variable region (VL) and heavy chain variable region (VH) determine antigen recognition and specificity.
  • the light chain constant region (CL) and heavy chain constant region (CH) confer important biological properties such as secretion, transplacental movement, Fc receptor binding, complement fixation, and the like. By convention, the numbering of constant regions increases as they become further from the antigen binding site or amino terminus of the antibody.
  • 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-terminus of the heavy and light chains, respectively.
  • CDR complementarity determining region
  • CDRs as defined by Kabat and Chothia include overlaps or subsets of amino acid residues when compared to each other. Nonetheless, it is within the scope of the invention to apply either definition to refer to the CDRs of an antibody or variant thereof.
  • the exact residue numbers encompassing a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can usually determine which specific residues the CDRs contain based on the amino acid sequence of the variable region of the antibody.
  • Kabat et al. also define a numbering system applicable to variable region sequences of any antibody.
  • One of ordinary skill in the art can apply this "Kabat numbering" system to any variable region sequence independent of experimental data other than the sequence itself.
  • Kabat Numbering means 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 may also use the EU or Chothia numbering system.
  • antibody drug conjugate refers to an antibody or antigen-binding fragment thereof chemically linked to one or more chemical agents, which may optionally be therapeutic or cytotoxic agents.
  • the ADC includes an antibody, cytotoxic or therapeutic drug, and a linker that enables the drug to be attached or conjugated to the antibody.
  • ADCs typically have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 number of drugs conjugated to the antibody.
  • Drugs that can be included in ADCs are, but are not limited to: mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, Hormones, antihormones, corticosteroids, photoactive therapeutics, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors and radiosensitizers.
  • the drug included in the ADC can be a maytansinoid drug.
  • the drug included in the ADC can be a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof.
  • the antibody in the ADC, is conjugated to the drug through self-cysteine or sulfylated amino acids, such as sulfylated lysine, to form a disulfide bond.
  • Treatment means therapeutic treatment and prophylactic or prophylactic measures, the purpose of which is to prevent, slow, ameliorate and stop adverse physiological changes or disorders, such as the progression of disease, including but not limited to the following whether detectable or undetectable As a result, alleviation of symptoms, reduction of disease severity, stabilization of disease state (ie, no worsening), delay or slowdown of disease progression, improvement or alleviation of disease state, alleviation or disappearance (whether in part or in whole), prolongation and Expected duration of survival when not receiving treatment, etc.
  • a patient in need of treatment includes a patient already suffering from a condition or disorder, a patient susceptible to a condition or disorder, or a patient in need of prevention of such a condition or disorder, may or may be expected from administration of the antibodies or compositions 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 refers to the amount of 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” means that a patient has been identified as in need of a particular method or treatment. In some embodiments, identification can be made by any diagnostic means. In any of the methods and treatments described herein, the patient may need.
  • Combination drugs include two or more drugs, which can each form an independent administration unit or together form a combined administration unit.
  • the combination drug comprises a separate anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the combination drug comprises a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
  • the different drugs may be administered simultaneously or separately when administering a combination of drugs.
  • Antibody-encoding DNA can be designed and synthesized according to the antibody amino acid sequences described herein by conventional methods, inserted into an expression vector, and then transfected into host cells, and the transfected host cells are cultured in culture to produce monoclonal antibodies.
  • 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.
  • Efficient transcription can be obtained by the early and late promoters of SV40, long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and the early promoter of cytomegalovirus, and other cellular promoters such as muscle can be used.
  • 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 HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells and CHO cells.
  • IC50 means the 50% inhibitory concentration, that is, the concentration of drug or inhibitor required to inhibit half the indicated biological process.
  • the DNA sequences of the heavy and light chains were constructed according to the amino acid sequences of the heavy and light chains of the antibody, the 5' ends of the DNA sequences were modified with PCR primers, and the kozak sequence and the signal peptide DNA were added to the 5' ends of the light and heavy chain DNA sequences sequence.
  • the constructed sequence was then cloned into the existing expression vector, and the correct construction of the recombinant plasmid was verified by sequencing analysis.
  • the above recombinant plasmid was transfected into expression cells for expression, and the supernatant was collected and purified to obtain antibody protein samples, which were used in the following various examples.
  • the expression vector used is pCDNA3.1 TM (+) (Invitrogen company, the product number is V79020), and the expression cells are CHO cells; 2) in the preparation process of the antibody h10D8OFKF, the expression vector used It is pCDNA3.1 TM (+), the expression cells are CHO cells with ⁇ -(1,6)-fucosyltransferase gene knockout, and the fucosylation level is about 0 after testing; 3) Anti-CTLA- 4 In the process of antibody preparation, the expression vector used was pCDNA3.1 TM (+), and the expression cells were ⁇ -(1,6)-fucosyltransferase gene knockout CHO cells, which were tested for fucosylation The level is about 0; 4) During the preparation of the anti-PD-1 antibody, the expression vector used was pCDNA3.1 TM (+), and the expression cells were CHO cells; 5) During the preparation of the reference antibody Tiragolum
  • amino acid sequences of the above antibodies are shown in Tables 1-4; wherein, the amino acid sequences of the antibodies h10D8OF and h10D8OFKF are the same.
  • the DNA sequences of the antibodies are shown in Table 5; wherein, the DNA sequences of the antibodies h10D8OF and h10D8OFKF are the same.
  • the DNA sequences added to the 5' ends of the light chain DNA sequences of antibody h10D8OF, antibody h10D8OFKF, anti-CTLA-4 antibody and anti-PD-1 antibody are all gccgccaccatgg actttcaggtgcagatcatctccttcctgctgatcagcgcctccgtgatcatgtccaggggc, as shown in SEQ ID NO: 35, and the kozak sequence is underlined , the signal peptide is shown in italics;
  • the DNA sequences added to the 5' ends of the heavy chain DNA sequences of antibody h10D8OF, antibody h10D8OFKF, anti-CTLA-4 antibody and anti-PD-1 antibody are all gccgccaccatgg gctggagcctgatcctgctgttcctggtggccgtggccaccagagtgctgtccc, as shown in SEQ
  • the DNA sequence added to the 5' end of the light chain DNA sequence of the reference antibody Tiragolumab is gccg ccaccatgg acatgagggtgctggcccagctgctgggactgctgctgctgtgcttcccaggcgccagatgc, as shown in SEQ ID NO: 37, the kozak sequence is underlined, and the signal peptide is shown in italics;
  • the DNA sequence added at the ' end is gccgccaccatgg agtttgggctgagctgggtttttccttgttgctatattaaaaggtgtccagt, as shown in SEQ ID NO: 38, the kozak sequence is underlined, and the signal peptide is shown in italics.
  • TIGIT-Jurkat cells The binding of free PVR-Fc to TIGIT on the surface of TIGIT-Jurkat cells was detected by flow cytometry.
  • the test steps are as follows: take TIGIT-Jurkat cells with good viability (cell viability greater than 90%), resuspend them with PBS to a density of 10 million/ml after centrifugation, and add 50 ⁇ l per well to a 96-well tip bottom plate, which is the number of cells per well.
  • PVR-Fc-bio biotinylated PVR-Fc
  • PBS phosphate buffered saline
  • PVR-Fc-bio dilution a final concentration of 12.5nM
  • Appropriate amount of anti-TIGIT antibody or reference antibody Tiragolumab was diluted with PVR-Fc-bio diluent.
  • the initial concentration of the antibody was 200nM, 2-fold gradient dilution, a total of 10 concentration gradients, and 3 duplicate wells were set for each concentration point; 2- Incubate at 8°C for 1 hour, then wash twice with PBS, add 1:1000 diluted fluorescent secondary antibody Streptavidin-PE (eBioscience, CAT#12-4317-87) dilution, 100 ⁇ l per well, 2-8°C Incubate for 30 min; then wash with PBS twice, and use a flow analyzer to detect the fluorescence intensity (Mean PE-A).
  • the preparation method of PVR-Fc-bio is as follows: the nucleic acid sequence of the extracellular region of human PVR is added with enzyme cleavage sites (HindIII and EcoRI), and is fused with the nucleic acid sequence of the constant region of the human IgG1 heavy chain through a linker; It was inserted into the pCDNA3.1(+) vector, and then transiently transfected into HEK293F cells; the cultured cell supernatant was purified by ProteinA affinity chromatography, and the purified fusion protein was named PVR-Fc; take an appropriate amount of PVR-Fc protein, Biotin labeling kit from Thermo scientific company ( HSulfo-NHS-LC-BiotinylationKit, product number: 21435), biotinylated PVR-Fc according to the operation steps in the manual, and the labeled protein was named PVR-Fc-bio.
  • amino sequence of the extracellular region of human PVR is shown in SEQ ID NO: 13
  • the gene sequence of the linker is shown in SEQ ID NO: 14
  • the amino acid sequence of the linker is shown in SEQ ID NO: 39
  • the human IgG1 heavy The amino acid sequence of the chain constant region is shown in SEQ ID NO: 15, and the amino acid sequence of PVR-Fc is shown in SEQ ID NO: 40 (see Table 6).
  • the preparation method of TIGIT-Jurkat cells is as follows: replace the target gene on pCMV2-CFD-Flag (Yiqiao Shenzhou, item number: HG10160-MF) with the human full-length TIGIT gene to obtain a recombinant plasmid, and use the restriction endonuclease ClaI (Bsu15I) to The recombinant plasmid was linearized and transfected into Jurkat cell line (ATCC, Clone E6-1, TIB-152 TM ) by electroporation.
  • the screening pressure is hygromycin, and the positive cell line is obtained and then subcloned to obtain a cell line that can stably express human TIGIT, namely: TIGIT-Jurkat cells.
  • TIGIT-Jurkat cells a cell line that can stably express human TIGIT, namely: TIGIT-Jurkat cells.
  • sequence of the human full-length TIGIT gene is shown in SEQ ID NO: 16 (see Table 6).
  • both the antibody h10D8OF and the antibody Tiragolumab can effectively block the binding of TIGIT to PVR-Fc, and their IC 50 values are 0.4409nM and 2.820nM respectively; the blocking ability of the antibody h10D8OF is better than that of the antibody Tiragolumab.
  • both the antibody h10D8OFKF and the antibody Tiragolumab can effectively block the binding of TIGIT to PVR-Fc, and their IC 50 values are 0.742nM and 2.820nM respectively; the blocking ability of the antibody h10D8OFKF is better than that of the antibody Tiragolumab.
  • mice BALB/c-hPD1/hTIGIT (Jiangsu JiCui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with CT26 colon cancer tumor cells; after inoculation with tumor cells, when the average tumor volume of the mice was 79.65 mm3 , the Group, 10 in each group.
  • the day of grouping was defined as D0 day, and was administered by intraperitoneal injection (IP) on D0 day, D4 day, D7 day, D11 day, D14 day, and D18 day, and the dose was 10 mg/kg or 30 mg/kg.
  • IP intraperitoneal injection
  • TGItw inhibition rate of tumor weight
  • TGItw (1-(mean TW administration group )/(mean TW control group )) ⁇ 100%;
  • Mean TW administration group mean tumor weight of mice in administration group at the end point treatment,
  • Mean TW control group control The mean value of tumor weight at the end point treatment of mice in the group.
  • Both antibody h10D8OF and antibody Tiragolumab can inhibit the growth of CT26 colon cancer, and the effect of antibody h10D8OF in inhibiting tumor growth is better than that of antibody Tiragolumab; at the dose of 30 mg/kg, the relative tumor inhibition rate TGitw (%) at the end of the trial (D20 day) h10D8OF was 92.89% and Tiragolumab was 71.07%.
  • Both antibody h10D8OFKF and antibody Tiragolumab can inhibit the growth of CT26 colon cancer, and the effect of antibody h10D8OFKF in inhibiting tumor growth is better than that of antibody Tiragolumab.
  • Example 4 Co-administration of antibody h10D8OFKF and anti-PD-1 antibody inhibits the proliferation of cancer cells
  • Mouse colon cancer cells were recovered, cells in logarithmic growth phase were collected, the culture medium was removed, and the cells were washed twice with PBS and then inoculated with an inoculation volume of 5 ⁇ 10 6 /100 ⁇ L per mouse.
  • the inoculation site was the right hind limb of the mouse.
  • mice When the tumor volume reached 89.19 mm 3 , 40 mice were randomly divided into 4 groups according to the tumor volume, with 10 mice in each group.
  • the day of grouping is defined as D0 day, and administration starts on D0 day; the grouping administration schedule is shown in Table 8, and the administration dates are: D0 day, D4 day, D7 day, D11 day, D14 day, D18 day, D21 day (G3 day)
  • the group was administered on D22, and the G4 group was administered on both D21 and D22) and D25.
  • mice Following cell inoculation, tumor effects on the animals' normal behavior were routinely monitored weekly. Specific indicators include mouse activity, food and water intake, weight gain or loss, eyes, coat and other abnormalities.
  • 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).
  • the independent sample T test was used to compare whether there were significant differences between the different administration groups and the control group. Data were analyzed using SPSS. P ⁇ 0.05 means there is a significant difference.
  • TGItv inhibition rate relative to tumor volume
  • RTVn Vnt / Vn0 ; Vnt : tumor volume of mouse number n on day t, Vn0 : tumor volume of mouse number n on day 0, RTVn: mouse number n Relative tumor volume in mice on day t
  • TGItv (1-(mean RTV administration group )/(mean RTV control group )) ⁇ 100%; mean RTV administration group : average RTV of administration group, mean RTV control group : average RTV of control group.
  • single-drug antibody h10D8OFKF and single-drug anti-PD-1 antibody can inhibit tumor growth, and the combined administration group of antibody h10D8OFKF and anti-PD-1 antibody has significant anti-tumor efficacy, and The anti-tumor effect was better than the anti-tumor effect of single-drug antibody h10D8OFKF and anti-PD-1 antibody (no tumor completely regressed in G1 and G2 groups, 2 mice in G3 group had complete tumor regression, and 1 mouse in G4 group had a small tumor.
  • the tumor inhibition rate (TGItv) of the G4 group was significantly improved, and the combination of the antibody h10D8OFKF and the anti-PD-1 antibody had a synergistic anti-tumor effect.
  • TGItv tumor inhibition rate
  • This study is a multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of antibody h10D8OFKF injection alone or in combination with tislelizumab in patients with advanced malignant solid tumors. Phase I clinical study.
  • Part I Single-agent dose escalation studies. The safety, tolerability and pharmacokinetics of the antibody h10D8OFKF were explored using accelerated titration and a "3+3" dose escalation rule.
  • a total of 8 dose groups were set, including 1mg (initial dose) group, 3mg group, 10mg group, 30mg group, 100mg group, 300mg group, 600mg group and 900mg group.
  • the whole is divided into two stages.
  • the first stage 1mg group, 3mg group and 10mg group adopt the accelerated titration method for dose escalation.
  • the second stage 30mg group, 100mg group, 300mg group, 600mg group and 900mg group will conduct a dose escalation study according to the standard "3+3" rule.
  • Antibody h10D8OFKF dosing regimen intravenous infusion, the recommended infusion time is ⁇ 60 minutes, and the study drug is tentatively scheduled to be administered once every 3 weeks (Q3W). If the patient has an infusion-related reaction and can continue treatment, the investigator may consider the use of diphenhydramine or acetaminophen for prophylaxis based on past experience and clinical reality. If no infusion-related reaction is observed, the subsequent infusion time can be adjusted by the investigator to 30 minutes to 2 hours to complete the infusion according to the actual clinical situation.
  • Tislelizumab dosing regimen The antibody h10D8OFKF is administered intravenously 30 minutes after the completion of the infusion. The recommended infusion time is 30-60 minutes, and it is administered once every 3 weeks (Q3W). For the detailed dosing schedule, refer to the instructions for Tislelizumab injection.
  • DLT dose-limiting toxicity
  • Grade 3 endocrine toxicity can be effectively controlled by hormone replacement therapy
  • MTD was defined as the highest dose level of DLT explored in ⁇ 1/6 subjects in a dose cohort observed during the DLT evaluation period.
  • DLT dose-limiting toxicity
  • Safety evaluation indicators vital signs and physical examination, laboratory tests (blood routine, blood biochemistry, thyroid function, coagulation routine, urine routine, stool routine, pregnancy test), ECOG score, electrocardiogram, adverse events (including immune-related adverse events) )Wait.
  • Subjects in all dose groups were required to collect blood samples at prescribed time points during the treatment period (first 6 treatment cycles) and monitor plasma concentrations (C trough ) within 2 hours prior to dosing.
  • a 3.5 mL blood sample is planned to be taken at each time point to detect the concentration level of the serum drug and study the pharmacokinetic (PK) characteristics.
  • PK parameters were calculated from actual doses administered, actual sampling times, and non-compartmental models:
  • the receptor occupancy study of antibody h10D8OFKF injection was achieved by detecting TIGIT receptor binding on the surface of T cells in peripheral blood.
  • Pharmacodynamic receptor occupancy studies were conducted only in dose-escalation subjects who had blood samples collected at specific time points during treatment. A 2 mL blood sample was planned to be collected at each time point, and intensive sampling was performed before administration, at the end of administration, 168h, 336h, and 504h in cycles 1 and 3, and before administration in cycles 2, 4, 5, and 6.
  • ORR Objective response rate
  • DOR duration of response
  • DCR disease control rate
  • PFS progression-free survival
  • OS overall survival

Abstract

The present invention provides a combination drug, comprising an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent. The present invention further provides a use of the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent in preparation of the combination drug for treating tumors or cancers.

Description

抗TIGIT抗体在联合用药中的应用Application of Anti-TIGIT Antibody in Combination Drugs 技术领域technical field
本发明属于生物医药领域，尤其涉及抗TIGIT抗体在联合用药中的应用。The invention belongs to the field of biomedicine, and particularly relates to the application of an anti-TIGIT antibody in combined medicine.
背景技术Background technique
TIGIT(T cell immunoreceptor with Ig and ITIM domains)是一种具有免疫球蛋白(Ig)和酪氨酸抑制剂基序(ITIM)结构域的T细胞免疫受体，主要表达于激活的T细胞和NK细胞上(Yu,X.,etal.(2009)."The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells."Nature immunology 10(1):48-57.)。TIGIT结构显示包含一个细胞外免疫球蛋白结构域，一个I型跨膜区和两个ITIM基序。TIGIT是共同刺激网络的一部分，这个共刺激网络主要由T细胞上的激活性受体CD226和抑制性受体TIGIT，以及在APC、肿瘤细胞、感染的细胞表面表达的配体CD155(也称为PVR，一种在人类中被PVR基因编码的脊髓灰质炎病毒受体蛋白质)和CD112组成。TIGIT与PVR或CD112结合后会引起TIGIT胞质内Tyr225被磷酸化，TIGIT和细胞自适应生长因子受体结合蛋白2(GRB2)进行结合。GRB2可以招募SHIP1抑制磷脂酰肌醇三激酶(PI3K)和促分裂原活化蛋白激酶(MAPK)信号。除此之外，磷酸化的TIGIT通过Beta抑制蛋白2(β-arrestin2)招募SHIP1和通过阻断TNF受体相关因子6(TRAF6)的自身泛素化并破坏核因子KB(NF-KB)激活，一系列的信号传导最终导致T细胞或NK细胞的功能受到抑制，细胞因子的产生受到抑制。PVR既是TIGIT的配体，又是CD226分子的配体。在和CD112或CD155结合之后，CD226的胞内结构域的Ser329和Tyr322被磷酸化；Ser329磷酸化促进蛋白激酶(PKC)的激活和CD226与淋巴细胞关联抗原1(LFA1)的相互结合。LFA1然后被用于TYN介导的Tyr322磷酸化和CD226介导的下游信号传导。一系列的信号传导最终导致T细胞或NK细胞的功能受到激活，促进细胞因子的产生。存在于T细胞或NK细胞表面的TIGIT分子与CD226分子之间也发生着相互作用，表现在TIGIT分子可以直接扰乱CD226形成正常的二聚体，从而破坏CD226的正常生理功能。TIGIT和CD226如同天平的两端，通过PVR这个支点，通过共刺激和共抑制信号的传导巧妙地调节着机体的免疫功能。TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a T cell immunoreceptor with immunoglobulin (Ig) and tyrosine inhibitor motif (ITIM) domains, mainly expressed on activated T cells and NK on cells (Yu, X., et al. (2009). "The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells." Nature immunology 10(1):48-57.). The TIGIT structure was shown to contain an extracellular immunoglobulin domain, a type I transmembrane region and two ITIM motifs. TIGIT is part of a co-stimulatory network consisting mainly of the activating receptor CD226 and the inhibitory receptor TIGIT on T cells, and the ligand CD155 (also known as the ligand CD155 expressed on the surface of APCs, tumor cells, infected cells) PVR, a poliovirus receptor protein encoded in humans by the PVR gene) and CD112. Binding of TIGIT to PVR or CD112 will lead to the phosphorylation of Tyr225 in the cytoplasm of TIGIT, and the binding of TIGIT to cell-adaptive growth factor receptor binding protein 2 (GRB2). GRB2 can recruit SHIP1 to inhibit phosphatidylinositol tri-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. In addition, phosphorylated TIGIT recruits SHIP1 via beta arrestin 2 (β-arrestin2) and by blocking autoubiquitination of TNF receptor-associated factor 6 (TRAF6) and disrupts nuclear factor KB (NF-KB) activation , a series of signal transduction eventually lead to the inhibition of T cell or NK cell function and the inhibition of cytokine production. PVR is both a ligand of TIGIT and a ligand of CD226 molecule. After binding to CD112 or CD155, Ser329 and Tyr322 of the intracellular domain of CD226 are phosphorylated; Ser329 phosphorylation promotes the activation of protein kinase (PKC) and the mutual binding of CD226 to lymphocyte-associated antigen 1 (LFA1). LFA1 is then used for TYN-mediated phosphorylation of Tyr322 and CD226-mediated downstream signaling. A series of signal transduction finally leads to the activation of T cell or NK cell function, which promotes the production of cytokines. There is also an interaction between TIGIT molecules and CD226 molecules that exist on the surface of T cells or NK cells, which means that TIGIT molecules can directly disrupt the formation of normal dimers of CD226, thereby destroying the normal physiological function of CD226. TIGIT and CD226 are like two ends of the balance, through the pivot point of PVR, they skillfully regulate the immune function of the body through the transduction of co-stimulatory and co-inhibitory signals.
