WO2024046389A1 - Utilisation combinée d'un anticorps anti-tigit et d'un anticorps anti-ctla-4 dans le traitement d'une tumeur - Google Patents

Utilisation combinée d'un anticorps anti-tigit et d'un anticorps anti-ctla-4 dans le traitement d'une tumeur Download PDF

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WO2024046389A1
WO2024046389A1 PCT/CN2023/115904 CN2023115904W WO2024046389A1 WO 2024046389 A1 WO2024046389 A1 WO 2024046389A1 CN 2023115904 W CN2023115904 W CN 2023115904W WO 2024046389 A1 WO2024046389 A1 WO 2024046389A1
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seq
amino acid
acid sequence
antibody
antigen
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PCT/CN2023/115904
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Chinese (zh)
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黄俊杰
吴精博
张少榆
黄贤明
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 WO2024046389A1 publication Critical patent/WO2024046389A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to the use of anti-TIGIT antibodies and anti-CTLA-4 antibodies in combination to treat tumors.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • Ig immunoglobulin
  • ITIM tyrosine inhibitor motif
  • the TIGIT structure is shown to contain an extracellular immunoglobulin domain, a type I transmembrane region and two ITIM motifs.
  • TIGIT is part of a costimulatory network, which mainly consists of the activating receptor CD226 and the inhibitory receptor TIGIT on T cells, as well as the ligand CD155 (also known as CD155) expressed on the surface of APCs, tumor cells, and infected cells.
  • TIGIT a poliovirus receptor protein encoded by the PVR gene in humans
  • CD112 CD112.
  • the binding of TIGIT to PVR or CD112 will cause the phosphorylation of Tyr225 in the cytoplasm of TIGIT, and TIGIT will bind to the cell adaptive growth factor receptor binding protein 2 (GRB2).
  • GRB2 can recruit SHIP1 to inhibit phosphatidylinositol trikinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling.
  • PI3K phosphatidylinositol trikinase
  • MAPK mitogen-activated protein kinase
  • phosphorylated TIGIT recruits SHIP1 through beta-arrestin2 ( ⁇ -arrestin2) and blocks the autoubiquitination of TNF receptor-associated factor 6 (TRAF6) and disrupts nuclear factor KB (NF-KB) activation.
  • ⁇ -arrestin2 beta-arrestin2
  • NF-KB nuclear factor KB
  • 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 Tyr322 phosphorylation and CD226-mediated downstream signaling. A series of signal transduction ultimately leads to the activation of T cell or NK cell function and promotes the production of cytokines.
  • PDC protein kinase
  • LFA1 lymphocyte-associated antigen 1
  • TIGIT molecules present on the surface of T cells or NK cells There is also an interaction between TIGIT molecules present on the surface of T cells or NK cells and CD226 molecules, which means that TIGIT molecules can directly disrupt CD226 to form normal dimers, thereby destroying the normal physiological functions of CD226.
  • TIGIT and CD226 are like two ends of a scale. Through the fulcrum of PVR, they subtly regulate the body's immune function through the transmission of co-stimulatory and co-inhibitory signals.
  • Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key inhibitory receptor that affects T cell function and plays a key role in the initiation phase of immune response (Scalapino KJ1, Daikh DI. (2008), Immunol Rev. 223:143-155).
  • TCR T cell receptor
  • MHC class I or class II antigen-presenting cells the signal on the TCR is amplified and counteracted by costimulatory molecules.
  • CD28 on T cells binds to B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells, it sends a signal that requires full activation of T cells.
  • This CD28/B7 combination leads to an increase in the production of interleukin 2 and other stimulatory cytokines, increases metabolism, promotes cell cycle progression, upregulates cell survival genes, and ultimately enables T cells to proliferate and differentiate.
  • CD28 binds and causes T cell proliferation
  • CTLA-4 is transported and expressed on the surface of T cells (Linsley PS, et al. (1996), Immunity. 4(6):535-543). The stronger the activation signal through the TCR, the more CTLA-4 is transported and expressed. While on the cell surface, CTLA-4's inhibitory signal is propagated (Egen JG, Allison JP. (2002), Immunity. 16(1):23-25).
  • CTLA-4 has a higher affinity for B7 than CD28 and blocks further coactivation (Krummel MF, Allison JP. (1995), J Exp Med. 182(2):458-465). Moreover, cells expressing CTLA-4 can capture and degrade B7-1 and B7-2 through endocytosis (Qureshi OS, et al. (2011), Science. 332 (6029): 600-603).