发明内容SUMMARY OF THE INVENTION
本发明公开了一种联合用药物，包括抗TIGIT抗体或抗原结合片段和另一种治疗 剂。在一些实施方案中，本发明提供了一种联合用药物，包括治疗有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。The present invention discloses a combination drug comprising an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent. In some embodiments, the present invention provides a combination drug comprising a therapeutically effective amount of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent.
另一方面，本发明公开了抗TIGIT抗体或抗原结合片段用于联合治疗肿瘤或癌症的方法或用途。在一些实施方案中，所述方法或用途包括：向有需要的患者施用有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。另一方面，本发明公开了抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段在制备与另一种治疗剂联合用于治疗肿瘤或癌症的药物中的应用。另一方面，本发明公开了抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和另一种治疗剂在制备用于治疗肿瘤或癌症的药物中的应用。In another aspect, the present invention discloses methods or uses of anti-TIGIT antibodies or antigen-binding fragments for combined treatment of tumors or cancers. In some embodiments, the method or use comprises administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent. In another aspect, the present invention discloses the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment in the preparation of a medicament for the treatment of tumors or cancer in combination with another therapeutic agent. In another aspect, the present invention discloses the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and another therapeutic agent in the manufacture of a medicament for the treatment of tumor or cancer.
另一方面，本发明还公开了一种试剂盒，试剂盒包含抗TIGIT抗体或抗原结合片段(或制剂)和用于指导有需要患者给药抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)的说明书。另一方面，本发明还公开了一种试剂盒，试剂盒包含抗TIGIT抗体或抗原结合片段(或制剂)、另一种治疗剂(或制剂)和用于指导有需要患者给药抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)的说明书。在一些实施方案中，本发明还公开了一种试剂盒，试剂盒包含抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物(或制剂)以及用于指导有需要患者给药抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物(或制剂)的说明书。On the other hand, the present invention also discloses a kit, which comprises an anti-TIGIT antibody or antigen-binding fragment (or preparation) and is used to instruct a patient in need to administer the anti-TIGIT antibody or antigen-binding fragment (or preparation) and another Instructions for a therapeutic agent (or formulation). In another aspect, the present invention also discloses a kit comprising an anti-TIGIT antibody or antigen-binding fragment (or preparation), another therapeutic agent (or preparation), and an anti-TIGIT antibody for guiding the administration of a patient in need thereof or an antigen-binding fragment (or formulation) and another therapeutic agent (or formulation). In some embodiments, the present invention also discloses a kit comprising a composition (or formulation) of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent and for instructing a patient in need to administer anti-TIGIT Instructions for a composition (or formulation) of an antibody or antigen-binding fragment and another therapeutic agent.
另一方面，本发明还公开了包含抗TIGIT抗体或抗原结合片段和另一种治疗剂的适合注射用的药物组合物，如推注型药物组合物或输液(滴注)型药物组合物。在一些实施方案中，药物组合物至少包含0.1％的抗TIGIT抗体或抗原结合片段和0.1％的另一种治疗剂。抗体和另一种治疗剂的百分比可以变化，并且为给定剂型重量的约2％和约90％之间。这种治疗上有用的药物组合物中抗TIGIT抗体或抗原结合片段和另一种治疗剂的量可以为给药的有效量。In another aspect, 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-TIGIT antibody or an antigen-binding fragment and another therapeutic agent. In some embodiments, the pharmaceutical composition comprises at least 0.1% anti-TIGIT antibody or antigen-binding fragment and 0.1% another therapeutic agent. The percentages of antibody and another therapeutic agent can vary and are between about 2% and about 90% by weight of a given dosage form. The amount of anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent in such a therapeutically useful pharmaceutical composition can be an effective amount for administration.
另一方面，本发明还公开了上述药物组合物的制备方法：分别将本文所述的抗TIGIT抗体和另一种治疗剂(或抗TIGIT抗体和另一种治疗剂的组合物)与药学上可接受的适合注射用的载体(例如注射用水，生理盐水等)混合。上述抗TIGIT抗体或抗原结合片段和另一种治疗剂与药学上可接受的载体的混合方法是本领域通常已知的。On the other hand, the present invention also discloses a preparation method of the above-mentioned pharmaceutical composition: respectively combining the anti-TIGIT antibody and another therapeutic agent (or the composition of the anti-TIGIT antibody and another therapeutic agent) described herein with a pharmaceutically An acceptable carrier suitable for injection (eg, water for injection, physiological saline, etc.) is mixed. Methods for admixing the above-described anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent with a pharmaceutically acceptable carrier are generally known in the art.
在一些实施方案中，抗TIGIT抗体或抗原结合片段联合另一种治疗剂用于治疗肿瘤或癌症。本发明将抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)用于肿瘤或癌症治疗中，可以减缓症状。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is used in combination with another therapeutic agent to treat a tumor or cancer. The present invention uses an anti-TIGIT antibody or antigen-binding fragment (or preparation) and another therapeutic agent (or preparation) in tumor or cancer treatment, which can alleviate symptoms.
在一些实施方案中，所述另一种治疗剂为抗体或抗原结合片段或抗体药物偶联物(ADC)。In some embodiments, the other therapeutic agent is an antibody or antigen-binding fragment or an antibody drug conjugate (ADC).
在一些实施方案中，抗TIGIT抗体或抗原结合片段(或制剂)、另一种治疗剂(或制剂)与其他治疗方法联合使用用于治疗肿瘤或癌症，例如化疗、放疗和手术治疗等。In some embodiments, an anti-TIGIT antibody or antigen-binding fragment (or formulation), another therapeutic agent (or formulation) is used in combination with other therapeutic methods for the treatment of tumors or cancers, such as chemotherapy, radiotherapy, surgery, and the like.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段至少包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2、SEQ ID NO:6所示的LCDR3中一个或多个。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment comprises at least HCDR1 set forth in SEQ ID NO:1, HCDR2 set forth in SEQ ID NO:2, HCDR3 set forth in SEQ ID NO:3, : one or more of LCDR1 shown in SEQ ID NO: 5, LCDR2 shown in SEQ ID NO: 6, and LCDR3 shown in SEQ ID NO: 6.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment comprises HCDR1 set forth in SEQ ID NO:1, HCDR2 set forth in SEQ ID NO:2, HCDR3 set forth in SEQ ID NO:3, SEQ ID NO:3 LCDR1 shown in 4, LCDR2 shown in SEQ ID NO:5 and LCDR3 shown in SEQ ID NO:6.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ ID NO:7所示的氨基酸序列，或与SEQ ID NO:7所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7, or is at least 80% identical to the sequence set forth in SEQ ID NO:7 The amino acid sequence of SEQ ID NO: 7 has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 7.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ ID NO:8所示的氨基酸序列，或与SEQ ID NO:8所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:8, or is at least 80% identical to the sequence set forth in SEQ ID NO:8 The amino acid sequence of SEQ ID NO: 8 has one or more conservative amino acid substitutions.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ ID NO:7所示的氨基酸序列，或与SEQ ID NO:7所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ ID NO:8所示的氨基酸序列，或与SEQ ID NO:8所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7, or is at least 80% identical to the sequence set forth in SEQ ID NO:7 A specific amino acid sequence, or an amino acid sequence with one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO: 7; the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises SEQ ID NO: 8 The amino acid sequence shown, or an amino acid sequence that is at least 80% identical to the sequence shown in SEQ ID NO: 8, or an amino acid that has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 8 sequence.
在一些实施方案中，所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ ID NO:7所示的氨基酸序列，所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ ID NO:8所示的氨基酸序列。In some embodiments, the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:7, and the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises SEQ ID NO: 7 The amino acid sequence shown in ID NO:8.
在一些实施方案中，所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列，或与SEQ ID NO:9所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO:9, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:9, or The sequence shown in SEQ ID NO: 9 is compared to an amino acid sequence with one or more conservative amino acid substitutions.
在一些实施方案中，所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列，或与SEQ ID NO:10所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the light chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 10, or is The sequence shown in SEQ ID NO: 10 is compared to an amino acid sequence with one or more conservative amino acid substitutions.
在一些实施方案中，所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列，或与SEQ ID NO:9所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列，或与SEQ ID NO:10所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:10所示序列相比具有一个或多个保 守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO:9, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:9, or The amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:9; the light chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:10, or the amino acid sequence shown in SEQ ID NO:10. An amino acid sequence having at least 80% identity compared to the sequence shown, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 10.
在一些实施方案中，所述抗TIGIT抗体为抗体h10D8OF或h10D8OFKF，抗体h10D8OF和h10D8OFKF的重链包含如SEQ ID NO:9所示的氨基酸序列，所述抗体h10D8OF和h10D8OFKF的轻链包含如SEQ ID NO:10所示的氨基酸序列。在一些实施方案中，抗体h10D8OF和h10D8OFKF分别含有两条序列相同的重链和两条序列相同的轻链。In some embodiments, the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF, the heavy chains of antibodies h10D8OF and h10D8OFKF comprise the amino acid sequence as set forth in SEQ ID NO: 9, and the light chains of antibodies h10D8OF and h10D8OFKF comprise as shown in SEQ ID The amino acid sequence shown in NO:10. In some embodiments, antibodies h10D8OF and h10D8OFKF contain two heavy chains with identical sequences and two light chains with identical sequences, respectively.
抗体蛋白可以通过基因工程在CHO细胞或HEK293细胞中表达，并通过纯化获得；纯化可以采用常规方法进行，例如先离心细胞悬液并收集上清液，再次离心进一步去除杂质。ProteinA亲和柱和离子交换柱等方法可以用于纯化抗体蛋白。Antibody protein can be expressed in CHO cells or HEK293 cells by genetic engineering and obtained by purification; purification can be carried out by conventional methods, such as centrifuging the cell suspension and collecting the supernatant, and centrifuging again to further remove impurities. Methods such as ProteinA affinity columns and ion exchange columns can be used to purify antibody proteins.
在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为0-10％。在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为0-5％。在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为约0、约0.1％、约0.5％、约0.8％、约1％、约1.3％、约1.6％、约2.1％、2.9％、约3％、约3.3％、3.8％、约4％、约4.2％、4.3％、约4.6％、约5％，或这些数值中任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段没有结合岩藻糖。在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段具有增强的ADCC效应(antibody-dependent cell-mediated cytotoxicity)。In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has a fucosylation level of 0-10%. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has a fucosylation level of 0-5%. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has a fucosylation level of 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 (including the endpoints) or any value therein. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment does not bind fucose. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OFKF) or antigen-binding fragment has an enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
在一些实施方案中，低岩藻糖基化或无岩藻糖基化的抗TIGIT抗体或抗原结合片段由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系表达。在一些实施方案中，抗体h10D8OFKF由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系表达，例如α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞。In some embodiments, the hypofucosylated or afucosylated anti-TIGIT antibody or antigen-binding fragment is expressed by an alpha-(1,6)-fucosyltransferase knockout cell line. In some embodiments, the antibody h10D8OFKF is expressed by an α-(1,6)-fucosyltransferase knockout cell line, eg, an α-(1,6)-fucosyltransferase knockout CHO cells.
在一些实施方案中，本发明公开了一种用于治疗有需要患者的肿瘤或癌症的方法，其包括施用有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。在一些实施方案中，抗TIGIT抗体或抗原结合片段以约0.05mg至1200mg、约0.05mg至1000mg、约0.05mg至500mg、约0.05mg至100mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、约0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg的剂量给药。在一些实施方案中，抗TIGIT抗体或抗原结合片段以约0.001 mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg的剂量给药。在一些实施方案中，抗TIGIT抗体或抗原结合片段施用的剂量为约0.05mg至1200mg、约0.05mg至1000mg、约0.05mg至500mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg每个治疗周期。在一些实施方案中，抗TIGIT抗体或抗原结合片段施用的剂量为约0.001mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，抗TIGIT抗体或抗原结合片段每天给药一次至每7周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次。在一些实施方案中，所述抗TIGIT抗体为抗体h10D8OF或h10D8OFKF。In some embodiments, 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-TIGIT antibody or antigen-binding fragment and another therapeutic agent. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at about 0.05 mg to 1200 mg, about 0.05 mg to 1000 mg, about 0.05 mg to 500 mg, about 0.05 mg to 100 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, About 0.1 mg to 30 mg, about 0.1 mg to 10 mg, about 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 300 mg, about 10 mg to 100 mg, about 10 mg to 30 mg, about 30 to 900 mg, about 30 to 600 mg, about 30 to 300 mg, about 30 to 100 mg, about 100 to 900 mg, about 100 to 600 mg, about 100 to 300 mg, about 300 to 900 mg, about 300 to 600 mg, about 600 mg Doses up to 900 mg are administered. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg to 1 mg/kg, about 0.005 mg/kg to Doses are administered at 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.05 mg to 1000 mg, about 0.05 mg to 500 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, about 0.1 mg to 30 mg, about 0.1 mg to 10 mg, 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 300 mg, about 10 mg to 100 mg, about 10 mg to 30 mg, about Each treatment cycle. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg to 1 mg/kg, about 0.005 mg /kg to 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks Dosing once or every 7 weeks. In some embodiments, the anti-TIGIT antibody is the antibody h10D8OF or h10D8OFKF.
在一些实施方案中，可以分别将抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)配制成药物组合物，并以适合于所选给药途径的多种形式向患者给药，例如通过肠胃外、静脉内(iv)、肌肉内、局部或皮下途径。在一些实施方案中，可以分别将抗TIGIT抗体或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)静脉输注。抗TIGIT抗体或抗原结合片段和另一种治疗剂的量将取决于药物的性质，细胞表面触发药物的内在化，运输和释放的程度，所治疗的疾病，患者的状况(如年龄，性别，体重等)。In some embodiments, an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and another therapeutic agent (or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent), respectively, can be formulated as Pharmaceutical compositions, and are administered to patients in a variety of forms suitable for the chosen route of administration, eg, by parenteral, intravenous (iv), intramuscular, topical or subcutaneous routes. In some embodiments, an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent (or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent) may be administered intravenously, respectively. The amount of anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent will depend on the nature of the drug, the extent to which internalization, transport and release of the drug is triggered on the cell surface, the disease being treated, and the condition of the patient (eg, age, gender, weight, etc.).
在一些实施方案中，每次施用的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段约0.001mg/kg至20mg/kg或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中，每次施用的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段约0.01mg/kg至20mg/kg或含此剂量抗TIGIT抗体或抗原结合片段的制剂。含抗TIGIT抗体或抗原结合片段的制剂可以为适于注射用途的制剂包括无菌水性溶液(在此是水溶性的)或分散体以及用于即时制备无菌注射液或分散体的无菌粉末。对于静脉内施用，合适的载体包括生理盐水、抑菌水或磷酸盐缓冲 盐水(PBS)、乙醇、多元醇(例如，甘油、丙二醇和液体聚乙二醇等)的溶剂或分散介质，及其适宜的混合物。在一些实施方案中，制剂至少包含0.1％的抗TIGIT抗体或抗原结合片段。抗体的百分比可以变化，并且为给定剂型重量可以约2％至90％之间。In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment or formulation containing this dose is about 0.001 mg/kg to 20 mg/kg per administration. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment or formulation containing this dose is about 0.01 mg/kg to 20 mg/kg per administration. The preparations containing the anti-TIGIT antibody or antigen-binding fragment can be those suitable for injectable use including sterile aqueous solutions (herein water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. . For intravenous administration, suitable carriers include physiological saline, bacteriostatic or phosphate buffered saline (PBS), ethanol, solvents or dispersion media of polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and the like, and suitable mixture. In some embodiments, the formulation comprises at least 0.1% anti-TIGIT antibody or antigen-binding fragment. The percentage of antibody can vary and can be between about 2% and 90% by weight for a given dosage form.
在一些实施方案中，每次施用的抗TIGIT抗体或抗原结合片段为约0.001mg/kg，约0.002mg/kg，约0.003mg/kg，约0.004mg/kg，约0.005mg/kg，约0.006mg/kg，约0.007mg/kg，约0.008mg/kg，约0.009mg/kg，约0.01mg/kg，约0.012mg/kg，约0.015mg/kg，约0.018mg/kg，约0.02mg/kg，约0.03mg/kg，约0.04mg/kg，约0.05mg/kg，约0.06mg/kg，约0.07mg/kg，约0.08mg/kg，约0.1mg/kg，约0.3mg/kg，约0.5mg/kg，约0.8mg/kg，约0.9mg/kg，约1mg/kg，约2mg/kg，约3mg/kg，约4mg/kg，约5mg/kg，约6mg/kg，约7mg/kg，约8mg/kg，约9mg/kg，约10mg/kg，约12mg/kg，约14mg/kg，约15mg/kg，约18mg/kg，约20mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中，抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段每次施用的剂量为约0.001mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg每天给药一次至每7周给药一次；或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次；或者每2、3或4周给药一次。在一些实施方案中，抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段每次施用的剂量为约0.001mg/kg，约0.002mg/kg，约0.003mg/kg，约0.004mg/kg，约0.005mg/kg，约0.006mg/kg，约0.007mg/kg，约0.008mg/kg，约0.009mg/kg，约0.01mg/kg，约0.012mg/kg，约0.015mg/kg，约0.018mg/kg，约0.02mg/kg，约0.03mg/kg，约0.04mg/kg，约0.05mg/kg，约0.06mg/kg，约0.07mg/kg，约0.08mg/kg，约0.1mg/kg，约0.3mg/kg，约0.5mg/kg，约0.8mg/kg，约0.9mg/kg，约1mg/kg，约2mg/kg，约3mg/kg，约4mg/kg，约5mg/kg，约6mg/kg，约7mg/kg，约8mg/kg，约9mg/kg，约10mg/kg，约12mg/kg，约14mg/kg，约15mg/kg，约18mg/kg，约20mg/kg每2、3或4周给药一次。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg per administration mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.012mg/kg, about 0.015mg/kg, about 0.018mg/kg, about 0.02mg/ kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.1mg/kg, about 0.3mg/kg, About 0.5mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 2mg/kg, about 3mg/kg, about 4mg/kg, about 5mg/kg, about 6mg/kg, about 7mg /kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg, about 14 mg/kg, about 15 mg/kg, about 18 mg/kg, about 20 mg/kg, or any two of these values A range between, inclusive of the endpoints, or any value therein, or a formulation containing this dose of anti-TIGIT antibody or antigen-binding fragment. In some embodiments, the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment per administration is about 0.001 mg/kg to 20 mg/kg, about 0.001 mg/kg to 2 mg/kg, about 0.001 mg/kg kg to 1 mg/kg, about 0.005 mg/kg to 1 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.01 mg/kg to 20 mg/kg once daily to once every 7 weeks; or weekly Dosing once, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks or once every 7 weeks; or every 2, Administer once every 3 or 4 weeks. In some embodiments, the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment per administration is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, About 0.005mg/kg, about 0.006mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.012mg/kg, about 0.015mg/kg, about 0.018 mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.1mg/kg kg, about 0.3 mg/kg, about 0.5 mg/kg, about 0.8 mg/kg, about 0.9 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 12mg/kg, about 14mg/kg, about 15mg/kg, about 18mg/kg, about 20mg/kg Dosing every 2, 3 or 4 weeks.
在一些实施方案中，抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每剂约0.05mg至1200mg。在一些实施方案中，抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每剂约9mg至1200mg。在一些实施方案中，抗PD-1抗体或抗原结合片段施用的剂量为每剂约1mg至600mg。在一些实施方案中，抗PD-1抗体或抗原结合片段施用的剂量为每剂约50mg至600mg。在一些实施方案中，抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每次约0.05mg至1200mg、约0.05mg至500mg、约0.05mg至100mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、约0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg 至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg每天给药一次至每7周给药一次；或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次；或者每2、3或4周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段每次施用的剂量为约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约40mg、约50mg、约100mg、约300mg、约600mg、约900mg、约1000mg、约1200mg每2、3或4周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段每次施用的剂量为约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约300mg、约600mg或约900mg每2、3或4周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段每次施用的剂量为约600mg至1200mg每2、3或4周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段每次施用的剂量为约700mg、约800mg、900mg或约1200mg每2、3或4周给药一次。In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg per dose. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is administered at a dose of about 9 mg to 1200 mg per dose. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1 mg to 600 mg per dose. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 50 mg to 600 mg per dose. In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.05 mg to 500 mg, about 0.05 mg to 100 mg, about 0.1 mg to 100 mg, About 0.1 mg to 50 mg, about 0.1 mg to 30 mg, about 0.1 mg to 10 mg, about 0.5 mg to 1 mg, about 9 mg to 1200 mg, about 1 mg to 900 mg, about 1 mg to 300 mg, about 1 mg to 100 mg, about 1 mg to 30 mg, about 1 mg to 10 mg, about 1 mg to 3 mg, about 3 mg to 900 mg, about 3 mg to 600 mg, about 3 mg to 100 mg, about 3 mg to 30 mg, about 3 mg to 10 mg, about 10 mg to 900 mg, about 10 mg to 600 mg, about 10 mg to 300 mg, about 10 mg to 100 mg, about 10 mg to 30 mg, about 30 mg to 900 mg, about 30 mg to 600 mg, about 30 mg to 300 mg, about 30 mg to 100 mg, about 100 mg to 900 mg, about 100 mg to 600 mg, about 100 mg to 300 mg, about 300 mg to 900 mg, about 300 mg to 600 mg, about 600 mg to 900 mg once daily to once every 7 weeks; or once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks Dosing once a week, once every 6 weeks, or once every 7 weeks; or once every 2, 3 or 4 weeks. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment per administration is about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg , about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg are administered every 2, 3 or 4 weeks. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment per administration is about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg , about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 300 mg, about 600 mg, or about 900 mg are administered every 2, 3 or 4 weeks. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 600 mg to 1200 mg per administration once every 2, 3, or 4 weeks. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 700 mg, about 800 mg, 900 mg, or about 1200 mg per administration every 2, 3, or 4 weeks.
在一些实施方案中，采用治疗有效量的另一种治疗剂和抗TIGTI抗体或抗原结合片段分别或者同时施加在患者上。另一种治疗剂和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。在一些实施方案中，抗TIGIT抗或抗原结合片段和另一种治疗剂是通过皮下(s.c.)注射、腹膜内(i.p.)注射、肠胃外注射、动脉内注射或静脉内(i.v.)注射或输液等方式进行给药。抗TIGIT抗体或抗原结合片段和另一种治疗剂可以通过相同或者不同方式进行给药。In some embodiments, a therapeutically effective amount of another therapeutic agent and an anti-TIGTI antibody or antigen-binding fragment are administered to a patient separately or simultaneously. The period of administration of the other therapeutic agent and the anti-TIGIT antibody or antigen-binding fragment can be the same or different. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intraarterial injection, or intravenous (i.v.) injection or infusion Dosing in other ways. The anti-TIGIT antibody or antigen-binding fragment and the other therapeutic agent can be administered by the same or different means.
在一些实施方案中，抗TIGIT抗体或抗原结合片段是通过静脉内(i.v.)输液方式进行给药。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered by intravenous (i.v.) infusion.
在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和所述另一种治疗剂分别为独立的给药单元，联合用药。在一些实施方案中，所述抗TIGIT抗体或抗原结合片段可以在施加所述另一种治疗剂之前给药，也可以在施加所述另一种治疗剂之后给药，也可以与所述另一种治疗剂同时给药。In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and the another therapeutic agent are separate administration units, administered in combination. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment may be administered prior to administration of the other therapeutic agent, may be administered after administration of the other therapeutic agent, or may be administered with the other therapeutic agent A therapeutic agent is administered concurrently.
在一些实施方案中，所述抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和所述另一种治疗剂同时形成组合给药单元，联合用药。In some embodiments, the anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and the other therapeutic agent form a combined administration unit simultaneously, and are administered in combination.
在一些实施方案中，患者患有肿瘤或癌症。在一些实施方案中，肿瘤和癌症包括但不限于血液癌症、实体瘤。在一些实施方案中，血液癌症包括但不限于白血病、淋巴瘤和骨髓瘤。在一些实施方案中，白血病包括急性淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)和骨髓性增生疾病/肿瘤(MPDS)。在一些实施方案中，淋巴瘤包括霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)。在一些实施方案中，骨髓瘤包括多发性骨髓瘤(MM)、巨细胞骨髓瘤、重链骨髓瘤和轻链或本斯-琼斯骨髓瘤。在一些实施方案中，实体瘤包括乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。在一些实施方案中，肿瘤和癌症为尚无有效治疗手段的经病理学确诊的局部晚期或转移性恶性实体肿瘤。In some embodiments, the patient has a tumor or cancer. In some embodiments, tumors and cancers include, but are not limited to, hematological cancers, solid tumors. In some embodiments, hematological cancers include, but are not limited to, leukemia, lymphoma, and myeloma. In some embodiments, the leukemia includes acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myeloproliferative disorders/neoplastics (MPDS) ). In some embodiments, lymphomas include Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell). In some embodiments, the myeloma includes multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma. In some embodiments, solid tumors include breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, and kidney cancer. In some embodiments, the tumor and cancer are pathologically confirmed locally advanced or metastatic malignant solid tumors for which there is no effective treatment.
在一些实施方案中，所述另一种治疗剂选自以下针对靶点的抗体或抗原结合片段或抗体药物偶联物(ADC)：EGFR(表皮生长因子受体)、VEGF(血管内皮生长因子)、VEGFR2(血管内皮生长因子受体2)、CTLA-4(细胞毒性T淋巴细胞相关蛋白4)、PD-1(程序性死亡受体-1)、PD-L1(程序性死亡配体-1)、HER2(人表皮生长因子受体2)、CD20(分化簇20)、Trop2(人滋养层细胞表面抗原2)、Lag3(淋巴细胞活化基因-3分子)、CD27(分化簇27)、OX40(肿瘤坏死因子受体超家族成员4)、ICOS(inducible costimulator)、BTLA(B和T淋巴细胞弱化因子)、TIM3(T细胞免疫球蛋白黏液素3)、BCMA(B细胞成熟抗原)、c-MET(间质表皮转化因子)和TAA-1/2/3(肿瘤相关抗原)。在一些实施方案中，所述抗体为抑制型抗体或激动型抗体。In some embodiments, the additional therapeutic agent is selected from the following antibodies or antigen-binding fragments or antibody drug conjugates (ADCs) directed against a 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 cell surface antigen 2), Lag3 (lymphocyte activation gene-3 molecule), CD27 (cluster of differentiation 27), OX40 (tumor necrosis factor receptor superfamily member 4), ICOS (inducible costimulator), BTLA (B and T lymphocyte attenuating factor), TIM3 (T cell immunoglobulin mucin 3), BCMA (B cell maturation antigen), c-MET (Mesenchymal Epidermal Transforming Factor) and TAA-1/2/3 (Tumor-Associated Antigen). In some embodiments, the antibody is an inhibitory antibody or an agonistic antibody.
在一些实施方案中，所述另一种治疗剂选自抗EGFR抗体、抗VEGF抗体、抗VEGFR2抗体、抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗HER2抗体、抗CD20抗体、抗Trop2抗体、抗OX40抗体和抗ICOS抗体。In some embodiments, the another therapeutic agent is selected from the group consisting of anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR2 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-HER2 antibody, anti- CD20 antibody, anti-Trop2 antibody, anti-OX40 antibody and anti-ICOS antibody.
在一些实施方案中，所述另一种治疗剂为靶向T淋巴细胞相关抗原4(CTLA-4)抗体(抗CTLA-4抗体)或抗原结合片段，如伊匹单抗(Yervoy TM或其生物类似物)或去岩藻糖基化伊匹单抗，如WO2014089113所述。在一些实施方案中，抗CTLA-4抗体的重链包含如SEQ ID NO:17所示的氨基酸序列，抗CTLA-4抗体的轻链包含如SEQ ID NO:18所示的氨基酸序列；抗CTLA-4抗体含有两条序列相同的重链和两条序列相同的轻链。 In some embodiments, the other therapeutic agent is an antibody targeting T lymphocyte-associated antigen 4 (CTLA-4) (anti-CTLA-4 antibody) or an antigen-binding fragment, such as ipilimumab (Yervoy ™ or its biosimilar) or defucosylated ipilimumab as described in WO2014089113. In some embodiments, the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 17 and the light chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 18; anti-CTLA The -4 antibody contains two heavy chains with identical sequences and two light chains with identical sequences.
在一些实施方案中，抗CTLA-4抗体或抗原结合片段由CHO细胞表达。在一些实施方案中，抗CTLA-4抗体或抗原结合片段由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系(如CHO细胞)表达。In some embodiments, 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 alpha-(1,6)-fucosyltransferase knockout cell line (eg, CHO cells).
在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的高甘露糖糖型总量<5％和/或唾液酸化糖型总量<3％。在一些实施方案中，抗CTLA-4抗体或抗原结合片段的 高甘露糖糖型总量为约0.1％、约0.3％、约0.9％、约1.18％、约1.7％、约2.6％、约3.3％、约4.1％、约4.9％、约4.99％，或这些数值中任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的唾液酸化糖型总量为约0.1％、0.2％、约0.36％、约0.8％、约1.5％、约2.2％、约2.7％、约2.9％、2.99％，或这些数值中任何两个值之间的范围(包括端点)或其中任何值。In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has <5% total high mannose glycoforms and/or <3% total sialylated glycoforms. In some embodiments, 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 (including endpoints) between any two of these values or any value therein. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a total amount of sialylated glycoforms of about 0.1%, 0.2%, about 0.36%, about 0.8%, about 1.5%, about 2.2%, about 2.7% %, about 2.9%, 2.99%, or a range (including endpoints) between any two of these values, or any value therein.
在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的高甘露糖糖型总量<2％和/或唾液酸化糖型总量<1％。In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has <2% total high mannose glycoforms and/or <1% total sialylated glycoforms.
在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为0-10％。在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为0-5％。在一些实施方案中，所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为约0、约0.1％、约0.3％、约0.4％、约0.6％、约1.3％、约1.9％、约2.2％、约2.8％、约3.3％、约3.7％、约4.1％、约4.5％、约5％，或这些数值中任何两个值之间的范围(包括端点)或其中任何值。In some embodiments, 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 anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 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 (including endpoints) between any two of these values or any value therein .
在一些实施方案中，伊匹单抗施用的剂量为约30mg至300mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，伊匹单抗施用的剂量为1mg/kg，3mg/kg或10mg/kg每3周、6周、或12周给药一次。在一些实施方案中，伊匹单抗施用的剂量为1mg/kg每3周或6周给药一次。在一些实施方案中，伊匹单抗施用的剂量为3mg/kg每3周或6周给药一次。在一些实施方案中，伊匹单抗施用的剂量为10mg/kg每3周或每12周给药一次。In some embodiments, the dose of ipilimumab administered is about 30 mg to 300 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, ipilimumab is administered at a dose of 1 mg/kg, 3 mg/kg, or 10 mg/kg administered every 3, 6, or 12 weeks. In some embodiments, ipilimumab is administered at a dose of 1 mg/kg administered every 3 or 6 weeks. In some embodiments, ipilimumab is administered at a dose of 3 mg/kg administered every 3 or 6 weeks. In some embodiments, ipilimumab is administered at a dose of 10 mg/kg administered every 3 weeks or every 12 weeks.
在一些实施方案中，每次施用的伊匹单抗为约0.5mg/kg至10mg/kg或含此剂量伊匹单抗的制剂。在一些实施方案中，每次施用的伊匹单抗为约0.5mg/kg，约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约6.9mg/kg，约7mg/kg，约8.4mg/kg，约9mg/kg，约10mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量伊匹单抗的制剂。In some embodiments, each administration of ipilimumab is about 0.5 mg/kg to 10 mg/kg or a formulation containing such dose of ipilimumab. In some embodiments, the ipilimumab 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 per administration 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 (including the endpoints) or any value therein, or a formulation containing ipilimumab at this dose.
在一些实施方案中，采用治疗有效量的伊匹单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。伊匹单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, therapeutically effective amounts of ipilimumab and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously. The period of administration of ipilimumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
在一些实施方案中，所述另一种治疗剂为抗PD-1抗体或抗原结合片段。在一些实施方案中，所述抗PD-1抗体为纳武利尤单抗(nivolumab；如欧狄沃或OPDIVO或其生物类似物)、帕博利单抗(pembrolizumab；如可瑞达或Keytruda或其生物类似物)、卡瑞利珠单抗(camrelizumab；如艾瑞卡或其生物类似物)、信迪利单抗(sintilimab；如
Figure PCTCN2022078682-appb-000001
或其生物类似物)、特瑞普利单抗(toripalimab；如拓益或其生物类似物)或替雷利珠单抗(tislelizumab；如称
Figure PCTCN2022078682-appb-000002
或其生物类似物)。 In some embodiments, the other therapeutic agent is an anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the anti-PD-1 antibody is nivolumab (eg Opdivo or OPDIVO or a biosimilar thereof), pembrolizumab (eg Keytruda or Keytruda or its biosimilars) biosimilars), camrelizumab (such as Erica or its biosimilars), sintilimab (such as
Figure PCTCN2022078682-appb-000001
or its biosimilars), toripalimab (toripalimab; such as Tuoyi or its biosimilars), or tislelizumab (tislelizumab; such as
Figure PCTCN2022078682-appb-000002
or its biological analogs).
在一些实施方案中，所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。In some embodiments, the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 set forth in SEQ ID NO:21, HCDR2 set forth in SEQ ID NO:22, HCDR3 set forth in SEQ ID NO:23, SEQ ID NO:23 LCDR1 shown in NO:24, LCDR2 shown in SEQ ID NO:25 and LCDR3 shown in SEQ ID NO:26.
在一些实施方案中，所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 Å compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 27.
在一些实施方案中，所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:28, or has at least 80 Å compared to the sequence set forth in SEQ ID NO:28 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 28.
在一些实施方案中，所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。In some embodiments, the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 Å compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO: 27; the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises SEQ ID NO: 27 The amino acid sequence shown in ID NO: 28, or an amino acid sequence that is at least 80% identical to the sequence shown in SEQ ID NO: 28, or has one or more conservations compared to the sequence shown in SEQ ID NO: 28 Amino acid sequence of amino acid substitutions.
在一些实施方案中，抗PD-1抗体的重链包含如SEQ ID NO:19所示的氨基酸序列，抗PD-1抗体的轻链包含如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中，其可以通过基因工程在细胞(如CHO)中表达，并通过纯化获得。In some embodiments, the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:19 and the light chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:20. In some embodiments, it can be expressed in cells (eg, CHO) by genetic engineering and obtained by purification.
在一些实施方案中，抗PD-1抗体为替雷利珠单抗。In some embodiments, the anti-PD-1 antibody is tislelizumab.
在一些实施方案中，抗PD-1抗体或抗原结合片段以每个治疗周期约1mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg、约50mg至600mg的剂量给药。在一些实施方案中，抗PD-1抗体或抗原结合片段以每个治疗周期约0.01mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg、约1mg/kg至10mg/kg的剂量给药。在一些实施方案中，抗PD-1抗体或抗原结合片段施用的剂量为约1mg至600mg、约50mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg每个治疗周期。在一些实施方案中，抗PD-1抗体或抗原结合片段施用的剂量为约0.01mg/kg至10mg/kg、约1mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，抗PD-1抗体或抗原结合片段每次施用的剂量为约1mg至600mg、约50mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg每天给药一次至每7周给 药一次，或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次；或者每2周或每3周给药一次。在一些实施方案中，抗PD-1抗体或抗原结合片段每次施用的剂量为约0.01mg/kg至10mg/kg、约1mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg每天给药一次至每7周给药一次，或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次；或者每2周或每3周给药一次。在一些实施方案中，抗PD-1抗体或抗原结合片段每次施用的剂量为约0.01mg/kg，约0.02mg/kg，约0.03mg/kg，约0.04mg/kg，约0.05mg/kg，约0.06mg/kg，约0.07mg/kg，约0.08mg/kg，约0.09mg/kg，约0.1mg/kg，约0.2mg/kg，约0.3mg/kg，约0.4mg/kg，约0.5mg/kg，约0.6mg/kg，约0.7mg/kg，约0.8mg/kg，约0.9mg/kg，约1mg/kg，约2mg/kg，约3mg/kg，约4mg/kg，约5mg/kg，约6mg/kg，约7mg/kg，约8mg/kg，约9mg/kg，约10mg/kg(或这些数值中的任何两个值之间的范围(包括端点)或其中任何值)每2周或每3周给药一次。在一些实施方案中，抗PD-1抗体或抗原结合片段每次施用的剂量为约10mg至约600mg每2、3或4周给药一次。在一些实施方案中，抗PD-1抗体或抗原结合片段每次施用的剂量为约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约200mg、约300mg、约400mg、约500mg、约600mg(或这些数值中的任何两个值之间的范围(包括端点)或其中任何值)每2、3或4周给药一次。In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at about 1 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg, about 15 to 35 mg, Doses of about 50 mg to 600 mg are administered. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at about 0.01 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 1 mg/kg, Doses of about 1 mg/kg to 10 mg/kg are administered. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1 to 600 mg, about 50 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg, about 15mg to 35mg per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg to 10 mg/kg, about 1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, about 0.1 mg/kg mg/kg to 1 mg/kg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 1 to 600 mg, about 50 to 600 mg, about 1 to 300 mg, about 1 to 100 mg, about 10 to 100 mg, about 10 to 50 mg , about 15 mg to 35 mg once daily to once every 7 weeks, or once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks Dosing once, every 6 weeks, or every 7 weeks; or every 2 weeks or every 3 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 0.01 mg/kg to 10 mg/kg, about 1 mg/kg to 10 mg/kg, about 0.1 mg/kg to 10 mg/kg, About 0.1 mg/kg to 1 mg/kg once daily to once every 7 weeks, or once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, every Dosing every 5 weeks, every 6 weeks, or every 7 weeks; or every 2 weeks or every 3 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg , about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, 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, about 10 mg/kg (or a range (including endpoints) between any two of these values, or any value therein ) every 2 weeks or every 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 10 mg to about 600 mg per administration once every 2, 3, or 4 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment per administration is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg , about 20 mg, about 30 mg, about 33 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg (or any of these values) The range between any two values of (including endpoints) or any value therein) is administered every 2, 3 or 4 weeks.
在一些实施方案中，每次施用的抗PD-1抗体或抗原结合片段为约0.1mg/kg至10mg/kg或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中，每次施用的抗PD-1抗体或抗原结合片段为约1mg/kg至10mg/kg或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中，每次施用的抗PD-1抗体或抗原结合片段为约0.1mg/kg，约0.2mg/kg，约0.3mg/kg，约0.4mg/kg，约0.5mg/kg，约0.6mg/kg，约0.7mg/kg，约0.8mg/kg，约0.9mg/kg，约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约7mg/kg，约10mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗PD-1抗体或抗原结合片段的制剂。In some embodiments, the anti-PD-1 antibody or antigen-binding fragment per administration is about 0.1 mg/kg to 10 mg/kg or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment per administration is about 1 mg/kg to 10 mg/kg or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment per administration is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, About 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg, about 1mg/kg, about 1.2mg/kg, about 2mg/kg, about 2.4mg/kg, about 3mg/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 between any two of these values range (including endpoints) or any value therein, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment.
在一些实施方案中，每次施用的替雷利珠单抗为100mg-300mg。在一些实施方案中，每次施用的替雷利珠单抗为约200mg。在一些实施方案中，每2-4周施用一次替雷利珠单抗。在一些实施方案中，约每3周施用一次替雷利珠单抗。In some embodiments, tislelizumab is 100 mg-300 mg per administration. In some embodiments, tislelizumab is about 200 mg per administration. In some embodiments, tislelizumab is administered every 2-4 weeks. In some embodiments, tislelizumab is administered about every 3 weeks.
在一些实施方案中，采用治疗有效量的抗PD-1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。抗PD-1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, therapeutically effective amounts of the anti-PD-1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously. The period of administration of the anti-PD-1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment may be the same or different.
在一些实施方案中，所述另一种治疗剂为是靶向PD-L1的抗体(抗PD-L1抗体)或抗原结合片段，如阿特珠单抗(Atezolizumab,如
Figure PCTCN2022078682-appb-000003
或其生物类似物)，或度伐利尤单抗(Durvalumab，如
Figure PCTCN2022078682-appb-000004
或其生物类似物)。阿特珠单抗及Durvalumab可以通过基因工程在细胞(如CHO)中表达，并通过纯化获得；纯化可以采用常规方法进行。 In some embodiments, the other therapeutic agent is an antibody that targets PD-L1 (anti-PD-L1 antibody) or an antigen-binding fragment, such as Atezolizumab, such as
Figure PCTCN2022078682-appb-000003
or its biosimilar), or durvalumab (Durvalumab, such as
Figure PCTCN2022078682-appb-000004
or its biological analogs). Atezolizumab and Durvalumab can be expressed in cells (such as CHO) through genetic engineering and obtained through purification; the purification can be performed by conventional methods.
在一些实施方案中，所述另一种治疗剂为阿特珠单抗，阿特珠单抗包括Tecentriq TM其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中，阿特珠单抗施用的剂量为约60mg至1200mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，阿特珠单抗施用的剂量为约1200mg每3周给药一次。 In some embodiments, the other therapeutic agent is atezolizumab, which includes Tecentriq ™ , its biosimilar, or ADCC effect-enhancing mAb or defucosylated mAb. In some embodiments, atezolizumab is administered at a dose of about 60 mg to 1200 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, atezolizumab is administered at a dose of about 1200 mg administered every 3 weeks.
在一些实施方案中，每次施用的阿特珠单抗为约1mg/kg至20mg/kg或含此剂量阿特珠单抗的制剂。在一些实施方案中，每次施用的阿特珠单抗为约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约9mg/kg，约12mg/kg，约15mg/kg，约18mg/kg，约20mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量阿特珠单抗的制剂。In some embodiments, each administration of atezolizumab is about 1 mg/kg to 20 mg/kg or a formulation containing such doses of atezolizumab. In some embodiments, the atezolizumab 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 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 a range (including endpoints) between any two of these values, or any value therein, or a formulation containing atezolizumab at this dose.