  • the object of the present invention is to provide a combined drug and its application in treating tumors.
  • the combination includes an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment. In some embodiments, the combination includes a therapeutically effective amount of an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment.
  • the present invention provides a pharmaceutical combination for treating tumors, including an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment.
  • the invention provides anti-TIGIT antibodies or antigen-binding fragments and anti-CTLA-4 antibodies or antigen-binding fragments in combination for the treatment of tumors.
  • the invention provides a method of treating tumors comprising administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment.
  • the invention provides the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or an antigen-binding fragment in the preparation of a medicament for treating tumors in combination with an anti-CTLA-4 antibody or antigen-binding fragment.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • an antigen-binding fragment in the preparation of a medicament for treating tumors in combination with an anti-CTLA-4 antibody or antigen-binding fragment.
  • the invention provides the use of an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment in the preparation of a medicament for treating tumors.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • an anti-CTLA-4 antibody or antigen-binding fragment in the preparation of a medicament for treating tumors.
  • the invention provides use of an anti-CTLA-4 antibody or antigen-binding fragment in the preparation of a medicament for treating tumors in combination with an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the invention provides the use of an anti-CTLA-4 antibody or antigen-binding fragment and an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment in the preparation of a medicament for treating tumors.
  • an anti-CTLA-4 antibody or antigen-binding fragment and an anti-TIGIT antibody (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragment in the preparation of a medicament for treating tumors.
  • an anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • the invention provides anti-TIGIT antibodies (eg, antibody h10D8OF or h10D8OFKF) or antigen-binding fragments and anti-CTLA-4 antibodies or antigen-binding fragments in the preparation of pharmaceutical compositions for treating tumors.
  • anti-TIGIT antibodies eg, antibody h10D8OF or h10D8OFKF
  • antigen-binding fragments and anti-CTLA-4 antibodies or antigen-binding fragments in the preparation of pharmaceutical compositions for treating tumors.
  • the invention provides a kit comprising an anti-TIGIT antibody and a package insert containing instructions for using the anti-TIGIT antibody in combination with an anti-CTLA-4 antibody to treat tumors.
  • the invention provides a kit comprising an anti-CTLA-4 antibody and a package insert containing instructions for using the anti-CTLA-4 antibody in combination with an anti-TIGIT antibody to treat tumors.
  • the present invention provides a kit comprising a medicament of an anti-TIGIT antibody and an anti-CTLA-4 antibody, and a package insert containing instructions for using the medicament of an anti-TIGIT antibody and an anti-CTLA-4 antibody. Instructions for treating tumors.
  • the present invention provides a kit comprising a medicament of an anti-TIGIT antibody and a package insert containing instructions for using the medicament of an anti-TIGIT antibody in combination with an anti-CTLA-4 antibody to treat tumors.
  • the present invention provides a kit comprising a medicament of an anti-CTLA-4 antibody and a package insert containing instructions for using the medicament of an anti-CTLA-4 antibody in combination with an anti-TIGIT antibody to treat tumors. .
  • the present invention provides a kit comprising an anti-TIGIT antibody or antigen-binding fragment (or preparation), an anti-CTLA-4 antibody or antigen-binding fragment (or preparation) and a method for instructing patients in need to administer anti-TIGIT Instructions for antibodies or antigen-binding fragments (or formulations) and anti-CTLA-4 antibodies or antigen-binding fragments (or formulations).
  • the anti-TIGIT antibody or antigen-binding fragment at least comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, SEQ ID NO : One or more of LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.
  • 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, SEQ ID NO: LCDR1 shown in 4, LCDR2 shown in SEQ ID NO:5 and LCDR3 shown in SEQ ID NO:6.
  • the anti-TIGIT antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region.
  • 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 unique 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: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 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 includes 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 is identical to the sequence set forth in SEQ ID NO: 9.
  • the sequence shown in SEQ ID NO:9 is compared to the 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 identical to the sequence set forth in SEQ ID NO: 10.
  • the sequence shown in SEQ ID NO:10 is compared to the 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 is identical to the sequence set forth in SEQ ID NO: 9.