在一些实施方案中，所述另一种治疗剂为Durvalumab，包括IMFINZI TM，其生物类似物，或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中，Durvalumab施用的剂量为约60mg至900mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，Durvalumab施用的剂量为约5mg/kg到15mg/kg每2周或每3周给药一次。在一些实施方案中，Durvalumab施用的剂量为约10mg/kg每2周给药一次。 In some embodiments, the other therapeutic agent is Durvalumab, including IMFINZI ™ , a biosimilar thereof, or an ADCC effect-enhancing mAb or a defucosylated mAb. In some embodiments, Durvalumab is administered at a dose of about 60 mg to 900 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, Durvalumab is administered at a dose of about 5 mg/kg to 15 mg/kg administered every 2 weeks or every 3 weeks. In some embodiments, Durvalumab is administered at a dose of about 10 mg/kg administered every 2 weeks.
在一些实施方案中，每次施用的Durvalumab为约1mg/kg至10mg/kg或含此剂量Durvalumab的制剂。在一些实施方案中，每次施用的Durvalumab为约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约9mg/kg，约10mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量Durvalumab的制剂。In some embodiments, the Durvalumab per administration is about 1 mg/kg to 10 mg/kg or a formulation containing such dose of Durvalumab. In some embodiments, the Durvalumab 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 6 mg/kg, about 9 mg/kg, about 10 mg/kg, or a range (including endpoints) between any two of these values or in which any value, or formulation containing this dose of Durvalumab.
在一些实施方案中，采用治疗有效量的抗PD-L1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。抗PD-L1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, therapeutically effective amounts of the anti-PD-L1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously. The period of administration of the anti-PD-L1 antibody or antigen-binding fragment and the anti-TIGIT antibody or antigen-binding fragment may be the same or different.
在一些实施方案中，所述另一种治疗剂为与表皮生长因子受体2(HER2)的细胞外二聚化结构域(亚结构域II)发生特异性结合的单克隆抗体(抗HER2抗体)，如帕妥珠单抗。帕妥珠单抗可以通过基因工程在细胞(如CHO)中表达，并通过纯化获 得。In some embodiments, the other therapeutic agent is a monoclonal antibody (anti-HER2 antibody) that specifically binds to the extracellular dimerization domain (subdomain II) of epidermal growth factor receptor 2 (HER2). ), such as Pertuzumab. Pertuzumab can be expressed in cells (such as CHO) by genetic engineering and obtained by purification.
在一些实施方案中，所述另一种治疗剂为帕妥珠单抗，帕妥珠单抗包括perjeta TM或其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中，帕妥珠单抗施用的剂量为约40mg至900mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，帕妥珠单抗施用的剂量为约初始840mg，之后420mg每3周给药一次。 In some embodiments, the other therapeutic agent is pertuzumab, which includes perjeta ™ or a biosimilar thereof or an ADCC effect-enhancing mAb or a defucosylated mAb. In some embodiments, the dose of Pertuzumab administered is about 40 mg to 900 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, Pertuzumab is administered at a dose of about 840 mg initially, followed by 420 mg administered every 3 weeks.
在一些实施方案中，每次施用的帕妥珠单抗为约1mg/kg至12mg/kg或含此剂量帕妥珠单抗的制剂。在一些实施方案中，每次施用的帕妥珠单抗为约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约6.9mg/kg，约7mg/kg，约8.4mg/kg，约9mg/kg，约11mg/kg，约12mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量帕妥珠单抗的制剂。In some embodiments, the Pertuzumab per administration is about 1 mg/kg to 12 mg/kg or a formulation containing this dose of Pertuzumab. In some embodiments, the Pertuzumab 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 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 11mg /kg, about 12 mg/kg, or a range between any two of these values (including the endpoints) or any value therein, or a formulation containing Pertuzumab at this dose.
在一些实施方案中，采用治疗有效量的帕妥珠单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。帕妥珠单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, therapeutically effective amounts of Pertuzumab and the anti-TIGIT antibody or antigen-binding fragment are administered to the patient separately or simultaneously. The period of administration of Pertuzumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
在一些实施方案中，所述另一种治疗剂是一种重组人源化免疫球蛋白G1(IgG1)单克隆抗体，可以结合VEGF-A，抑制其与VEGF受体-2(VEGFR-2)结合(抗VEGF抗体)，如贝伐珠单抗。贝伐珠单抗可以通过基因工程在细胞(如CHO)中表达，并通过纯化获得。In some embodiments, the other therapeutic agent is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds VEGF-A and inhibits its interaction with VEGF receptor-2 (VEGFR-2) Binding (anti-VEGF antibody) such as bevacizumab. Bevacizumab can be expressed in cells (eg, CHO) by genetic engineering and obtained by purification.
在一些实施方案中，所述另一种治疗剂为贝伐珠单抗，贝伐珠单抗包括Avastin TM或其生物类似物，如
Figure PCTCN2022078682-appb-000005
或BAT1706(或称
Figure PCTCN2022078682-appb-000006
Figure PCTCN2022078682-appb-000007
或
Figure PCTCN2022078682-appb-000008
)，或ADCC效应增强单抗或去岩藻糖基化单抗。 In some embodiments, the other therapeutic agent is bevacizumab, and bevacizumab includes Avastin ™ or a biosimilar thereof, such as
Figure PCTCN2022078682-appb-000005
or BAT1706 (or
Figure PCTCN2022078682-appb-000006
Figure PCTCN2022078682-appb-000007
or
Figure PCTCN2022078682-appb-000008
), or ADCC effect-enhancing mAb or defucosylated mAb.
在一些实施方案中，贝伐珠单抗施用的剂量为约50mg至400mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，贝伐珠单抗施用的剂量为约5mg/kg到15mg/kg每2周或每3周给药一次。在一些实施方案中，贝伐珠单抗施用的剂量为约5mg/kg，7.5mg/kg，10mg/kg，或15mg/kg每2周或每3周给药一次。在一些实施方案中，贝伐珠单抗施用的剂量为约5mg/kg每2周给药一次，10mg/kg每2周给药一次，7.5mg/kg每3周给药一次，15mg/kg每3周给药一次。In some embodiments, the dose of bevacizumab administered is about 50 mg to 400 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, bevacizumab is administered at a dose of about 5 mg/kg to 15 mg/kg administered every 2 weeks or every 3 weeks. In some embodiments, bevacizumab is administered at a dose of about 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg administered every 2 weeks or every 3 weeks. In some embodiments, bevacizumab is administered at a dose of about 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks, 15 mg/kg Dosing every 3 weeks.
在一些实施方案中，每次施用的贝伐珠单抗为约1mg/kg至9mg/kg或含此剂量贝伐珠单抗的制剂。在一些实施方案中，每次施用的贝伐珠单抗为约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约6.9mg/kg，约7mg/kg，约8.4mg/kg，约9 mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量贝伐珠单抗的制剂。In some embodiments, the bevacizumab per administration is about 1 mg/kg to 9 mg/kg or a formulation containing bevacizumab at this dose. In some embodiments, the bevacizumab 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 6 mg/kg, about 6.9 mg/kg, about 7 mg/kg, about 8.4 mg/kg, about 9 mg/kg, or A range (including endpoints) between any two of these values, or any value therein, or a formulation containing bevacizumab at this dose.
在一些实施方案中，采用治疗有效量的贝伐珠单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。贝伐珠单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, a therapeutically effective amount of bevacizumab and an anti-TIGIT antibody or antigen-binding fragment is administered to the patient separately or simultaneously. The period of administration of bevacizumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
在一些实施方案中，所述另一种治疗剂为是靶向CD20的抗体(抗CD20抗体)，如奥法木单抗，或obinutuzumab。奥法木单抗及obinutuzumab可以通过基因工程在细胞(如CHO)中表达，并通过纯化获得。In some embodiments, the other therapeutic agent is an antibody that targets CD20 (anti-CD20 antibody), such as ofatumumab, or obinutuzumab. Ofatumumab and obinutuzumab can be expressed in cells (such as CHO) through genetic engineering and obtained through purification.
在一些实施方案中，所述另一种治疗剂为奥法木单抗，奥法木单抗包括Arzerra TM或
Figure PCTCN2022078682-appb-000009
其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗，如CN109096399A公开的BAT4406F。在一些实施方案中，奥法木单抗施用的剂量为约10mg至2000mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，奥法木单抗施用的剂量为约20mg每周或每月给药一次。在一些实施方案中，奥法木单抗施用的剂量为约初始300mg，1周后1000mg，之后1000mg每4周或每8周给药一次。在一些实施方案中，奥法木单抗施用的剂量为约初始300mg，1周后2000mg，之后2000mg每1周或每4周给药一次。 In some embodiments, the other therapeutic agent is ofatumumab, and ofatumumab comprises Arzerra ™ or
Figure PCTCN2022078682-appb-000009
Its biosimilar or ADCC effect-enhancing monoclonal antibody or defucosylated monoclonal antibody, such as BAT4406F disclosed in CN109096399A. In some embodiments, ofatumumab is administered at a dose of about 10 mg to 2000 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, ofatumumab is administered at a dose of about 20 mg administered weekly or monthly. In some embodiments, ofatumumab is administered at a dose of about 300 mg initially, 1000 mg after 1 week, and then 1000 mg administered every 4 weeks or every 8 weeks. In some embodiments, ofatumumab is administered at a dose of about 300 mg initially, 2000 mg after 1 week, and then 2000 mg administered every 1 week or every 4 weeks.
在一些实施方案中，每次施用的奥法木单抗为约0.5mg/kg至18mg/kg或含此剂量奥法木单抗的制剂。在一些实施方案中，每次施用的奥法木单抗为约0.5mg/kg，约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约6.9mg/kg，约7mg/kg，约8.4mg/kg，约9mg/kg，约11mg/kg，约13mg/kg，约14mg/kg，约15mg/kg，约17mg/kg，约18mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量奥法木单抗的制剂。In some embodiments, ofatumumab per administration is about 0.5 mg/kg to 18 mg/kg or a formulation containing such dose of ofatumumab. In some embodiments, 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 a range between any two of these values (including endpoints) or any of these values, or a formulation containing this dose of ofatumumab.
在一些实施方案中，采用治疗有效量的奥法木单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。奥法木单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, a therapeutically effective amount of ofatumumab and an anti-TIGIT antibody or antigen-binding fragment is administered to a patient separately or simultaneously. The period of administration of ofatumumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
在一些实施方案中，所述另一种治疗剂为obinutuzumab，包括
Figure PCTCN2022078682-appb-000010
其生物类似物，或ADCC效应增强单抗或去岩藻糖基化单抗，如CN109096399A所述BAT4306F。在一些实施方案中，obinutuzumab施用的剂量为约10mg至2000mg每个治疗周期。在一些实施方案中，一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，obinutuzumab施用的剂量为第1天100mg，第2天900mg，第8天、第15天1,000mg，之后1,000mg每疗程。在一些实施方案中，obinutuzumab施 用的有效量为第1天、第8天、第15天各1,000mg，之后1,000mg每疗程。每疗程可以是1个月或2个月。 In some embodiments, the other therapeutic agent is obinutuzumab, comprising
Figure PCTCN2022078682-appb-000010
Its biosimilar, or ADCC effect-enhancing monoclonal antibody or defucosylated monoclonal antibody, such as BAT4306F described in CN109096399A. In some embodiments, the dose of obinutuzumab administered is about 10 mg to 2000 mg per treatment cycle. In some embodiments, 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 of its values. In some embodiments, obinutuzumab is administered at a dose of 100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8, 15, and 1,000 mg per course thereafter. In some embodiments, the effective amount of obinutuzumab administered is 1,000 mg each on day 1, day 8, day 15, and then 1,000 mg per course of treatment thereafter. Each course of treatment can be 1 month or 2 months.
在一些实施方案中，每次施用的obinutuzumab为约0.5mg/kg至15mg/kg或含此剂量obinutuzumab的制剂。在一些实施方案中，每次施用的obinutuzumab为约0.5mg/kg，约1mg/kg，约1.2mg/kg，约2mg/kg，约2.4mg/kg，约3mg/kg，约3.6mg/kg，约4mg/kg，约4.8mg/kg，约5mg/kg，约5.5mg/kg，约6mg/kg，约6.9mg/kg，约7mg/kg，约8.4mg/kg，约9mg/kg，约11mg/kg，约13mg/kg，约14mg/kg，约15mg/kg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量obinutuzumab的制剂。In some embodiments, the obinutuzumab per administration is about 0.5 mg/kg to 15 mg/kg or a formulation containing such dose of obinutuzumab. In some embodiments, the obinutuzumab 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 per administration , 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 11 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, or a range between any two of these values (including endpoints) or any value therein, or a formulation containing obinutuzumab at this dose.
在一些实施方案中，采用治疗有效量的obinutuzumab和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。obinutuzumab和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。In some embodiments, a therapeutically effective amount of obinutuzumab and an anti-TIGIT antibody or antigen-binding fragment is administered to the patient separately or simultaneously. The period of administration of obinutuzumab and the anti-TIGIT antibody or antigen-binding fragment can be the same or different.
在一些实施方案中，所述另一种治疗剂为抗HER2抗体药物偶联物(HER2-ADC)或抗Trop2抗体药物偶联物(Trop2-ADC)，例如ado-trastuzumab emtansine(T-DM1),trastuzumab deruxtecan(DS-8201)，CN103333246B及CN109078181A所述抗体药物偶联物。In some embodiments, the other therapeutic agent is an anti-HER2 antibody drug conjugate (HER2-ADC) or an anti-Trop2 antibody drug conjugate (Trop2-ADC), eg, ado-trastuzumab emtansine (T-DM1) , trastuzumab deruxtecan (DS-8201), the antibody drug conjugate described in CN103333246B and CN109078181A.
在一些实施方案中，本发明公开了一种治疗肿瘤或癌症的方法，其包括向有需要的患者施用有效量的抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)。在一些实施方案中，抗TIGIT抗体或抗原结合片段以约0.05mg至1200mg的剂量施用。在一些实施方案中，抗TIGIT抗体或抗原结合片段的有效量为单次给药约9mg至1200mg(或含此剂量抗TIGIT抗体的制剂)。在一些实施方案中，另一种治疗剂为抗PD-1抗体或抗原结合片段。在一些实施方案中，所述抗PD-1抗体包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。在一些实施方案中，所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。在一些实施方案中，所述抗PD-1抗体的重链包含如SEQ ID NO:19所示的氨基酸序列，抗PD-1抗体的轻链包含如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中，抗PD-1抗体或抗原结合片段的有效量为单次给药约1mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。剂量时间表和给药方式取决于某些患者群中的抗PD-1抗体或抗原结合片段(或制剂)、抗TIGIT抗体或抗原结合片段(或 制剂)的获益风险评估和一般临床实践指南。In some embodiments, 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-TIGIT antibody or antigen-binding fragment (or formulation) and another therapeutic agent (or formulation) ). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg. In some embodiments, the effective amount of the anti-TIGIT antibody or antigen-binding fragment is about 9 mg to 1200 mg (or a formulation containing such a dose of the anti-TIGIT antibody) in a single administration. In some embodiments, the other therapeutic agent is an anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the anti-PD-1 antibody comprises HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, HCDR3 shown in SEQ ID NO:23, HCDR3 shown in SEQ ID NO:24 LCDR1 shown in SEQ ID NO: 25, LCDR2 shown in SEQ ID NO: 25, and LCDR3 shown in SEQ ID NO: 26. In some embodiments, the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO:27, or has at least 80 Å compared to the sequence set forth in SEQ ID NO:27 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared with the sequence shown in SEQ ID NO: 27; and/or the light chain variable of the anti-PD-1 antibody or antigen-binding fragment The region comprises the amino acid sequence shown in SEQ ID NO: 28, or an amino acid sequence that is at least 80% identical to the sequence shown in SEQ ID NO: 28, or has one or more identities compared to the sequence shown in SEQ ID NO: 28. Amino acid sequence of multiple conservative amino acid substitutions. In some embodiments, the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:19 and the light chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO:20. In some embodiments, the effective amount of the anti-PD-1 antibody or antigen-binding fragment is about 1 mg to 600 mg (or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment) in a single administration. Dosage schedule and mode of administration depend on benefit-risk assessment of anti-PD-1 antibody or antigen-binding fragment (or preparation), anti-TIGIT antibody or antigen-binding fragment (or preparation) in certain patient populations and general clinical practice guidelines .
在一些实施方案中，患者每个治疗周期内抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为约0.05mg至1200mg(或含此剂量抗TIGIT抗体或抗原结合片段的制剂)，患者每个治疗周期内抗PD-1抗体或抗原结合片段施用的剂量为约1mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.05 mg to 1200 mg per treatment cycle (or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment) , the dose of anti-PD-1 antibody or antigen-binding fragment administered to patients per treatment cycle is about 1 mg to 600 mg (or a preparation containing this dose of anti-PD-1 antibody or antigen-binding fragment).
在一些实施方案中，患者每个治疗周期内抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为约9mg至1200mg(或含此剂量抗TIGIT抗体或抗原结合片段的制剂)，患者每个治疗周期内抗PD-1抗体或抗原结合片段施用的剂量为约50mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。In some embodiments, the patient is administered an anti-TIGIT antibody (e.g., antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 9 mg to 1200 mg (or a formulation containing such a dose of anti-TIGIT antibody or antigen-binding fragment) per treatment cycle, The dose of anti-PD-1 antibody or antigen-binding fragment administered to a patient per treatment cycle is about 50 mg to 600 mg (or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment).
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量是约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约12mg、约20mg、约30mg、约50mg、约60mg、约80mg、约100mg、约120mg、约200mg、约250mg、约290mg、约300mg、约330mg、约380mg、约400mg、约434mg、约480mg、约500mg、约567mg、约580mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中，一个治疗周期为1周至7周给药一次。在一些实施方案中，每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量是约0.05mg至1200mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约1mg至30mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量是9mg至100mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约100mg至约300mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、或约4周。在一些 实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约300mg至约600mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约600mg至约900mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约50mg、约74mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约260mg、约300mg、约350mg、约400mg、约430mg、约460mg、约520mg、约600mg、约900mg，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, About 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg , about 10 mg, about 12 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 80 mg, about 100 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, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or a range between any two of these values (including the endpoints) ) or any value therein, or a formulation containing this dose of anti-TIGIT antibody or antigen-binding fragment. In some embodiments, one treatment cycle is administered once every 1 week to 7 weeks. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment administered per treatment cycle is about 0.05 mg to 1200 mg, or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one 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. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 1 mg to 30 mg per treatment cycle, or a formulation containing such dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one 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. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment administered in each treatment cycle is 9 mg to 100 mg, or a formulation containing such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one 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. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 100 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 300 mg to about 600 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 600 mg to about 900 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the dose of the anti-TIGIT antibody or antigen-binding fragment administered to the patient per treatment cycle is about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 50 mg, about 74 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 350 mg, about 400 mg, about 430 mg, about 460 mg, about 520 mg, about 600 mg, about 900 mg, or any two of these values A range between values (including endpoints) or any value therein, or a formulation comprising such dose of anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约0.8mg至2mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约1mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约1mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 0.8 mg to 2 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; For example, about 1 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 1 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约2mg至5mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约3mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约3mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 2 mg to 5 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 3 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 3 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约7mg至20mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约10mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约10mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 7 mg to 20 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 10 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 10 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约23mg至50mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约30mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约30mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4 周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 23 mg to 50 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 30 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 30 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约75mg至150mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约100mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约100mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 75 mg to 150 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 100 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 100 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约167mg至250mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约200mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约200mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 167 mg to 250 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 200 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 200 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约267mg至354mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约300mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约300mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 267 mg to 354 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 300 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 300 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约347mg至430mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约400mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约400mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 347 mg to 430 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 400 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 400 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约557mg至650mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约600mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约600mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 557 mg to 650 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 600 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 600 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约877mg至950mg，或含此剂量抗TIGIT抗体或抗原结合片段的制剂；比如约900mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约900mg，或含此剂量抗 TIGIT抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment at a dose of about 877 mg to 950 mg per treatment cycle, or a formulation containing such a dose of an anti-TIGIT antibody or antigen-binding fragment; such as About 900 mg is administered once. In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment at a dose of about 900 mg per treatment cycle, or a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; wherein one treatment cycle is about 1 week, About 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约0.05mg至1200mg每3周给药一次。在一些实施方案中，抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约1mg至900mg每3周给药一次。在一些实施方案中，抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约10mg至900mg每3周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段的剂量为约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg或约900mg每3周给药一次。在一些实施方案中，抗TIGIT抗体或抗原结合片段的剂量为约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约300mg、约600mg或约900mg每3周给药一次。In some embodiments, the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 0.05 mg to 1200 mg administered once every 3 weeks. In some embodiments, the dose of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 1 mg to 900 mg administered every 3 weeks. In some embodiments, the dose of anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment is about 10 mg to 900 mg administered once every 3 weeks. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, About 600 mg, about 700 mg, about 800 mg, or about 900 mg are administered every 3 weeks. In some embodiments, the dose of anti-TIGIT antibody or antigen-binding fragment is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 30 mg, about 100 mg, about 300 mg, about 600 mg, or about 900 mg are administered every 3 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约80mg、约120mg、约200mg、约250mg、约290mg、约300mg、约330mg、约380mg、约400mg、约434mg、约480mg、约500mg、约567mg、约580mg、约600mg，或这些数值中任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中，一个治疗周期为1周至7周给药一次。在一些实施方案中，每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是15mg至35mg、10mg至50mg、10mg至100mg、1mg至100mg、50mg至600mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是10mg至200mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg至约300mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1 周、约2周、约3周、或约4周。在一些实施方案中，每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是100mg至200mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中，一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约200mg至约300mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约80mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the dose of the anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 33 mg, about 40 mg, 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 any of these values A range between, inclusive of the endpoints, or any value therein, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment. In some embodiments, one treatment cycle is administered once every 1 week to 7 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment administered per treatment cycle is 15 mg to 35 mg, 10 mg to 50 mg, 10 mg to 100 mg, 1 mg to 100 mg, 50 mg to 600 mg, or containing such dose of anti-PD -1 A preparation of an antibody or antigen-binding fragment; wherein one 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 any of these values A range between two values (including the endpoints) or any value within it. In some embodiments, one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment administered in each treatment cycle is 10 mg to 200 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one 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. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 10 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one of The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment administered in each treatment cycle is 100 mg to 200 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one 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. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 200 mg to about 300 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one of The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 33 mg, about 40 mg, about 50 mg, about 60 mg, about 80 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, or a range between any two of these values (including endpoints) or any value therein, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; wherein one The treatment period is about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg至20mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约16mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约16mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 10 mg to 20 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; such as about 16 mg given medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 16 mg per treatment cycle, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约20mg至45mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约33mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约33mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 20 mg to 45 mg per treatment cycle, or a formulation containing such a dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 33 mg administered medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 33 mg per treatment cycle, or a formulation containing this dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约45mg至80mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约50mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约50mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 45 mg to 80 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 50 mg given medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 50 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约87mg至130mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约100mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约100mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 87 mg to 130 mg per treatment cycle, or a formulation containing such a dose of an anti-PD-1 antibody or antigen-binding fragment; such as about 100 mg administered medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 100 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约180mg至230mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约200mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约200mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 180 mg to 230 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 200 mg given medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 200 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约267mg至343mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约300mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约300mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 267 mg to 343 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 300 mg given medicine once. In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 300 mg per treatment cycle, or a formulation containing this dose of the anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约300mg至700mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；比如约600mg给药一次。在一些实施方案中，患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约600mg，或含此剂量抗PD-1抗体或抗原结合片段的制剂；其中，一个治疗周期为约1周、约2周、约3周或约4周。In some embodiments, the patient is administered an anti-PD-1 antibody or antigen-binding fragment at a dose of about 300 mg to 700 mg per treatment cycle, or a formulation containing such dose of the anti-PD-1 antibody or antigen-binding fragment; such as about 600 mg given medicine once. In some embodiments, the dose of anti-PD-1 antibody or antigen-binding fragment administered to the patient per treatment cycle is about 600 mg, or a formulation containing such dose of anti-PD-1 antibody or antigen-binding fragment; wherein one treatment cycle is About 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.
在一些实施方案中，患者每个治疗周期内分别给药一次抗TIGIT抗体或抗原结合片段和另一种治疗剂(或给药一次抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)。在一些实施方案中，每个治疗周期内多次分别给药抗TIGIT抗体或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)，例如2次、3次、4次或5次。在一些实施方案中，患者每个治疗周期只能给药一次或四次。In some embodiments, the patient is administered an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent (or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent once per treatment cycle) ). In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent (or a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent) are administered separately multiple times per treatment cycle, eg 2, 3, 4 or 5 times. In some embodiments, the patient is only dosed once or four times per treatment cycle.
在一些实施方案中，患者接受一个治疗周期治疗。在一些实施方案中，患者接受多个(例如2个、3个或4个)治疗周期治疗。在一些实施方案中，患者接受治疗直至病症得到缓解而不再需要治疗。In some embodiments, the patient is treated with one treatment cycle. In some embodiments, the patient is treated with multiple (eg, 2, 3, or 4) treatment cycles. In some embodiments, the patient receives treatment until the condition resolves and no longer requires treatment.
在一些实施方案中，本发明公开了一种用于治疗肿瘤或癌症的方法，所述方法包括：向有需要的患者给予约0.05mg至10mg、约10mg至100mg、约100mg至300mg、约300mg至600mg或约600mg至1200mg，比如约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约20mg、约30mg、约100mg、约120mg、约200mg、约300mg、约600mg或约900mg的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段，含此剂量抗TIGIT抗体或抗原结合片段的制剂；还向有需要的患者给予约1mg至10mg、约10mg至50mg、约50mg至100mg、约100mg至200mg、约200mg至400mg或约400mg至600mg，比如约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、 约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约120mg、约150mg、约200mg或约250mg的抗PD-1抗体或抗原结合片段，含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中，患者接受单剂量抗TIGIT抗体或抗原结合片段的治疗，以及单剂量抗PD-1抗体或抗原结合片段的治疗。在一些实施方案中，患者接受单剂量抗TIGIT抗体或抗原结合片段和抗PD-1抗体或抗原结合片段组合物的治疗。In some embodiments, the present invention discloses a method for treating a tumor or cancer, the method comprising: administering to a patient in need thereof about 0.05 mg to 10 mg, about 10 mg to 100 mg, about 100 mg to 300 mg, about 300 mg to 600 mg or about 600 mg to 1200 mg, such as about 0.05 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 100 mg, about 120 mg, about 200 mg, about 300 mg , about 600 mg or about 900 mg of an anti-TIGIT antibody (e.g., antibody h10D8OF or h10D8OFKF) or antigen-binding fragment, a formulation containing this dose of an anti-TIGIT antibody or antigen-binding fragment; also administer about 1 mg to 10 mg, about 10 mg to about 10 mg to a patient in need thereof 50 mg, 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, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 33 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg , about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg or about 250 mg of an anti-PD-1 antibody or antigen-binding fragment, a preparation containing this dose of the anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the patient is treated with a single dose of an anti-TIGIT antibody or antigen-binding fragment, and a single dose of an anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the patient is treated with a single dose of a combination of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
在一些实施方案中，每3周一次给药抗TIGIT抗体或抗原结合片段和抗PD-1抗体或抗原结合片段。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment are administered every 3 weeks.
在一些实施方案中，单剂量给药后，患者的症状得到缓解。在一些实施方案中，单剂量给药后，患者后的症状未得到预期缓解，再对患者分别给药约0.05mg至1200mg抗TIGIT抗体或抗原结合片段和约1mg至600mg抗PD-1抗体或抗原结合片段。在一些实施方案中，单剂量给药后，患者的症状得到缓解。在一些实施方案中，单剂量给药后，患者后的症状未得到预期缓解，再对患者分别给药约9mg至1200mg抗TIGIT抗体或抗原结合片段和约50mg至600mg抗PD-1抗体或抗原结合片段。In some embodiments, the patient's symptoms are relieved after a single dose is administered. In some embodiments, after a single dose is administered and the patient's symptoms are not relieved as expected, the patient is administered about 0.05 mg to 1200 mg of anti-TIGIT antibody or antigen-binding fragment and about 1 mg to 600 mg of anti-PD-1 antibody or antigen, respectively Combine fragments. In some embodiments, the patient's symptoms are relieved after a single dose is administered. In some embodiments, after a single dose is administered and the patient's symptoms are not relieved as expected, the patient is administered about 9 mg to 1200 mg of anti-TIGIT antibody or antigen-binding fragment and about 50 mg to 600 mg of anti-PD-1 antibody or antigen-binding fragment, respectively. Fragment.
在一些实施方案中，抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是通过皮下(s.c.)注射、腹膜内(i.p.)注射、肠胃外注射、动脉内注射或静脉内(i.v.)注射等方式进行给药。在一些实施方案中，抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是输液方式进行给药。在一些实施方案中，抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是推注方式进行给药。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, Administration by intra-arterial injection or intravenous (i.v.) injection. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered by infusion. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered as a bolus injection.
在一些实施方案中，抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是通过静脉内(i.v.)输液方式进行给药。在一些实施方案中，静脉内输液持续时间为约50分钟、约55分钟、约60分钟、约65分钟、约70分钟、约75分钟、约81分钟、约87分钟、约90分钟、约95分钟，或这些数值中任何两个值之间的范围(包括端点)或其中任何值。In some embodiments, the anti-TIGIT antibody or antigen-binding fragment (or formulation), anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered by intravenous (i.v.) infusion. In some embodiments, 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 (including the endpoints) between any two of these values, or any value therein.
在一些实施方案中，在抗TIGIT抗体或抗原结合片段(或制剂)给药后，进行抗PD-1抗体或抗原结合片段(或制剂)给药。在一些实施方案中，在抗TIGIT抗体或抗原结合片段(或制剂)给药约15-60分钟(如约30分钟)后进行抗PD-1抗体或抗原结合片段(或制剂)给药。In some embodiments, administration of the anti-PD-1 antibody or antigen-binding fragment (or formulation) occurs after administration of the anti-TIGIT antibody or antigen-binding fragment (or formulation). In some embodiments, administration of the anti-PD-1 antibody or antigen-binding fragment (or formulation) occurs about 15-60 minutes (eg, about 30 minutes) after administration of the anti-TIGIT antibody or antigen-binding fragment (or formulation).
附图说明Description of drawings
图1示抗体抑制肿瘤体生长；其中横坐标表示给药的天数，纵坐标表示肿瘤体积。Figure 1 shows that the antibody inhibits the growth of tumor body; the abscissa represents the days of administration, and the ordinate represents the tumor volume.
图2示抗体小鼠体重的影响；其中横坐标表示给药的天数，纵坐标表示小鼠体重。Figure 2 shows the effect of antibody on the body weight of mice; the abscissa represents the days of administration, and the ordinate represents the weight of mice.
术语the term
除非另作说明，否则下列的每一个术语应当具有下文所述的含义。Unless otherwise specified, each of the following terms shall have the meaning set forth below.
定义definition
应当注意的是，术语“一种”实体是指一种或多种该实体，例如“一种抗体”应当被理解为一种或多种抗体，因此，术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。It should be noted that the term "an" entity refers to one or more of such entities, eg "an antibody" should be understood to mean one or more antibodies, thus the term "an" (or "an" ), "one or more" and "at least one" are used interchangeably herein.
本文所用的术语“包含”或“包括”意味着组合物和方法等包括所列举的元素，例如组份或步骤，但不排除其它。“基本上由……组成”意味着组合物和方法排除对组合的特征有根本影响的其它元素，但不排除对组合物或方法无本质上影响的元素。“由……组成”意味着排除未特别列举的元素。The terms "comprising" or "comprising" as used herein mean that the compositions, methods and the like include the recited elements, such as components or steps, but do not exclude others. "Consisting essentially of" means that the compositions and methods exclude other elements that have an essential effect on the characteristics of the combination, but do not exclude elements that have no essential effect on the compositions or methods. "Consisting of" means excluding elements not specifically recited.
术语“多肽”旨在涵盖单数的“多肽”以及复数的“多肽”，并且是指由通过酰胺键(也称为肽键)线性连接的氨基酸单体构成的分子。术语“多肽”是指两个或更多个氨基酸的任何单条链或多条链，并且不涉及产物的特定长度。因此，“多肽”的定义中包括肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指两个或多个氨基酸链的任何其他术语，并且术语“多肽”可以用来代替上述任何一个术语，或者与上述任何一个术语交替使用。术语“多肽”也意在指多肽表达后修饰的产物，包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割或非天然发生的氨基酸修饰。多肽可以源自天然生物来源或通过重组技术产生，但其不必从指定的核酸序列翻译所得，它可能以包括化学合成的任何方式产生。The term "polypeptide" is intended to encompass the singular "polypeptide" as well as the plural "polypeptide", and refers to a molecule composed of amino acid monomers linked linearly by amide bonds (also known as peptide bonds). The term "polypeptide" refers to any single chain or chains of two or more amino acids, and does not refer to a particular length of the product. Thus, the definition of "polypeptide" includes a peptide, dipeptide, tripeptide, oligopeptide, "protein", "amino acid chain" or any other term used to refer to two or more amino acid chains, and the term "polypeptide" may Used in place of, or used interchangeably with, any of the above terms. The term "polypeptide" is also intended to refer to the product 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-native Amino acid modifications that occur. A polypeptide may be derived from a natural biological source or produced by recombinant techniques, but it need not be translated from a given nucleic acid sequence, and it may be produced by any means including chemical synthesis.
“氨基酸”是指既含氨基又含羧基的有机化合物，比如α-氨基酸，其可直接或以前体的形式由核酸编码。单个氨基酸由三个核苷酸(所谓的密码子或碱基三联体)组成的核酸编码。每一个氨基酸由至少一个密码子编码。相同氨基酸由不同密码子编码称为“遗传密码的简并性”。氨基酸包括天然氨基酸和非天然氨基酸。天然氨基酸包括丙氨酸(三字母代码：ala，一字母代码：A)、精氨酸(arg，R)、天冬酰胺(asn，N)、天冬氨酸(asp，D)、半胱氨酸(cys，C)、谷氨酰胺(gln，Q)、谷氨酸(glu，E)、甘氨酸(gly，G)、组氨酸(his，H)、异亮氨酸(ile，I)、亮氨酸(leu，L)、赖氨酸(lys，K)、甲硫氨酸(met，M)、苯丙氨酸(phe，F)、脯氨酸(pro，P)、丝氨酸(ser，S)、苏氨酸(thr，T)、色氨酸(trp，W)、酪氨酸(tyr，Y)和缬氨酸(val，V)。"Amino acid" refers to an organic compound containing both an amino group and a carboxyl group, such as an alpha-amino acid, which can be encoded by a nucleic acid directly or in a precursor form. 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 same amino acid is encoded by different codons 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).
“保守氨基酸取代”是指一个氨基酸残基被另一个含有化学性质(例如电荷或疏水性)相似的侧链(R基团)的氨基酸残基所取代。一般而言，保守氨基酸取代不大会在实质上改变蛋白质的功能性质。含有化学性质相似侧链的氨基酸类别的实例包括：1)脂族侧链：甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸；2)脂族羟基侧链：丝氨酸和苏氨酸；3)含酰胺的侧链：天冬酰胺和谷氨酰胺；4)芳族侧链：苯丙氨酸、酪氨酸和色氨酸；5)碱性侧链：赖氨酸、精氨酸和组氨酸；6)酸性侧链：天冬氨酸和谷氨酸。"Conservative amino acid substitution" refers to the replacement of one amino acid residue by another amino acid residue containing a side chain (R group) of similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions will not substantially alter the functional properties of the protein. Examples of amino acid classes containing 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.
“VL、VH的保守氨基酸取代”的氨基酸数目可为约1个、约2个、约3个、约4个、约5个、约6个、约8个、约9个、约10个、约11个、约13个、约14个、约15个保守氨基酸取代，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。“重链或轻链的保守氨基酸取代”的氨基酸数目可为约1个、约2个、约3个、约4个、约5个、约6个、约8个、约9个、约10个、约11个、约13个、约14个、约15个、约18个、约19个、约22个、约24个、约25个、约29个、约31个、约35个、约38个、约41个、约45个保守氨基酸取代，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。The number of amino acids for "conservative amino acid substitutions of VL and 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 (including endpoints) between any two of these values, or any value therein. The number of amino acids for a "conservative amino acid substitution of a 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 (including endpoints) between any two of these values, or any value therein.
术语“编码”应用于多聚核苷酸时，是指被称为“编码”多肽的多聚核苷酸，在其天然状态或当通过本领域技术人员公知的方法操作时，经转录和/或翻译可以产生该多肽和/或其片段。The term "encoding" when applied to a polynucleotide refers to a polynucleotide referred to as "encoding" a polypeptide, transcribed and/or in its native state or when manipulated by methods well known to those skilled in the art Or translation can yield the polypeptide and/or fragments thereof.
本发明公开的抗体、抗原结合片段或衍生物包括但不限于多克隆、单克隆、多特异性、全人源、人源化、灵长类化、嵌合抗体、单链抗体、表位结合片段(例如类Fab、类Fab'和类F(ab') 2)、类单链Fvs(scFv)。 Antibodies, antigen-binding fragments or derivatives disclosed herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies, epitope binding Fragments (eg, Fab-like, Fab'-like, and F(ab') 2 ), single-chain-like Fvs (scFv).
术语“重组”涉及多肽或多聚核苷酸，意指天然不存在的多肽或多聚核苷酸的形式，不受限制的实施例可以通过组合产生通常并不存在的多聚核苷酸或多肽。The term "recombinant" refers to a polypeptide or polynucleotide and means a form of the polypeptide or polynucleotide that does not occur in nature, non-limiting examples may be combined to produce polynucleotides that do not normally exist or peptide.
“同源性”或“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。可以通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时，则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。"Homology" or "identity" or "similarity" refers to the sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing the positions within each sequence that can be aligned. A molecule is homologous when a position in the sequences being compared is occupied by the same base or amino acid. The degree of homology between sequences is a function of the number of matches or homologous positions shared by the sequences.
“至少80％同一性”为约80％同一性、约81％同一性、约82％同一性、约83％同一性、约85％同一性、约86％同一性、约87％同一性、约88％同一性、约90％同一性、约91％同一性、约92％同一性、约94％同一性、约95％同一性、约98％同一性、约99％同一性，或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。"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 (including endpoints) between any two values in a numerical value or any value therein.
多聚核苷酸或多聚核苷酸序列(或多肽或抗体序列)与另一序列有具有一定百分比(例如90％、95％、98％或者99％)的“同一性”或“序列同一性”是指当序列比对时，所比较的两个序列中该百分比的碱基(或氨基酸)相同。可以使用目测或本领域已知的软件程序来确定该比对同一性百分比或序列同一性，比如Ausubel et al.eds.(2007)在Current Protocols in Molecular Biology中所述的软件程序。优选使用默认参数进行比对。其中一种比对程序是使用默认参数的BLAST，例如BLASTN和BLASTP，两者使用下列默认参数：Geneticcode＝standard；filter＝none；strand＝both；cutoff＝60；expect＝10；Matrix＝BLOSUM62；Descriptions＝50sequences；sortby＝HIGHSCORE；Databases＝non-redundant；GenBank+EMBL+DDBJ+PDB+GenBankCDStranslations+SwissProtein+SPupdate+PIR。生物学上等同的多聚核苷酸是具有上述指定百分比的同一性并编码具有相同或相似生物学活性的多肽的多聚核苷酸。A polynucleotide or polynucleotide sequence (or polypeptide or antibody sequence) has a certain percentage (eg, 90%, 95%, 98% or 99%) "identity" or "sequence identity" to 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. The percent alignment 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. The default parameters are preferably used for alignment. One such alignment program is BLAST using default parameters, such as BLASTN and BLASTP, both of which use the following default parameters: Geneticcode=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions =50sequences; sortby=HIGHSCORE; Databases=non-redundant; GenBank+EMBL+DDBJ+PDB+GenBankCDStranslations+SwissProtein+SPupdate+PIR. Biologically equivalent polynucleotides are polynucleotides that have the above-specified percentages of identity and encode polypeptides having the same or similar biological activity.
“抗体”、“抗原结合片段”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。抗体和抗原结合片段包括但不局限重链或轻链或其配体结合部分的互补决定区(CDR)、重链可变区(VH)、轻链可变区(VL)、重链恒定区(CH)、轻链恒定区(CL)、框架区(FR)或其任何部分，或结合蛋白的至少一部分。CDR区包括轻链的CDR区(LCDR1-3)和重链的CDR区(HCDR1-3)。"Antibody", "antigen-binding fragment" refers to a polypeptide or polypeptide complex that specifically recognizes and binds 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 in the molecule that contains at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen. Antibodies and antigen-binding fragments include, but are not limited to, the 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), a light chain constant region (CL), a framework region (FR), or any portion thereof, or at least a portion of a binding protein. The CDR regions include the CDR regions of the light chain (LCDR1-3) and the CDR regions of the heavy chain (HCDR1-3).
术语“抗体”包括可以在生物化学上区分的各种广泛种类的多肽。本领域技术人员将会理解，重链的类别包括gamma、mu、alpha、delta或epsilon(γ、μ、α、δ、ε)，其中还有一些亚类(例如γ1-γ4)。该链的性质决定了抗体的“种类”分别为IgG、IgM、IgA、IgG或IgE。免疫球蛋白亚类(同种型)，例如IgG1、IgG2、IgG3、IgG4、IgG5等已被充分表征并且赋予的功能特异性也已知。所有的免疫球蛋白种类都在本发明公开的保护范围内。在一些实施方案中，免疫球蛋白分子为IgG种类。The term "antibody" includes a wide variety of biochemically distinguishable polypeptides. Those of skill in the art will appreciate that classes of heavy chains include gamma, mu, alpha, delta, or epsilon (gamma, mu, alpha, delta, epsilon), with some subclasses (eg, gamma1-gamma4). The nature of this chain determines the "class" of the antibody as IgG, IgM, IgA, IgG or IgE, respectively. Immunoglobulin subclasses (isotypes), eg, IgGl, IgG2, IgG3, IgG4, IgG5, etc., are well characterized and the functional specificities conferred are known. All immunoglobulin species are within the scope of the present disclosure. In some embodiments, the immunoglobulin molecule is of the IgG class.
轻链可以分为kappa(κ)或lambda(λ)。每个重链可以与κ或λ轻链结合。一般来说，当由杂交瘤，B细胞或基因工程宿主细胞生产免疫球蛋白时，其轻链和重链通过共价键结合，两条重链的“尾巴”部分通过共价二硫键或非共价键结合。在重链中，氨基酸序列从Y构型的叉状末端的N末端延伸至每条链底部的C末端。免疫球蛋白κ轻链可变区为Vκ；免疫球蛋白λ轻链可变区为V λ。 Light chains can be classified as kappa (κ) or lambda (λ). Each heavy chain can bind to a kappa or lambda light chain. In general, when 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" portion of the two heavy chains is joined by a covalent disulfide bond or non-covalent bond. In heavy chains, the amino acid sequence extends from the N-terminus of the forked terminus in the Y configuration to the C-terminus at the bottom of each chain. The variable region of immunoglobulin kappa light chain is Vκ; the variable region of immunoglobulin lambda light chain is Vλ.