  • the sequence shown in SEQ ID NO:9 is an amino acid sequence with one or more conservative amino acid substitutions;
  • the light chain of the anti-TIGIT antibody includes the amino acid sequence shown in SEQ ID NO:10, or is identical to the amino acid sequence shown in SEQ ID NO:10
  • the anti-TIGIT antibody is an antibody h10D8OF or h10D8OFKF, the heavy chain of which comprises the amino acid sequence shown in SEQ ID NO:9, and the light chain of which comprises the amino acid sequence of SEQ ID NO:10.
  • antibody h10D8OF or h10D8OFKF contains two sequence-identical heavy chains and two sequence-identical light chains.
  • 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 The range between (inclusive) 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 enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
  • the anti-CTLA-4 antibody or antigen-binding fragment at least comprises HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12, HCDR3 shown in SEQ ID NO: 13, SEQ One or more of LCDR1 shown in ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16.
  • the anti-CTLA-4 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12, HCDR3 shown in SEQ ID NO: 13, SEQ ID LCDR1 shown in NO:14, LCDR2 shown in SEQ ID NO:15 and LCDR3 shown in SEQ ID NO:16.
  • the anti-CTLA-4 antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region.
  • the heavy chain variable region of the anti-CTLA-4 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 17, or has an amino acid sequence of at least 80% compared to the sequence set forth in SEQ ID NO: 17. % identical 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:17.
  • the light chain variable region of the anti-CTLA-4 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 18, or has an amino acid sequence of at least 80% compared to the sequence set forth in SEQ ID NO: 18. % identity of the 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:18.
  • the heavy chain variable region of the anti-CTLA-4 antibody or antigen-binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 17, or has an amino acid sequence of at least 80% compared to the sequence set forth in SEQ ID NO: 17. % identical 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: 17; the light chain variable region of the anti-CTLA-4 antibody or antigen-binding fragment includes SEQ The amino acid sequence shown in ID NO:18, or an amino acid sequence with at least 80% identity compared to the sequence shown in SEQ ID NO:18, or one or more conserved amino acid sequences compared with the sequence shown in SEQ ID NO:18 Amino acid sequence of amino acid substitutions.
  • the heavy chain variable region of the anti-CTLA-4 antibody or antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO: 17, and the light chain of the anti-CTLA-4 antibody or antigen-binding fragment can The variable region contains the amino acid sequence shown in SEQ ID NO:18.
  • the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 19, Or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:19.
  • the light chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO:20, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO:20, Or an amino acid sequence with one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:20.
  • the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 19, or with SEQ
  • the sequence shown in ID NO: 19 is compared to the amino acid sequence having one or more conservative amino acid substitutions
  • the light chain of the anti-CTLA-4 antibody includes the amino acid sequence shown in SEQ ID NO: 20, or is the same as SEQ ID NO: 20
  • the sequence shown is an amino acid sequence that has at least 80% identity compared to the sequence shown in SEQ ID NO: 20, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 20.
  • the heavy chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 19
  • the light chain of the anti-CTLA-4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 20 sequence.
  • an anti-CTLA-4 antibody contains two sequence-identical heavy chains and two sequence-identical light chains.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a total amount of high-mannose glycoforms ⁇ 5% and/or a total amount of sialylated glycoforms ⁇ 3%.
  • the total amount of high-mannose glycoforms of the anti-CTLA-4 antibody or antigen-binding fragment is about 0.1%, about 0.3%, about 0.9%, about 1.18%, about 1.7%, about 2.6%, about 3.3 %, about 4.1%, about 4.9%, about 4.99%, or a range between any two of these values (inclusive of the endpoints) 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 between any two of these values (inclusive of the endpoints) or any value therein.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a total amount of high mannose glycoforms ⁇ 2% and/or a total amount of sialylated glycoforms ⁇ 1%.
  • 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 0.5%, 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 between any two of these values Range (including endpoints) or any value therein.
  • the anti-CTLA-4 antibody or antigen-binding fragment does not bind fucose. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has enhanced ADCC effect (antibody-dependent cell-mediated cytotoxicity).