轻链和重链都分成结构和功能同源性的区域。术语“恒定的”和“可变的”根据功能被使用。轻链可变区(VL)和重链可变区(VH)决定了抗原识别和特异性。轻链恒定区(CL)和重链恒定区(CH)赋予重要的生物学性质，如分泌、经胎盘移动、Fc受体结合、补体结合等。按照惯例，恒定区的编号随着它们变得更远离抗体的抗原结合位点或氨基末端而增加。N端部分是可变区，C端部分是恒定区；CH3和CL结构域实际上分别包含重链和轻链的羧基端。Both light and heavy chains are divided into regions of structural and functional homology. The terms "constant" and "variable" are used according to function. The light chain variable region (VL) and heavy chain variable region (VH) determine antigen recognition and specificity. The light chain constant region (CL) and heavy chain constant region (CH) confer important biological properties such as secretion, transplacental movement, Fc receptor binding, complement fixation, and the like. By convention, the numbering of constant regions increases as they become further from the antigen binding site or amino terminus of the antibody. 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-terminus of the heavy and light chains, respectively.
在本领域中使用和/或接受的术语有两个或多个定义的情况下，除非明确地对立指出，否则本文使用的术语的定义包括所有这些含义。一个具体的例子是使用“互补决定区”(“CDR”)一词来描述在重链和轻链多肽的可变区内发现的非连续的抗原结合位点。这一特定区域在Kabat et al.,U.S.Dept.of Health and Human Services,Sequences of Proteins of Immunological Interest(1983)和Chothia等在J.Mol.Biol.196:901-917(1987)有相关描述，其通过引用全部并入本文。Where there are two or more definitions of a term used and/or accepted in the art, the definition of the term used herein includes all such meanings unless explicitly stated to the contrary. A specific example is the use of the term "complementarity determining region" ("CDR") to describe the non-contiguous antigen binding sites found within the variable regions of heavy and light chain polypeptides. This particular region is described in Kabat et al., U.S. Dept. of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and Chothia et al. in J. Mol. Biol. 196:901-917 (1987), It is hereby incorporated by reference in its entirety.
根据Kabat和Chothia定义的CDR包括相互比较时的氨基酸残基的重叠或子集。尽管如此，应用任一定义来指代抗体或其变体的CDR都在本发明范围内。包含特定CDR的确切残基编号将根据CDR的序列和大小而变化。本领域技术人员通常可以根据抗体的可变区氨基酸序列确定出CDR包含哪些特定的残基。CDRs as defined by Kabat and Chothia include overlaps or subsets of amino acid residues when compared to each other. Nonetheless, it is within the scope of the invention to apply either definition to refer to the CDRs of an antibody or variant thereof. The exact residue numbers encompassing a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can usually determine which specific residues the CDRs contain based on the amino acid sequence of the variable region of the antibody.
Kabat等人还定义了适用于任何抗体的可变区序列的编号系统。本领域普通技术人 员可以不依赖于序列本身以外的其他实验数据将该“Kabat编号”系统应用到任何可变区序列。“Kabat编号”是指由Kabat et al.,U.S.Dept.of Health and Human Services在“Sequence of Proteinsof Immunological Interest”(1983)提出的编号系统。抗体还可以用EU或Chothia编号系统。Kabat et al. also define a numbering system applicable to variable region sequences of any antibody. One of ordinary skill in the art can apply this "Kabat numbering" system to any variable region sequence independent of experimental data other than the sequence itself. "Kabat Numbering" means 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 may also use the EU or Chothia numbering system.
本发明中术语“抗体药物偶联物”或“ADC”是指与一个或多个化学药物(其可以任选地是治疗剂或细胞毒性剂)化学连接的抗体或其抗原结合片段。在一些实施方案中，ADC包括抗体、细胞毒性或治疗药物和使得药物能够与抗体连接或偶联的接头。ADC通常具有与抗体偶联的1、2、3、4、5、6、7、8、9或10个数的药物。可以包括在ADC中的药物有但不限于：有丝分裂抑制剂、抗肿瘤抗生素、免疫调节剂、基因治疗的载体、烷化剂、抗血管生成剂、抗代谢物、含硼试剂、化疗保护剂、激素、抗激素剂、皮质类固醇、光活性治疗剂、寡核苷酸、放射性核素试剂、拓扑异构酶抑制剂、酪氨酸激酶抑制剂和放射致敏剂。在一些实施方案中，包括在ADC中的药物可以是类美登素药物。在一些实施方案中，包括在ADC中的药物可以是如本申请所述的如式Ⅰ所示的化合物或其药学上可接受的盐。在一些实施方案中，在ADC中，抗体通过自身半胱氨酸或疏基化的氨基酸如疏基化赖氨酸，形成二硫键，与药物偶联。The term "antibody drug conjugate" or "ADC" in the present invention refers to an antibody or antigen-binding fragment thereof chemically linked to one or more chemical agents, which may optionally be therapeutic or cytotoxic agents. In some embodiments, the ADC includes an antibody, cytotoxic or therapeutic drug, and a linker that enables the drug to be attached or conjugated to the antibody. ADCs typically have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 number of drugs conjugated to the antibody. Drugs that can be included in ADCs are, but are not limited to: mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, Hormones, antihormones, corticosteroids, photoactive therapeutics, oligonucleotides, radionuclide agents, topoisomerase inhibitors, tyrosine kinase inhibitors and radiosensitizers. In some embodiments, the drug included in the ADC can be a maytansinoid drug. In some embodiments, the drug included in the ADC can be a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, in the ADC, the antibody is conjugated to the drug through self-cysteine or sulfylated amino acids, such as sulfylated lysine, to form a disulfide bond.
“治疗”是指治疗性治疗和预防性或防治性措施，其目的是预防、减缓、改善和停止不良的生理改变或紊乱，例如疾病的进程，包括但不限于以下无论是可检测还是不可检测的结果，症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善或缓和，减轻或消失(无论是部分还是全部)、延长与不接受治疗时预期的生存期限等。需要治疗的患者包括已经患有病症或紊乱的患者，容易患有病症或紊乱的患者，或者需要预防该病症或紊乱的患者，可以或预期从施用本发明公开的抗体或组合物用于检测、诊断过程和/或治疗中受益的患者。"Treatment" means therapeutic treatment and prophylactic or prophylactic measures, the purpose of which is to prevent, slow, ameliorate and stop adverse physiological changes or disorders, such as the progression of disease, including but not limited to the following whether detectable or undetectable As a result, alleviation of symptoms, reduction of disease severity, stabilization of disease state (ie, no worsening), delay or slowdown of disease progression, improvement or alleviation of disease state, alleviation or disappearance (whether in part or in whole), prolongation and Expected duration of survival when not receiving treatment, etc. A patient in need of treatment includes a patient already suffering from a condition or disorder, a patient susceptible to a condition or disorder, or a patient in need of prevention of such a condition or disorder, may or may be expected from administration of the antibodies or compositions disclosed herein for detection, Patients who benefit from the diagnostic process and/or treatment.
“患者”指需要诊断、预后或治疗的任何哺乳动物，包括人类、狗、猫、豚鼠、兔子、大鼠、小鼠、马、牛等。在一些实施方案中，患者为人。"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.
“约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中，本文中提到“约”指所描述的数值以及其±10％、±5％或±1％的范围。"About" refers to the conventional error range of the corresponding numerical value readily known to those skilled in the relevant art. In some embodiments, references herein to "about" refer to the recited value and ranges of ±10%, ±5%, or ±1% thereof.
“有效量”是指活性化合物或药剂的量，其能引起组织、系统、动物、个体或人类的生物学或医学反应；有效量由研究人员、兽医、医生或其他临床医生寻求的。"Effective amount" refers to the amount of 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.
如本文所用，短语“有需要”是指已将患者鉴定为需要特定方法或治疗。在一些实施例中，可以通过任何诊断方式进行识别。在本文描述的任何方法和治疗中，患者可能需要。As used herein, the phrase "in need" means that a patient has been identified as in need of a particular method or treatment. In some embodiments, identification can be made by any diagnostic means. In any of the methods and treatments described herein, the patient may need.
“联合用药物”包括两种或两种以上药物，所述药物可以分别形成独立的给药单元或共同形成组合的给药单元。在一些实施例中，联合用药物包括分开的抗TIGIT抗体或抗原结合片段和另一种治疗剂。在一些实施例中，联合用药物包括抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物。在一些实施例中，在施用联合用药物时，不 同的药物可以同时或分别给药。"Combination drugs" include two or more drugs, which can each form an independent administration unit or together form a combined administration unit. In some embodiments, the combination drug comprises a separate anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent. In some embodiments, the combination drug comprises a combination of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent. In some embodiments, the different drugs may be administered simultaneously or separately when administering a combination of drugs.
可以按常规方法根据本文所述抗体氨基酸序列设计合成编码抗体的DNA，将其置入表达载体中，然后转染宿主细胞，在培养基中培养被转染的宿主细胞产生单克隆抗体。在一些实施方案中，表达抗体载体包括至少一个启动子元件，抗体编码序列，转录终止信号和polyA尾。其他元件包括增强子，Kozak序列及插入序列两侧RNA剪接的供体和受体位点。可以通过SV40的前期和后期启动子，来自逆转录病毒的长末端重复序列如RSV、HTLV1、HIVI及巨细胞病毒的早期启动子来获得高效的转录，也可应用其它一些细胞的启动子如肌动蛋白启动子。合适的表达载体可包括pIRES1neo，pRetro-Off，pRetro-On，PLXSN，或者pLNCX，pcDNA3.1(+/-)，pcDNA/Zeo(+/-)，pcDNA3.1/Hygro(+/-)，PSVL，PMSG，pRSVcat，pSV2dhfr，pBC12MI和pCS2等。常使用的哺乳动物细胞包括HEK293细胞，Cos1细胞，Cos7细胞，CV1细胞，鼠L细胞和CHO细胞等。Antibody-encoding DNA can be designed and synthesized according to the antibody amino acid sequences described herein by conventional methods, inserted into an expression vector, and then transfected into host cells, and the transfected host cells are cultured in culture to produce monoclonal antibodies. In some embodiments, 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. Efficient transcription can be obtained by the early and late promoters of SV40, long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and the early promoter of cytomegalovirus, and other cellular promoters such as muscle can be used. kinesin 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 HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells and CHO cells.
“IC 50”表示50％抑制浓度，即对指定的生物过程抑制一半时所需的药物或者抑制剂的浓度。 " IC50 " means the 50% inhibitory concentration, that is, the concentration of drug or inhibitor required to inhibit half the indicated biological process.
本文中引用的所有出版物，专利，和专利申请全部内容通过参考并入本文用于所有目的。All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.
具体实施方式Detailed ways
以下通过具体的实施例进一步说明本发明的技术方案，具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。The technical solutions of the present invention are further described below through specific embodiments, which do not represent limitations on the protection scope of the present invention. Some non-essential modifications and adjustments made by others according to the concept of the present invention still belong to the protection scope of the present invention.
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.
实施例1 抗体的制备方法The preparation method of embodiment 1 antibody
根据抗体的重链和轻链氨基酸序列构建重链和轻链的DNA序列，用PCR引物修饰DNA序列的5’端，在轻链和重链DNA序列的5’端添加kozak序列及信号肽DNA序列。构建好的序列再克隆到现有表达载体中，通过测序分析验证重组质粒的正确构建。将上述重组质粒转染表达细胞中进行表达，收集上清液、纯化获得抗体蛋白样品，并用于下面各种实施例。The DNA sequences of the heavy and light chains were constructed according to the amino acid sequences of the heavy and light chains of the antibody, the 5' ends of the DNA sequences were modified with PCR primers, and the kozak sequence and the signal peptide DNA were added to the 5' ends of the light and heavy chain DNA sequences sequence. The constructed sequence was then cloned into the existing expression vector, and the correct construction of the recombinant plasmid was verified by sequencing analysis. The above recombinant plasmid was transfected into expression cells for expression, and the supernatant was collected and purified to obtain antibody protein samples, which were used in the following various examples.
其中，1)抗体h10D8OF制备过程中，采用的表达载体为pCDNA3.1 TM(+)(Invitr ogen公司，货号为V79020)，表达细胞为CHO细胞；2)抗体h10D8OFKF制备过程中，采用的表达载体为pCDNA3.1 TM(+)，表达细胞为α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞，经测试岩藻糖基化水平约为0；3)抗CTLA-4抗体制备过程中，采用的表达载体为pCDNA3.1 TM(+)，表达细胞为α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞，经测试岩藻糖基化水平约为0；4)抗PD-1抗体制备过程中，采用的表达载体 为pCDNA3.1 TM(+)，表达细胞为CHO细胞；5)参照抗体Tiragolumab制备过程中，采用的表达载体为pCDNA3.1 TM(+)，表达细胞为CHO细胞。上述抗体的氨基酸序列见表1-4；其中，抗体h10D8OF和h10D8OFKF的氨基酸序列是相同的。抗体的DNA序列见表5；其中，抗体h10D8OF和h10D8OFKF的DNA序列是相同的。 Among them, 1) in the preparation process of the antibody h10D8OF, the expression vector used is pCDNA3.1 TM (+) (Invitrogen company, the product number is V79020), and the expression cells are CHO cells; 2) in the preparation process of the antibody h10D8OFKF, the expression vector used It is pCDNA3.1 TM (+), the expression cells are CHO cells with α-(1,6)-fucosyltransferase gene knockout, and the fucosylation level is about 0 after testing; 3) Anti-CTLA- 4 In the process of antibody preparation, the expression vector used was pCDNA3.1 TM (+), and the expression cells were α-(1,6)-fucosyltransferase gene knockout CHO cells, which were tested for fucosylation The level is about 0; 4) During the preparation of the anti-PD-1 antibody, the expression vector used was pCDNA3.1 TM (+), and the expression cells were CHO cells; 5) During the preparation of the reference antibody Tiragolumab, the expression vector used was pCDNA3 .1 TM (+), the expressing cells are CHO cells. The amino acid sequences of the above antibodies are shown in Tables 1-4; wherein, the amino acid sequences of the antibodies h10D8OF and h10D8OFKF are the same. The DNA sequences of the antibodies are shown in Table 5; wherein, the DNA sequences of the antibodies h10D8OF and h10D8OFKF are the same.
抗体h10D8OF、抗体h10D8OFKF、抗CTLA-4抗体和抗PD-1抗体的轻链DNA序列的5’端添加的DNA序列均为 gccgccaccatggactttcaggtgcagatcatctccttcctgctgatcagcgcctccgtgatcatgtccaggggc，如SEQ ID NO:35所示，kozak序列用下划线示出，信号肽用斜体示出；抗体h10D8OF、抗体h10D8OFKF、抗CTLA-4抗体和抗PD-1抗体的重链DNA序列的5’端添加的DNA序列均为 gccgccaccatgggctggagcctgatcctgctgttcctggtggccgtggccaccagagtgctgtcc，如SEQ ID NO:36所示，kozak序列用下划线示出，信号肽用斜体示出。参照抗体Tiragolumab的轻链DNA序列的5’端添加的DNA序列为 gccg ccaccatggacatgagggtgctggcccagctgctgggactgctgctgctgtgcttcccaggcgccagatgc，如SEQ ID NO:37所示，kozak序列用下划线示出，信号肽用斜体示出；重链DNA序列的5’端添加的DNA序列为 gccgccaccatggagtttgggctgagctgggttttccttgttgctatattaaaaggtgtccagtgt，如SEQ ID NO:38所示，kozak序列用下划线示出，信号肽用斜体示出。 The DNA sequences added to the 5' ends of the light chain DNA sequences of antibody h10D8OF, antibody h10D8OFKF, anti-CTLA-4 antibody and anti-PD-1 antibody are all gccgccaccatgg actttcaggtgcagatcatctccttcctgctgatcagcgcctccgtgatcatgtccaggggc, as shown in SEQ ID NO: 35, and the kozak sequence is underlined , the signal peptide is shown in italics; the DNA sequences added to the 5' ends of the heavy chain DNA sequences of antibody h10D8OF, antibody h10D8OFKF, anti-CTLA-4 antibody and anti-PD-1 antibody are all gccgccaccatgg gctggagcctgatcctgctgttcctggtggccgtggccaccagagtgctgtcc, as shown in SEQ ID NO:36 shown, the kozak sequence is underlined and the signal peptide is italicized. The DNA sequence added to the 5' end of the light chain DNA sequence of the reference antibody Tiragolumab is gccg ccaccatgg acatgagggtgctggcccagctgctgggactgctgctgctgtgcttcccaggcgccagatgc, as shown in SEQ ID NO: 37, the kozak sequence is underlined, and the signal peptide is shown in italics; The DNA sequence added at the ' end is gccgccaccatgg agtttgggctgagctgggttttccttgttgctatattaaaaggtgtccagtgt, as shown in SEQ ID NO: 38, the kozak sequence is underlined, and the signal peptide is shown in italics.
表1抗体h10D8OF和h10D8OFKF的氨基酸序列Table 1 Amino acid sequences of antibodies h10D8OF and h10D8OFKF
Figure PCTCN2022078682-appb-000011
Figure PCTCN2022078682-appb-000011
Figure PCTCN2022078682-appb-000012
Figure PCTCN2022078682-appb-000012
表2参照抗体Tiragolumab的氨基酸序列Table 2 The amino acid sequence of the reference antibody Tiragolumab
Figure PCTCN2022078682-appb-000013
Figure PCTCN2022078682-appb-000013
表3抗CTLA-4抗体的氨基酸序列Table 3 Amino acid sequences of anti-CTLA-4 antibodies
Figure PCTCN2022078682-appb-000014
Figure PCTCN2022078682-appb-000014
Figure PCTCN2022078682-appb-000015
Figure PCTCN2022078682-appb-000015
表4抗PD-1抗体的氨基酸序列Table 4 Amino acid sequences of anti-PD-1 antibodies
Figure PCTCN2022078682-appb-000016
Figure PCTCN2022078682-appb-000016
Figure PCTCN2022078682-appb-000017
Figure PCTCN2022078682-appb-000017
表5抗体的DNA序列Table 5 DNA sequences of antibodies
Figure PCTCN2022078682-appb-000018
Figure PCTCN2022078682-appb-000018
Figure PCTCN2022078682-appb-000019
Figure PCTCN2022078682-appb-000019
Figure PCTCN2022078682-appb-000020
Figure PCTCN2022078682-appb-000020
Figure PCTCN2022078682-appb-000021
Figure PCTCN2022078682-appb-000021
实施例2 阻断TIGIT与配体PVR结合试验Example 2 Blocking TIGIT and ligand PVR binding test
采用流式细胞术检测抗TIGIT抗体阻断游离的PVR-Fc与TIGIT-Jurkat细胞表面的TIGIT的结合。试验步骤为：取活力良好(细胞活力大于90％)的TIGIT-Jurkat细胞，离心后用PBS重悬为密度1000万/ml，加入到96孔尖底板中，每孔50μl，即每孔细胞数量为50万；取适量的生物素化的PVR-Fc(即PVR-Fc-bio)，用PBS(磷酸缓冲液)进行稀释，配制成PVR-Fc-bio稀释液，终浓度为12.5nM；取适量抗TIGIT抗体或参照抗体Tiragolumab，用PVR-Fc-bio稀释液进行稀释，抗体起始浓度为200nM，2倍梯度稀释，共10个浓度梯度，每个浓度点设3个复孔；2-8℃条件下孵育1个小时，然后用PBS洗涤2次，加入1:1000稀释的荧光二抗Streptavidin-PE(eBioscience，CAT#12-4317-87)稀释液，每孔100μl，2-8℃孵育30min；然后PBS洗涤2次，采用流式分析仪检测荧光强度(Mean PE-A)。The binding of free PVR-Fc to TIGIT on the surface of TIGIT-Jurkat cells was detected by flow cytometry. The test steps are as follows: take TIGIT-Jurkat cells with good viability (cell viability greater than 90%), resuspend them with PBS to a density of 10 million/ml after centrifugation, and add 50 μl per well to a 96-well tip bottom plate, which is the number of cells per well. 500,000; take an appropriate amount of biotinylated PVR-Fc (ie PVR-Fc-bio), dilute it with PBS (phosphate buffered saline), and prepare a PVR-Fc-bio dilution with a final concentration of 12.5nM; Appropriate amount of anti-TIGIT antibody or reference antibody Tiragolumab was diluted with PVR-Fc-bio diluent. The initial concentration of the antibody was 200nM, 2-fold gradient dilution, a total of 10 concentration gradients, and 3 duplicate wells were set for each concentration point; 2- Incubate at 8°C for 1 hour, then wash twice with PBS, add 1:1000 diluted fluorescent secondary antibody Streptavidin-PE (eBioscience, CAT#12-4317-87) dilution, 100μl per well, 2-8°C Incubate for 30 min; then wash with PBS twice, and use a flow analyzer to detect the fluorescence intensity (Mean PE-A).