  • the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-10%, a total high-mannose glycoform ⁇ 5% and/or a total sialylated glycoform ⁇ 5%. 3%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-5%, a total high-mannose glycoform ⁇ 5% and/or a total sialylated glycoform ⁇ 3%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of about 0%, a total high-mannose glycoform ⁇ 5% and/or a total sialylated glycoform ⁇ 3 %.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-10%, a total high-mannose glycoform ⁇ 3% and/or a total sialylated glycoform ⁇ 3%. 2%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-5%, a total high-mannose glycoform ⁇ 3% and/or a total sialylated glycoform ⁇ 3%. 2%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of about 0%, a total high-mannose glycoform ⁇ 3% and/or a total sialylated glycoform ⁇ 2 %.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-10%, high glycerol The total amount of unglucose glycoforms is ⁇ 2% and/or the total amount of sialylated glycoforms is ⁇ 1%. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of 0-5%, a total high-mannose glycoform ⁇ 2% and/or a total sialylated glycoform ⁇ 2%. 1%.
  • the anti-CTLA-4 antibody or antigen-binding fragment has a fucosylation level of about 0%, a total amount of high-mannose glycoforms ⁇ 2%, and/or a total amount of sialylated glycoforms ⁇ 1 %.
  • the anti-CTLA-4 antibody or antigen-binding fragment is ipilimumab (Yervoy TM or a biosimilar thereof).
  • Antibodies can be expressed in host cells through genetic engineering and obtained through purification; purification can be performed using 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 antibodies.
  • a hypofucosylated or afucosylated anti-TIGIT antibody eg, antibody h10D8OFKF
  • antigen-binding fragment or an anti-CTLA-4 antibody or antigen-binding fragment is composed of ⁇ -(1,6) - Expression from a fucosyltransferase gene knockout cell line, such as expression from ⁇ -(1,6)-fucosyltransferase gene knockout CHO-K1 cells.
  • the invention also provides pharmaceutical compositions comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment.
  • the pharmaceutical composition is a pharmaceutical composition suitable for injection, such as a push-type pharmaceutical composition or an infusion (drip)-type pharmaceutical composition.
  • the pharmaceutical composition contains at least 0.1% anti-TIGIT antibody or antigen-binding fragment and 0.1% anti-CTLA-4 antibody or antigen-binding fragment.
  • the percentage of antibody can vary and can be between about 2% and about 90% by weight of a given dosage form.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment in this therapeutically useful pharmaceutical composition can be administered in effective amounts.
  • the present invention also provides a method for preparing the above-mentioned pharmaceutical composition: respectively, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment described herein are combined with a pharmaceutically acceptable suitable for injection.
  • a pharmaceutically acceptable suitable for injection such as water for injection, physiological saline, etc.
  • the above pharmaceutical composition is prepared by: combining the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment described herein with a pharmaceutically acceptable carrier suitable for injection (e.g., injection Mix with water, saline, etc.).
  • a pharmaceutically acceptable carrier suitable for injection e.g., injection Mix with water, saline, etc.
  • the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 1-50:1. In some embodiments, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 5-25:1. In some embodiments, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 1-15:1. In some embodiments, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 1-10:1.
  • the mass ratio of the anti-TIGIT antibody or antigen-binding fragment to the anti-CTLA-4 antibody or antigen-binding fragment is about 5:1. In some embodiments, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 15-30:1. In some embodiments, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is 20-30:1. In some implementations In this case, the mass ratio of the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment is approximately 25:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.5 mg to 1000 mg, about 5 mg to 500 mg, about 5 mg to 100 mg, about 10 mg to 100 mg, about 10 mg to 50 mg. , or preparations containing anti-TIGIT antibodies or antigen-binding fragments at this dose.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7mg, about 8mg, about 9mg, about 10mg, about 12mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 80mg, about 100mg, about 120mg, about 200mg, about 250mg, about 290mg, about 300mg, About 330 mg, about 380 mg, about 400 mg, about 480 mg, about 500 mg, about 580 mg, about 600 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, or a range between any two of these values (inclusive of the endpoints), or Any of these values, or a formulation containing this dose of anti-TIGIT antibody or antigen-binding fragment.
  • the 480 mg about 500 mg,
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg to 20 mg/kg, about 0.01 mg/kg to 2 mg/kg, about 0.01 mg/kg to 1 mg/kg, about 0.05 mg/kg to 1 mg/kg, about 0.1 mg/kg to 1 mg/kg, or preparations containing anti-TIGIT antibodies or antigen-binding fragments at this dose.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/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 8mg/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 a range between any two of these values (including endpoint) or any value therein, or a formulation containing such a dose of anti-TIGIT antibody or antigen-binding fragment.
  • the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 1200 mg, about 0.5 mg to 1000 mg, about 5 mg to 500 mg, about 5 mg to 100 mg, about 10 mg to 100 mg, about 10 mg per treatment cycle. to 50 mg, or preparations containing anti-TIGIT antibodies or antigen-binding fragments at this dose.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg per treatment cycle.
  • the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF.
  • the anti-TIGIT antibody or antigen-binding fragment is administered per treatment cycle at a dose of about 0.01 mg/kg to 20 mg/kg, about 0.01 mg/kg to 2 mg/kg, about 0.01 mg/kg to 1 mg/kg , about 0.05 mg/kg to 1 mg/kg, about 0.1 mg/kg to 1 mg/kg, or preparations containing anti-TIGIT antibodies or antigen-binding fragments at this dose.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 0.5 mg/kg per treatment cycle.
  • the anti-TIGIT antibody is antibody h10D8OF or h10D8OFKF.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 600 mg, about 0.5 mg to 600 mg, about 1 mg to 100 mg, about 1 mg to 50 mg, about 1 mg to 10 mg, or containing Preparation of anti-CTLA-4 antibodies or antigen-binding fragments at this dose.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.5 mg, about 0.8 mg, about 1 mg, about 2 mg per administration.
  • the anti-CTLA-4 antibody is Antibody 1.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg to 10 mg/kg, about 0.01 mg/kg to 2 mg/kg, about 0.01 mg/kg to 1 mg/kg per administration , about 0.02 mg/kg to 1 mg/kg, about 0.02 mg/kg to 0.5 mg/kg, about 0.02 mg/kg to 0.2 mg/kg, or preparations containing anti-CTLA-4 antibodies or antigen-binding fragments at this dose.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of 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 per administration.
  • the anti-CTLA-4 antibody is Antibody 1.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.05 mg to 600 mg, about 0.5 mg to 600 mg, about 1 mg to 100 mg, about 1 mg to 50 mg, about 1 mg to 10 mg per treatment cycle, or preparations containing anti-CTLA-4 antibodies or antigen-binding fragments at this dose.
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.05 mg, about 0.1 mg per treatment cycle mg, about 0.2mg, about 0.3mg, about 0.5mg, about 0.8mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 12mg , about 20mg, about 30mg, about 50mg, about 60mg, about 80mg, about 100mg, about 120mg, about 200mg, about 250mg, about 290mg, about 300mg, about 330mg, about 380mg, about 400mg, about 434mg, about 480mg, about 500 mg, about 567 mg, about 580 mg, about 600 mg, or a range between any two of these values (inclusive of the endpoints) or any value therein, or a formulation containing such
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg/kg to 10 mg/kg, about 0.01 mg/kg to 2 mg/kg, about 0.01 mg/kg to 1 mg per treatment cycle. /kg, about 0.02 mg/kg to 1 mg/kg, about 0.02 mg/kg to 0.5 mg/kg, about 0.02 mg/kg to 0.2 mg/kg, or preparations containing anti-CTLA-4 antibodies or antigen-binding fragments at this dose .
  • the anti-CTLA-4 antibody or antigen-binding fragment is administered per treatment cycle at a dose of 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 0.1mg/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 8mg/kg, about 9mg/kg, about 10mg/kg , or a range between any two of these values (inclusive of the endpoints) or any value therein, or a formulation containing such a dose of anti-CTLA-4 antibody or antigen-binding fragment.
  • the invention provides a method of treating tumors, the method comprising: administering to a patient in need thereof about 0.05 mg to 1200 mg, about 0.5 mg to 1000 mg, about 5 mg to 500 mg, about 5 mg to 100 mg, About 10 mg to 100 mg, about 10 mg to 50 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 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 12mg, about 20mg, about 30mg, about 50mg, about 60mg, About 80mg, about 100mg, about 120mg, about 200mg, about 250mg, about 290mg, about 300mg, about 330mg, about 380m
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 1-50:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 5-25:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 1-15:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 1-10:1.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of about 5:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 15-30:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of 20-30:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered at a mass ratio of about 25:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 1-50:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 5-25:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 1-15:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 1-10:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is approximately 5:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 15-30:1.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is 20-30:1. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, or 900 mg per treatment cycle, and the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or The mass ratio of antigen-binding fragments administered is approximately 25:1.