PVR-Fc-bio的制备方法为：人PVR胞外区的核酸序列添加酶切位点(HindIII和EcoRI)，通过连接子与人IgG1重链恒定区的核酸序列进行融合；融合之后的序列被插入到pCDNA3.1(+)载体中，然后瞬时转染HEK293F细胞；培养完成的细胞上清通过ProteinA亲和层析纯化，纯化得到的融合蛋白命名为PVR-Fc；取适量PVR-Fc蛋白，使用Thermo scientific公司的生物素标记试剂盒(
Figure PCTCN2022078682-appb-000022
HSulfo-NHS-LC-BiotinylationKit，货号：21435)，按照说明书中的操作步骤对PVR-Fc进行生物素化标记，标记后的蛋白命名为PVR-Fc-bio。其中，人PVR胞外区的氨基序列如SEQ ID NO:13所示，连接子的基因序列如SEQ ID NO:14所示，连接子的氨基酸序列如SEQ ID NO:39所示，人IgG1重链恒定区的氨基酸序列如SEQ ID NO:15所示，PVR-Fc的氨基酸序列如SEQ ID NO:40所示(见表6)。 The preparation method of PVR-Fc-bio is as follows: the nucleic acid sequence of the extracellular region of human PVR is added with enzyme cleavage sites (HindIII and EcoRI), and is fused with the nucleic acid sequence of the constant region of the human IgG1 heavy chain through a linker; It was inserted into the pCDNA3.1(+) vector, and then transiently transfected into HEK293F cells; the cultured cell supernatant was purified by ProteinA affinity chromatography, and the purified fusion protein was named PVR-Fc; take an appropriate amount of PVR-Fc protein, Biotin labeling kit from Thermo scientific company (
Figure PCTCN2022078682-appb-000022
HSulfo-NHS-LC-BiotinylationKit, product number: 21435), biotinylated PVR-Fc according to the operation steps in the manual, and the labeled protein was named PVR-Fc-bio. Wherein, the amino sequence of the extracellular region of human PVR is shown in SEQ ID NO: 13, the gene sequence of the linker is shown in SEQ ID NO: 14, the amino acid sequence of the linker is shown in SEQ ID NO: 39, and the human IgG1 heavy The amino acid sequence of the chain constant region is shown in SEQ ID NO: 15, and the amino acid sequence of PVR-Fc is shown in SEQ ID NO: 40 (see Table 6).
TIGIT-Jurkat细胞的制备方法为：用人全长TIGIT基因替换pCMV2-CFD-Flag(义翘神州，货号：HG10160-M-F)上的目的基因得到重组质粒，用限制性内切酶ClaI(Bsu15I)将重组质粒线性化之后采用电穿孔法进行转染Jurkat细胞系(ATCC，Clone  E6-1，TIB-152 TM)。筛选压为潮霉素，得到阳性细胞株再进行亚克隆进而得到可以稳定表达人TIGIT细胞系，即：TIGIT-Jurkat细胞。其中，人全长TIGIT基因的序列如SEQ ID NO:16所示(见表6)。 The preparation method of TIGIT-Jurkat cells is as follows: replace the target gene on pCMV2-CFD-Flag (Yiqiao Shenzhou, item number: HG10160-MF) with the human full-length TIGIT gene to obtain a recombinant plasmid, and use the restriction endonuclease ClaI (Bsu15I) to The recombinant plasmid was linearized and transfected into Jurkat cell line (ATCC, Clone E6-1, TIB-152 ™ ) by electroporation. The screening pressure is hygromycin, and the positive cell line is obtained and then subcloned to obtain a cell line that can stably express human TIGIT, namely: TIGIT-Jurkat cells. Wherein, the sequence of the human full-length TIGIT gene is shown in SEQ ID NO: 16 (see Table 6).
1)在同样条件下，抗体h10D8OF和抗体Tiragolumab均可以有效地阻断TIGIT与PVR-Fc的结合，两者的IC 50值分别为0.4409nM和2.820nM；抗体h10D8OF的阻断能力要优于抗体Tiragolumab。 1) Under the same conditions, both the antibody h10D8OF and the antibody Tiragolumab can effectively block the binding of TIGIT to PVR-Fc, and their IC 50 values are 0.4409nM and 2.820nM respectively; the blocking ability of the antibody h10D8OF is better than that of the antibody Tiragolumab.
2)在同样条件下，抗体h10D8OFKF和抗体Tiragolumab均可以有效地阻断TIGIT与PVR-Fc的结合，两者的IC 50值分别为0.742nM和2.820nM；抗体h10D8OFKF的阻断能力要优于抗体Tiragolumab。 2) Under the same conditions, both the antibody h10D8OFKF and the antibody Tiragolumab can effectively block the binding of TIGIT to PVR-Fc, and their IC 50 values are 0.742nM and 2.820nM respectively; the blocking ability of the antibody h10D8OFKF is better than that of the antibody Tiragolumab.
表6相关序列Table 6 Related sequences
Figure PCTCN2022078682-appb-000023
Figure PCTCN2022078682-appb-000023
Figure PCTCN2022078682-appb-000024
Figure PCTCN2022078682-appb-000024
实施例3 抗体h10D8OFKF体内药效试验Example 3 In vivo efficacy test of antibody h10D8OFKF
人源化小鼠BALB/c-hPD1/hTIGIT(江苏集萃药康生物科技股份有限公司)皮下接种CT26结肠癌肿瘤细胞；接种肿瘤细胞后，当小鼠的平均肿瘤体积为79.65mm 3时，进行分组，每组10只。分组当天定义为D0天，并于D0天、D4天、D7天、D11天、D14天、D18天采用腹腔注射(I.P.)方式进行给药，给药的剂量为10mg/kg或30mg/kg。给药方案见表7。 Humanized mice BALB/c-hPD1/hTIGIT (Jiangsu JiCui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with CT26 colon cancer tumor cells; after inoculation with tumor cells, when the average tumor volume of the mice was 79.65 mm3 , the Group, 10 in each group. The day of grouping was defined as D0 day, and was administered by intraperitoneal injection (IP) on D0 day, D4 day, D7 day, D11 day, D14 day, and D18 day, and the dose was 10 mg/kg or 30 mg/kg. The dosing schedule is shown in Table 7.
表7给药方案Table 7 Dosing schedule
Figure PCTCN2022078682-appb-000025
Figure PCTCN2022078682-appb-000025
细胞接种后，每周常规监测肿瘤对动物正常行为的影响；具体指标包括：小鼠的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。肿瘤体积(mm 3)为0.5×(肿瘤长径×肿瘤短径 2)，各组小鼠的肿瘤体积以平均值±标准误差(mean±SEM)表示。TGItw(肿瘤重量的抑制率)计算公式为： After cell inoculation, the effects of tumor on the normal behavior of animals were routinely monitored weekly; specific indicators included: mouse activity, food and water intake, weight gain or loss, eyes, coat and other abnormalities. The tumor volume (mm 3 ) was 0.5×(longer diameter of tumor×shorter diameter of tumor 2 ), and the tumor volume of mice in each group was expressed as the mean±standard error (mean±SEM). The formula for calculating TGItw (inhibition rate of tumor weight) is:
TGItw＝(1-(mean TW 给药组)/(mean TW 对照组))×100％；Mean TW 给药组：给药组小鼠终点处理时肿瘤重量的平均值，Mean TW 对照组：对照组小鼠终点处理时肿瘤重量的平均值。 TGItw=(1-(mean TW administration group )/(mean TW control group ))×100%; Mean TW administration group : mean tumor weight of mice in administration group at the end point treatment, Mean TW control group : control The mean value of tumor weight at the end point treatment of mice in the group.
1)抗体h10D8OF和抗体Tiragolumab都可以抑制CT26结肠癌增长，并且抗体h10D8OF抑制肿瘤增长的效果优于抗体Tiragolumab；在30mg/kg剂量下，试验终点(D20天)时相对肿瘤抑制率TGItw(％)h10D8OF为92.89％，Tiragolumab为71.07％。1) Both antibody h10D8OF and antibody Tiragolumab can inhibit the growth of CT26 colon cancer, and the effect of antibody h10D8OF in inhibiting tumor growth is better than that of antibody Tiragolumab; at the dose of 30 mg/kg, the relative tumor inhibition rate TGitw (%) at the end of the trial (D20 day) h10D8OF was 92.89% and Tiragolumab was 71.07%.
2)抗体h10D8OFKF和抗体Tiragolumab都可以抑制CT26结肠癌增长，并且抗体h10D8OFKF抑制肿瘤增长的效果优于抗体Tiragolumab。h10D8OFKF在10mg/kg和30mg/kg剂量下以及Tiragolumab在30mg/kg剂量下，试验终点时(D20天)相对肿瘤抑制率TGItw(％)分别为92.39％、95.94％和71.07％。2) Both antibody h10D8OFKF and antibody Tiragolumab can inhibit the growth of CT26 colon cancer, and the effect of antibody h10D8OFKF in inhibiting tumor growth is better than that of antibody Tiragolumab. h10D8OFKF at 10mg/kg and 30mg/kg dose and Tiragolumab at 30mg/kg dose, the relative tumor inhibition rate TGitw (%) at the end of the trial (D20 day) were 92.39%, 95.94% and 71.07%, respectively.
实施例4 抗体h10D8OFKF与抗PD-1抗体联合给药抑制癌细胞的增殖Example 4 Co-administration of antibody h10D8OFKF and anti-PD-1 antibody inhibits the proliferation of cancer cells
本研究评价了测试药物抗体h10D8OFKF和抗PD-1抗体(实施例1制备)在免疫检查点人源化小鼠BALB/c-hPD1/hTIGIT(江苏集萃药康生物科技有限公司)皮下接种CT26.WT结肠癌细胞中的药效。This study evaluated the test drug antibody h10D8OFKF and anti-PD-1 antibody (prepared in Example 1) subcutaneously inoculated with CT26 in immune checkpoint humanized mice BALB/c-hPD1/hTIGIT (Jiangsu JiCui Yaokang Biotechnology Co., Ltd.). Efficacy in WT colon cancer cells.
1)肿瘤细胞接种1) Tumor cell inoculation
小鼠结肠癌细胞复苏，收集对数生长期的细胞，去除培养液并用PBS洗两次后接种，接种量为5×10 6/100μL/只，接种位置为小鼠右后肢。 Mouse colon cancer cells were recovered, cells in logarithmic growth phase were collected, the culture medium was removed, and the cells were washed twice with PBS and then inoculated with an inoculation volume of 5×10 6 /100 μL per mouse. The inoculation site was the right hind limb of the mouse.
2)分组给药2) group administration
等肿瘤体积达到89.19mm 3时，40只小鼠根据肿瘤体积随机分成4组，每组10只。分组当天定义为D0天，并于D0天开始给药；分组给药方案见表8，给药日期为：D0天、D4天、D7天、D11天、D14天、D18天、D21天(G3组在D22天进行给药，G4组在D21天和D22天均进行给药)、D25天。 When the tumor volume reached 89.19 mm 3 , 40 mice were randomly divided into 4 groups according to the tumor volume, with 10 mice in each group. The day of grouping is defined as D0 day, and administration starts on D0 day; the grouping administration schedule is shown in Table 8, and the administration dates are: D0 day, D4 day, D7 day, D11 day, D14 day, D18 day, D21 day (G3 day) The group was administered on D22, and the G4 group was administered on both D21 and D22) and D25.
3)实验观察和数据采集3) Experimental observation and data collection
细胞接种后，每周常规监测肿瘤对动物正常行为的影响。具体指标包括小鼠的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。Following cell inoculation, tumor effects on the animals' normal behavior were routinely monitored weekly. Specific indicators include mouse activity, food and water intake, weight gain or loss, eyes, coat and other abnormalities.
开始给药后，于D0天、D4天、D6天、D8天、D11天、D13天、D15天、D18天、D20天、D22天、D25天、D27天、D29天观测肿瘤大小并称量小鼠体重。肿瘤体积计算方式为：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。 After starting administration, the tumor size was observed and weighed on D0, D4, D6, D8, D11, D13, D15, D18, D20, D22, D25, D27, and D29 days. mouse body weight. The tumor volume was calculated as follows: tumor volume (mm 3 )=0.5×(tumor long diameter×tumor short diameter 2 ).
4)统计4) Statistics
各组小鼠的肿瘤体积、小鼠体重、肿瘤重量等实验结果以平均值±标准误差(mean±SEM)表示。采用独立样本T检验比较不同给药组与对照组相比有无显著性差异。数据采用SPSS进行分析。P<0.05为具有显著性差异。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). The independent sample T test was used to compare whether there were significant differences between the different administration groups and the control group. Data were analyzed using SPSS. P<0.05 means there is a significant difference.
TGItv(相对肿瘤体积的抑制率)计算公式：TGItv (inhibition rate relative to tumor volume) calculation formula:
RTV n＝V nt/V n0；V nt：编号为n的小鼠在第t天的肿瘤体积，V n0：编号为n的小鼠在第0天的肿瘤体积，RTV n：编号为n的小鼠在第t天的肿瘤相对体积 RTVn = Vnt / Vn0 ; Vnt : tumor volume of mouse number n on day t, Vn0 : tumor volume of mouse number n on day 0, RTVn: mouse number n Relative tumor volume in mice on day t
TGItv＝(1-(mean RTV 给药组)/(mean RTV 对照组))×100％；mean RTV 给药组：给药组RTV平均值，mean RTV 对照组：对照组RTV平均值。 TGItv=(1-(mean RTV administration group )/(mean RTV control group ))×100%; mean RTV administration group : average RTV of administration group, mean RTV control group : average RTV of control group.
表8给药方案Table 8 Dosing schedule
Figure PCTCN2022078682-appb-000026
Figure PCTCN2022078682-appb-000026
备注：单药组给药体积：10μL/g(小鼠给药体积＝10μL/g×小鼠体重(g))Remarks: Dosing volume of single drug group: 10 μL/g (dosing volume of mice = 10 μL/g × weight of mice (g))
如图1所示，与对照组相比，单药抗体h10D8OFKF和单药抗PD-1抗体能抑制肿瘤生长，抗体h10D8OFKF和抗PD-1抗体联合给药组有显著的抗肿瘤药效，且抗肿瘤效果优于单药抗体h10D8OFKF和抗PD-1抗体的抗肿瘤效果(G1、G2组未发现小鼠肿瘤完全消退，G3组有2只小鼠的肿瘤完全消退，G4组有1只小鼠的肿瘤完全消退)；与G2和G3单药组相比，G4组肿瘤抑制率(TGItv)明显提高，抗体h10D8OFKF和抗PD-1抗体联合具有协同抗肿瘤作用。如图2所示，各组之间的小鼠体重未发现明显差异，表明小鼠对当前体系中的药物耐受性良好。As shown in Figure 1, compared with the control group, single-drug antibody h10D8OFKF and single-drug anti-PD-1 antibody can inhibit tumor growth, and the combined administration group of antibody h10D8OFKF and anti-PD-1 antibody has significant anti-tumor efficacy, and The anti-tumor effect was better than the anti-tumor effect of single-drug antibody h10D8OFKF and anti-PD-1 antibody (no tumor completely regressed in G1 and G2 groups, 2 mice in G3 group had complete tumor regression, and 1 mouse in G4 group had a small tumor. Compared with the G2 and G3 single drug groups, the tumor inhibition rate (TGItv) of the G4 group was significantly improved, and the combination of the antibody h10D8OFKF and the anti-PD-1 antibody had a synergistic anti-tumor effect. As shown in Figure 2, no significant difference was found in the body weight of the mice between the groups, indicating that the mice tolerated the drugs in the current system well.
实施例5 临床研究Example 5 Clinical study
本研究是一项评价抗体h10D8OFKF注射液单药或联合替雷利珠单抗在晚期恶性实体肿瘤患者中的安全性、耐受性、药代动力学特征和初步临床有效性的多中心、开放的I期临床研究。This study is a multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of antibody h10D8OFKF injection alone or in combination with tislelizumab in patients with advanced malignant solid tumors. Phase I clinical study.
研究分为两部分：The research is divided into two parts:
第一部分：单药剂量递增研究。采用加速滴定和“3+3”的剂量递增规则来探索抗体h10D8OFKF的安全性、耐受性和药代动力学特征。Part I: Single-agent dose escalation studies. The safety, tolerability and pharmacokinetics of the antibody h10D8OFKF were explored using accelerated titration and a "3+3" dose escalation rule.
共设置8个剂量组，分别设置1mg(起始剂量)组、3mg组、10mg组、30mg组、100mg组、300mg组、600mg组以及900mg组。总体分为两个阶段。第一阶段：1mg组、3mg组、10mg组采用加速滴定方法进行剂量递增。第二阶段：30mg组、100mg组、300mg组、600mg组、900mg组按标准“3+3”规则进行剂量递增研究。A total of 8 dose groups were set, including 1mg (initial dose) group, 3mg group, 10mg group, 30mg group, 100mg group, 300mg group, 600mg group and 900mg group. The whole is divided into two stages. The first stage: 1mg group, 3mg group and 10mg group adopt the accelerated titration method for dose escalation. The second stage: 30mg group, 100mg group, 300mg group, 600mg group and 900mg group will conduct a dose escalation study according to the standard "3+3" rule.
第二部分：抗体h10D8OFKF联合替雷利珠单抗联合给药剂量递增研究。研究抗体h10D8OFKF单药或联合替雷利珠单抗的安全性和临床有效性。Part II: Dose escalation study of antibody h10D8OFKF combined with tislelizumab. To study the safety and clinical efficacy of the antibody h10D8OFKF alone or in combination with tislelizumab.
给药方案：Dosing regimen:
抗体h10D8OFKF给药方案：静脉输注给药，建议输注时长≥60分钟，研究用药暂定每3周给药一次(Q3W)。如果患者出现输液相关反应并能够继续治疗，则研究者基于既往经验和临床实际情况可以考虑使用如苯海拉明或对乙酰氨基酚等进行预防给药。如果未观察到输液相关反应，后续的输注时间可由研究者根据临床实际情况酌情调整到30分钟～2小时完成输液均可。Antibody h10D8OFKF dosing regimen: intravenous infusion, the recommended infusion time is ≥ 60 minutes, and the study drug is tentatively scheduled to be administered once every 3 weeks (Q3W). If the patient has an infusion-related reaction and can continue treatment, the investigator may consider the use of diphenhydramine or acetaminophen for prophylaxis based on past experience and clinical reality. If no infusion-related reaction is observed, the subsequent infusion time can be adjusted by the investigator to 30 minutes to 2 hours to complete the infusion according to the actual clinical situation.
替雷利珠单抗给药方案：抗体h10D8OFKF输注完毕30分钟后开始静脉输注给药，建议输注时长30～60分钟，每3周给药一次(Q3W)。详细给药方案参照替雷利珠单抗注射液药品说明书执行。Tislelizumab dosing regimen: The antibody h10D8OFKF is administered intravenously 30 minutes after the completion of the infusion. The recommended infusion time is 30-60 minutes, and it is administered once every 3 weeks (Q3W). For the detailed dosing schedule, refer to the instructions for Tislelizumab injection.
DLT定义：不良事件(AE)将基于CTCAE v5.0进行评估。剂量限制性毒性(DLT)定义为在DLT观察期发生并被认为至少可能与研究药物相关的AE，具体如下：DLT Definitions: Adverse events (AEs) will be assessed based on CTCAE v5.0. A dose-limiting toxicity (DLT) was defined as an AE that occurred during the DLT observation period and was considered at least possibly related to the study drug, as follows:
■5级毒性；■ Grade 5 toxicity;
■血液学毒性：■Hematological toxicity:
·4级贫血；Grade 4 anemia;
·4级血小板减少症持续≥7天；Grade 4 thrombocytopenia lasting ≥7 days;
·伴有出血(≥2级)或需进行血小板输注的3级血小板减少症；Grade 3 thrombocytopenia with bleeding (≥ grade 2) or requiring platelet transfusion;
·4级中性粒细胞减少症≥7天或3级的中性粒细胞减少伴感染≥7天；Grade 4 neutropenia ≥ 7 days or grade 3 neutropenia with infection ≥ 7 days;
·≥3级的中性粒细胞减少伴发热；≥ Grade 3 neutropenia with fever;
■非血液学毒性：■Non-hematological toxicity:
·≥3级非血液学毒性(非单纯实验室检查发现的AE)；≥Grade 3 non-hematological toxicity (AEs not found by laboratory tests alone);
·符合任一以下条件的、因临床实验室检查发现的3、4级非血液学毒性：①需要进行临床干预；②导致住院治疗；③任何导致第2周期给药延迟超过2周的治疗相关毒性；·Grade 3 or 4 non-hematologic toxicities identified by clinical laboratory tests that meet any of the following conditions: ① clinical intervention required; ② result in hospitalization; toxicity;
以下AE不被定义为DLT：The following AEs are not defined as DLTs:
·3级的内分泌毒性经激素替代治疗后可有效控制的；· Grade 3 endocrine toxicity can be effectively controlled by hormone replacement therapy;
·3级的癌性疼痛；Grade 3 cancer pain;
·3级的皮疹；a grade 3 rash;
·3级的输液反应在6小时内经处理能缓解的；· Grade 3 infusion reactions that can be relieved with treatment within 6 hours;
·3级的恶心、呕吐或腹泻经处理或支持治疗后在72小时内下降至≤2级的；· Grade 3 nausea, vomiting or diarrhea decreased to ≤ Grade 2 within 72 hours after management or supportive care;
·3级的疲乏持续≤7天的；·Grade 3 fatigue lasting ≤7 days;
·3级或以上的电解质紊乱在72小时内自行缓解或经处理后缓解的；·The electrolyte disturbance of grade 3 or above resolves spontaneously or after treatment within 72 hours;
MTD定义：MTD被定义为某一剂量组在DLT评估期内观察到≤1/6的受试者中探索到的DLT的最高剂量水平。MTD Definition: MTD was defined as the highest dose level of DLT explored in ≤1/6 subjects in a dose cohort observed during the DLT evaluation period.
耐受性与安全性评价：Tolerability and Safety Evaluation:
耐受性评价指标：剂量限制性毒性(DLT)事件及其发生率。Tolerability evaluation indicators: dose-limiting toxicity (DLT) events and their incidence.
安全性评价指标：生命体征与体格检查、实验室检查(血常规、血生化、甲状腺功能、凝血常规、尿常规、便常规、妊娠试验)、ECOG评分、心电图、不良事件(包括免疫相关不良事件)等。Safety evaluation indicators: vital signs and physical examination, laboratory tests (blood routine, blood biochemistry, thyroid function, coagulation routine, urine routine, stool routine, pregnancy test), ECOG score, electrocardiogram, adverse events (including immune-related adverse events) )Wait.
药代动力学评价：Pharmacokinetic evaluation:
所有剂量组的受试者在治疗期间(前6个治疗周期)的规定时间点需要收集血样，在给药前2小时内监测血浆浓度(C trough)。每个时间点计划采3.5mL血样，检测血清药物的浓度水平，研究药代动力学(PK)特征。 Subjects in all dose groups were required to collect blood samples at prescribed time points during the treatment period (first 6 treatment cycles) and monitor plasma concentrations (C trough ) within 2 hours prior to dosing. A 3.5 mL blood sample is planned to be taken at each time point to detect the concentration level of the serum drug and study the pharmacokinetic (PK) characteristics.
通过实际给药剂量、实际采样时间和非房室模型计算下述PK参数：The following PK parameters were calculated from actual doses administered, actual sampling times, and non-compartmental models:
单次给药：C maxT max、T 1/2、CL、Vd、Ke、MRT、AUC (0-τ)、AUC (0-∞)； Single dose: Cmax Tmax , T1 /2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) ;
多次给药：C max,ss、C avg,ss、C min,ss、AUC (0-τ)ss、AUC (0-∞)ss、T max,ss、T 1/2,ss、CL、Vss、Ke、MRT、蓄积指数(R ac)、波动指数DF。 Multiple doses: Cmax,ss , Cavg,ss , Cmin,ss , AUC (0-τ)ss , AUC (0-∞)ss , Tmax,ss , T1 /2,ss , CL, Vss, Ke, MRT, accumulation index (R ac ), volatility index DF.
药效学受体占有率(RO)研究：Pharmacodynamic receptor occupancy (RO) studies:
抗体h10D8OFKF注射液的受体占有率研究是通过检测外周血中T细胞表面TIGIT受体结合来实现的。药效学受体占有率研究只在剂量递增的受试者中开展，受试者在治疗期间的特定时间点收集血样。每个时间点计划采集2mL血样，分别于第1、3周期给药前、给药结束时、168h、336h及504h密集采样，第2、4、5、6个周期给药前采样。The receptor occupancy study of antibody h10D8OFKF injection was achieved by detecting TIGIT receptor binding on the surface of T cells in peripheral blood. Pharmacodynamic receptor occupancy studies were conducted only in dose-escalation subjects who had blood samples collected at specific time points during treatment. A 2 mL blood sample was planned to be collected at each time point, and intensive sampling was performed before administration, at the end of administration, 168h, 336h, and 504h in cycles 1 and 3, and before administration in cycles 2, 4, 5, and 6.
临床有效性评价：根据RECIST 1.1定义的客观缓解率(ORR)、缓解持续时间(DOR)、疾病控制率(DCR)、无进展生存期(PFS)及总生存期(OS)。Evaluation of clinical efficacy: Objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) defined according to RECIST 1.1.

Claims (24)

  1. 一种联合用药物，包括抗TIGIT抗体或抗原结合片段和另一种治疗剂；A combination drug that includes an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent;
    所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。The anti-TIGIT 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, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5 and LCDR3 shown in SEQ ID NO:6.
  2. 如权利要求1所述的联合用药物，所述抗TIGIT抗体或抗原结合片段包含重链可变区和轻链可变区，其中：The combination drug of claim 1, wherein the anti-TIGIT antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein:
    所述重链可变区包含SEQ ID NO:7所示的氨基酸序列，或与SEQ ID NO:7所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:7, or an amino acid sequence shown in SEQ ID NO:7 The sequence is compared to an amino acid sequence with one or more conservative amino acid substitutions; and/or
    所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列，或与SEQ ID NO:8所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:8, or an amino acid sequence shown in SEQ ID NO:8 Sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  3. 如权利要求1或2所述的联合用药物，所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列，或与SEQ ID NO:9所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The combination drug according to claim 1 or 2, wherein the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:9, or is at least 80% identical to the sequence shown in SEQ ID NO:9 A specific amino acid sequence, or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 9; and/or
    所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列，或与SEQ ID NO:10所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO: 10, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO: 10, or the amino acid sequence shown in SEQ ID NO: 10. The indicated sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  4. 如权利要求1-3任一项所述的联合用药物，所述另一种治疗剂选自针对以下靶点的抗体或抗原结合片段或抗体药物偶联物：EGFR、VEGF、VEGFR2、CTLA-4、PD-L1、PD-1、HER2、CD20、Trop2、Lag3、TIGIT、CD27、OX40、ICOS、BTLA、TIM3、BCMA、c-MET和TAA-1/2/3；或者，所述另一种治疗剂为抗PD-1抗体或抗原结合片段；或者，所述抗PD-1抗体为纳武利尤单抗、帕博利单抗、卡瑞利珠单抗、信迪利单抗、特瑞普利单抗或替雷利珠单抗；或者，所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。The combination drug of any one of claims 1-3, wherein the another therapeutic agent is selected from the group consisting of antibodies or antigen-binding fragments or antibody-drug conjugates directed against the following targets: EGFR, VEGF, VEGFR2, CTLA- 4. PD-L1, PD-1, HER2, CD20, Trop2, Lag3, TIGIT, CD27, OX40, ICOS, BTLA, TIM3, BCMA, c-MET and TAA-1/2/3; or, the other The therapeutic agent is an anti-PD-1 antibody or an antigen-binding fragment; alternatively, the anti-PD-1 antibody is nivolumab, pembrolizumab, camrelizumab, sintilimab, torelizumab Plimumab or tislelizumab; or, the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO: 21, HCDR2 shown in SEQ ID NO: 22, SEQ ID NO: HCDR3 shown in 23, LCDR1 shown in SEQ ID NO:24, LCDR2 shown in SEQ ID NO:25 and LCDR3 shown in SEQ ID NO:26.
  5. 如权利要求4所述的联合用药物，所述抗PD-1抗体或抗原结合片段包含重链可变区和轻链可变区，其中：The combination drug of claim 4, wherein the anti-PD-1 antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein:
    所述重链可变区包含SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:27, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:27, or an amino acid sequence shown in SEQ ID NO:27 The sequence is compared to an amino acid sequence with one or more conservative amino acid substitutions; and/or
    所述轻链可变区包含SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 28, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO: 28, or an amino acid sequence shown in SEQ ID NO: 28 Sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  6. 如权利要求4或5所述的联合用药物，所述抗PD-1抗体的重链包含SEQ ID NO:19所示的氨基酸序列，或与SEQ ID NO:19所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:19所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The combination drug according to claim 4 or 5, wherein the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO: 19, or has at least 80% compared with the sequence shown in SEQ ID NO: 19 % identical amino acid sequence, or amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 19; and/or
    所述抗PD-1抗体的轻链包含SEQ ID NO:20所示的氨基酸序列，或与SEQ ID NO:20所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:20所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having at least 80% identity compared with the sequence shown in SEQ ID NO: 20, or an amino acid sequence with SEQ ID NO: The sequences shown in 20 are compared to amino acid sequences with one or more conservative amino acid substitutions.
  7. 如权利要求1-6任一项所述的联合用药物，所述抗TIGIT抗体或抗原结合片段和另一种治疗剂分别或同时给药。The combination medicament of any one of claims 1-6, wherein the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered separately or simultaneously.
  8. 如权利要求1-7任一项所述的联合用药物，所述抗TIGIT抗体或抗原结合片段和另一种治疗剂的质量比为0.01:10-1:1；或者为0.01:1-1:1；或者为0.1:3。The drug combination according to any one of claims 1-7, wherein the mass ratio of the anti-TIGIT antibody or antigen-binding fragment to another therapeutic agent is 0.01:10-1:1; or 0.01:1-1 :1; or 0.1:3.
  9. 权利要求1-8任一项所述的联合用药物在制备用于治疗肿瘤或癌症的药物中的应用。The application of the combined medicine according to any one of claims 1-8 in the preparation of a medicine for the treatment of tumor or cancer.
  10. 如权利要求9所述的应用，所述肿瘤或癌症为血液癌症或实体瘤；或者，所述肿瘤或癌症选自于急性淋巴细胞性白血病、急性骨髓性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、骨髓性增生疾病/肿瘤、霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、多发性骨髓瘤、巨细胞骨髓瘤、重链骨髓瘤、轻链或本斯-琼斯骨髓瘤、乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。The application according to claim 9, the tumor or cancer is hematological cancer or solid tumor; or, the tumor or cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia Leukemia, Myeloproliferative Disorders/Tumors, Hodgkin Lymphoma, Painless and Aggressive Non-Hodgkin Lymphoma, Burkitt Lymphoma, Follicular Lymphoma, Multiple Myeloma, Giant Cell Myeloma , heavy chain myeloma, light chain or Bence-Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, Liver and kidney cancer.
  11. 一种用于治疗肿瘤或癌症的方法，其包括：向有需要的患者给药有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂；A method for treating a tumor or cancer, comprising: administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent;
    所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。The anti-TIGIT 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, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5 and LCDR3 shown in SEQ ID NO:6.
  12. 如权利要求11所述的方法，所述抗TIGIT抗体或抗原结合片段包含重链可变 区和轻链可变区，其中：The method of claim 11, wherein the anti-TIGIT antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein:
    所述重链可变区包含SEQ ID NO:7所示的氨基酸序列，或与SEQ ID NO:7所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:7, or an amino acid sequence shown in SEQ ID NO:7 The sequence is compared to an amino acid sequence with one or more conservative amino acid substitutions; and/or
    所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列，或与SEQ ID NO:8所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:8, or an amino acid sequence shown in SEQ ID NO:8 Sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  13. 如权利要求11或12所述的方法，所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列，或与SEQ ID NO:9所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The method of claim 11 or 12, wherein the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:9, or has at least 80% identity compared to the sequence shown in SEQ ID NO:9 An amino acid sequence, 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
    所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列，或与SEQ ID NO:10所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO: 10, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO: 10, or the amino acid sequence shown in SEQ ID NO: 10. The indicated sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  14. 如权利要求11-13任一项所述的方法，所述另一种治疗剂选自针对以下靶点的抗体或抗原结合片段或抗体药物偶联物：EGFR、VEGF、VEGFR2、CTLA-4、PD-L1、PD-1、HER2、CD20、Trop2、Lag3、TIGIT、CD27、OX40、ICOS、BTLA、TIM3、BCMA、c-MET和TAA-1/2/3；或者，所述另一种治疗剂为抗PD-1抗体或抗原结合片段。The method of any one of claims 11-13, wherein the another therapeutic agent is selected from the group consisting of antibodies or antigen-binding fragments or antibody drug conjugates directed against: EGFR, VEGF, VEGFR2, CTLA-4, PD-L1, PD-1, HER2, CD20, Trop2, Lag3, TIGIT, CD27, OX40, ICOS, BTLA, TIM3, BCMA, c-MET, and TAA-1/2/3; alternatively, the other treatment The agent is an anti-PD-1 antibody or an antigen-binding fragment.
  15. 如权利要求14所述的方法，所述抗PD-1抗体为纳武利尤单抗、帕博利单抗、卡瑞利珠单抗、信迪利单抗、特瑞普利单抗或替雷利珠单抗；或者，所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。The method of claim 14, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, or tislel Libizumab; or, the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:21, HCDR2 shown in SEQ ID NO:22, HCDR3 shown in SEQ ID NO:23, SEQ ID NO:23 LCDR1 shown in ID NO: 24, LCDR2 shown in SEQ ID NO: 25, and LCDR3 shown in SEQ ID NO: 26.
  16. 如权利要求15所述的方法，所述抗PD-1抗体或抗原结合片段包含重链可变区和轻链可变区，其中：The method of claim 15, wherein the anti-PD-1 antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein:
    所述重链可变区包含SEQ ID NO:27所示的氨基酸序列，或与SEQ ID NO:27所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:27, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO:27, or an amino acid sequence shown in SEQ ID NO:27 The sequence is compared to an amino acid sequence with one or more conservative amino acid substitutions; and/or
    所述轻链可变区包含SEQ ID NO:28所示的氨基酸序列，或与SEQ ID NO:28所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:28所示序列相比具有 一个或多个保守氨基酸取代的氨基酸序列。The light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 28, or an amino acid sequence with at least 80% identity compared with the sequence shown in SEQ ID NO: 28, or an amino acid sequence shown in SEQ ID NO: 28 Sequences are compared to amino acid sequences with one or more conservative amino acid substitutions.
  17. 如权利要求15或16所述的方法，所述抗PD-1抗体的重链包含SEQ ID NO:19所示的氨基酸序列，或与SEQ ID NO:19所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:19所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列；和/或The method of claim 15 or 16, wherein the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO: 19, or is at least 80% identical to the sequence shown in SEQ ID NO: 19 A specific amino acid 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
    所述抗PD-1抗体的轻链包含SEQ ID NO:20所示的氨基酸序列，或与SEQ ID NO:20所示序列相比具有至少80％同一性的氨基酸序列，或与SEQ ID NO:20所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。The light chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence having at least 80% identity compared with the sequence shown in SEQ ID NO: 20, or an amino acid sequence with SEQ ID NO: The sequences shown in 20 are compared to amino acid sequences with one or more conservative amino acid substitutions.
  18. 如权利要求11-17任一项所述的方法，所述抗TIGIT抗体或抗原结合片段以0.05mg至1200mg、0.05mg至1000mg、0.05mg至500mg、0.05mg至100mg、0.1mg至100mg、0.1mg至50mg、0.1mg至30mg、0.1mg至10mg、0.5mg至1mg、9mg至1200mg、1mg至900mg的剂量给药；或者，所述抗TIGIT抗体或抗原结合片段以0.001mg/kg至20mg/kg、0.001mg/kg至2mg/kg、0.001mg/kg至1mg/kg、0.005mg/kg至1mg/kg、0.01mg/kg至1mg/kg、0.01mg/kg至20mg/kg的剂量给药；或者，每个治疗周期内抗TIGIT抗体或抗原结合片段给药的剂量为0.05mg至1200mg、0.05mg至1000mg、0.05mg至500mg、0.05mg至100mg、0.1mg至100mg、0.1mg至50mg、0.1mg至30mg、0.1mg至10mg、0.5mg至1mg、9mg至1200mg、1mg至900mg；或者，每个治疗周期内抗TIGIT抗体或抗原结合片段给药的剂量为0.001mg/kg至20mg/kg、0.001mg/kg至2mg/kg、0.001mg/kg至1mg/kg、0.005mg/kg至1mg/kg、0.01mg/kg至1mg/kg、0.01mg/kg至20mg/kg；或者，所述抗TIGIT抗体或抗原结合片段的每次给药量为0.05mg至1200mg、9mg至1200mg、1mg至900mg；或者，所述抗TIGIT抗体或抗原结合片段的每次给药量为0.001mg/kg至20mg/kg、0.01mg/kg至20mg/kg。The method of any one of claims 11-17, wherein the anti-TIGIT antibody or antigen-binding fragment is 0.05 mg to 1200 mg, 0.05 mg to 1000 mg, 0.05 mg to 500 mg, 0.05 mg to 100 mg, 0.1 mg to 100 mg, 0.1 mg mg to 50 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.5 mg to 1 mg, 9 mg to 1200 mg, 1 mg to 900 mg; alternatively, the anti-TIGIT antibody or antigen-binding fragment is administered at 0.001 mg/kg to 20 mg/kg kg, 0.001 mg/kg to 2 mg/kg, 0.001 mg/kg to 1 mg/kg, 0.005 mg/kg to 1 mg/kg, 0.01 mg/kg to 1 mg/kg, 0.01 mg/kg to 20 mg/kg ; or, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of 0.05 mg to 1200 mg, 0.05 mg to 1000 mg, 0.05 mg to 500 mg, 0.05 mg to 100 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 30 mg, 0.1 mg to 10 mg, 0.5 mg to 1 mg, 9 mg to 1200 mg, 1 mg to 900 mg; alternatively, the anti-TIGIT antibody or antigen-binding fragment administered at a dose of 0.001 mg/kg to 20 mg/kg per treatment cycle , 0.001 mg/kg to 2 mg/kg, 0.001 mg/kg to 1 mg/kg, 0.005 mg/kg to 1 mg/kg, 0.01 mg/kg to 1 mg/kg, 0.01 mg/kg to 20 mg/kg; or, the The anti-TIGIT antibody or antigen-binding fragment is administered in an amount of 0.05 mg to 1200 mg, 9 mg to 1200 mg, 1 mg to 900 mg; or, the anti-TIGIT antibody or antigen-binding fragment is administered in an amount of 0.001 mg/kg to 20 mg/kg, 0.01 mg/kg to 20 mg/kg.
  19. 如权利要求15-18任一项所述的方法，所述抗PD-1抗体或抗原结合片段以1mg至600mg、50mg至600mg、1mg至300mg、1mg至100mg、10mg至100mg、10mg至50mg、15mg至35mg的剂量给药；或者，所述抗PD-1抗体或抗原结合片段以0.01mg/kg至10mg/kg、1mg/kg至10mg/kg、0.1mg/kg至10mg/kg、0.1mg/kg至1mg/kg的剂量给药；或者，每个治疗周期内抗PD-1抗体或抗原结合片段给药的剂量为1mg至600mg、50mg至600mg、1mg至300mg、1mg至100mg、10mg至100mg、10mg至50mg、15mg至35mg；或者，每个治疗周期内抗PD-1抗体或抗原结合片段给药的剂量为0.01mg/kg至10mg/kg、1mg/kg至10mg/kg、0.1mg/kg至10mg/kg、0.1mg/kg至1mg/kg；或者，所述抗PD-1抗体或抗原结合片段的每次给药量为1mg至600mg、50mg至600mg；或者，所述抗PD-1抗体或抗原结合片段的每 次给药量为0.01mg/kg至10mg/kg、1mg/kg至10mg/kg。The method of any one of claims 15-18, wherein the anti-PD-1 antibody or antigen-binding fragment is 1 mg to 600 mg, 50 mg to 600 mg, 1 mg to 300 mg, 1 mg to 100 mg, 10 mg to 100 mg, 10 mg to 50 mg, Doses of 15 mg to 35 mg; alternatively, the anti-PD-1 antibody or antigen-binding fragment is administered at 0.01 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 0.1 mg/kg to 10 mg/kg, 0.1 mg /kg to 1 mg/kg; alternatively, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of 1 mg to 600 mg, 50 mg to 600 mg, 1 mg to 300 mg, 1 mg to 100 mg, 10 mg to 10 mg per treatment cycle 100 mg, 10 mg to 50 mg, 15 mg to 35 mg; alternatively, anti-PD-1 antibody or antigen-binding fragment administered at a dose of 0.01 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 0.1 mg per treatment cycle /kg to 10 mg/kg, 0.1 mg/kg to 1 mg/kg; or, each administration amount of the anti-PD-1 antibody or antigen-binding fragment is 1 mg to 600 mg, 50 mg to 600 mg; or, the anti-PD-1 antibody or antigen-binding fragment The dose of -1 antibody or antigen-binding fragment per administration is 0.01 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg.
  20. 如权利要求11-19任一项所述的方法，所述抗TIGIT抗体或抗原结合片段和另一种治疗剂分别或同时给药。The method of any one of claims 11-19, wherein the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered separately or simultaneously.
  21. 如权利要求11-20任一项所述的方法，所述抗TIGIT抗体或抗原结合片段每天给药一次至每7周给药一次，或者所述抗TIGIT抗体或抗原结合片段每周给药三次、每周给药两次、每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次；和/或，所述抗PD-1抗体或抗原结合片段每天给药一次至每7周给药一次，或者所述抗PD-1抗体或抗原结合片段每周给药三次、每周给药两次、每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次。The method of any one of claims 11-20, wherein the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks, or the anti-TIGIT antibody or antigen-binding fragment is administered three times a week , twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks or every Once every 7 weeks; and/or, the anti-PD-1 antibody or antigen-binding fragment is administered once a day to every 7 weeks, or the anti-PD-1 antibody or antigen-binding fragment is administered three times a week , twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks or every Dosing once every 7 weeks.
  22. 如权利要求11-21任一项所述的方法，所述抗TIGIT抗体或抗原结合片段和另一种治疗剂给药的质量比为0.01:10-1:1；或者为0.01:1-1:1；或者为0.1:3。The method of any one of claims 11-21, wherein the anti-TIGIT antibody or antigen-binding fragment and another therapeutic agent are administered in a mass ratio of 0.01:10-1:1; or 0.01:1-1 :1; or 0.1:3.
  23. 如权利要求11-22任一项所述的方法，所述肿瘤或癌症为血液癌症或实体瘤；或者，所述肿瘤或癌症选自于急性淋巴细胞性白血病、急性骨髓性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、骨髓性增生疾病/肿瘤、霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、多发性骨髓瘤、巨细胞骨髓瘤、重链骨髓瘤、轻链或本斯-琼斯骨髓瘤、乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。The method of any one of claims 11-22, wherein the tumor or cancer is a hematological cancer or a solid tumor; or, the tumor or cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia Myeloproliferative Disorders/Tumors, Hodgkin Lymphoma, Painless and Aggressive Non-Hodgkin Lymphoma, Burkitt Lymphoma, Follicular Lymphoma, Multiple Myeloma , giant cell myeloma, heavy chain myeloma, light chain or Bence-Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer cancer, esophagus, liver and kidney cancer.
  24. 一种试剂盒，其包含权利要求1-8任一项所述的联合用药物和用于指导有需要患者给药权利要求1-8任一项所述的联合用药物的说明书。A kit comprising the combination drug according to any one of claims 1-8 and instructions for instructing a patient in need to administer the combination drug according to any one of claims 1-8.
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