  • the anti-TIGIT antibody is antibody h10D8OFKF and the anti-CTLA-4 antibody is antibody 1.
  • the anti-TIGIT antibody is antibody h10D8OF and the anti-CTLA-4 antibody is antibody 1.
  • the formulations may be formulations suitable for injectable use including sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • Suitable carriers include physiological saline, bacteriostatic water or phosphate buffered saline (PBS), solvents or dispersion media of ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof.
  • the formulation contains at least 0.1% antibody or antigen-binding fragment.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 5 months, 6 months, one year, or any combination thereof.
  • the dosing frequency ranges from once daily to once every 7 weeks.
  • the dosing frequency is once daily, three times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, every 4 weeks. Dosing once a week, once every 5 weeks, once every 6 weeks, or once every 7 weeks.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment may be administered at the same or different frequencies.
  • the patient receives a single treatment with an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment.
  • the patient's symptoms are relieved after a single administration.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered to the patient after the patient does not experience expected relief of symptoms after a single dose.
  • patients receive treatment until the condition resolves and treatment is no longer required.
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment separately once per treatment cycle.
  • the patient is administered the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment multiple times per treatment cycle, such as 2, 3, 4, or 5 times.
  • the patient receives one treatment cycle.
  • a patient is treated with multiple treatment cycles (eg, 2, 3, or 4).
  • the anti-TIGIT antibody or antigen-binding fragment, anti-CTLA-4 antibody or antigen-binding fragment is administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intraarterial injection, or intravenous (i.v.) injection. ) administration by injection or infusion.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment can be administered in the same or different ways.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are administered by intraperitoneal injection.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment are separate administration units and administered in combination.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment can be administered at different times.
  • the anti-TIGIT antibody or antigen-binding fragment is administered prior to administration of the anti-CTLA-4 antibody or antigen-binding fragment.
  • the anti-TIGIT antibody or antigen-binding fragment is administered after administration of the anti-CTLA-4 antibody or antigen-binding fragment.
  • the anti-TIGIT antibody or antigen-binding fragment is administered simultaneously with the anti-CTLA-4 antibody or antigen-binding fragment.
  • An anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • an anti-CTLA-4 antibody or antigen-binding fragment are formulated into a pharmaceutical composition and administered to the patient in a form suitable for the chosen route of administration, for example, enterally External, intravenous (iv), intramuscular, topical or subcutaneous routes.
  • the anti-TIGIT antibody eg, antibody h10D8OF or h10D8OFKF
  • antigen-binding fragment and the anti-CTLA-4 antibody or antigen-binding fragment simultaneously form a combined dosage unit for combined administration.
  • an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment are combined into a pharmaceutical composition and administered to the patient in a form suitable for the chosen route of administration, such as enterally. External, intravenous (iv), intramuscular, topical or subcutaneous routes.
  • anti-TIGIT antibodies or antigen-binding fragments (or formulations), anti-CTLA-4 antibodies or antigen-binding fragments (or formulations) can be used in combination with other treatments to treat tumors, such as chemotherapy, radiation therapy, and surgical treatment. wait.
  • tumors include, but are not limited to, benign tumors, cancer.
  • tumors include, but are not limited to, hematological cancers, solid tumors.
  • blood cancers include, but are not limited to, leukemias, lymphomas, and myeloma.
  • leukemias include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and myeloid proliferative diseases/neoplasms (MPDS ).
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MPDS myeloid proliferative diseases/neoplasms
  • lymphomas include Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell).
  • myeloma includes multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bence-Jones myeloma.
  • solid tumors include breast cancer, pancreatic cancer, prostate cancer, melanoma, head and neck cancer, liver cancer, renal cancer, squamous cell carcinoma, esophageal squamous cell carcinoma, lung cancer, non-small cell lung cancer, cervical cancer, Esophageal cancer, endometrial cancer, ovarian cancer, colon cancer, colorectal cancer, urothelial cancer, bladder cancer, brain cancer.
  • the tumor is a pathologically confirmed locally advanced or metastatic malignant solid tumor for which there is no effective treatment.
  • the combination of an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment compared to treatment with an anti-TIGIT antibody or antigen-binding fragment and an anti-CTLA-4 antibody or antigen-binding fragment alone can improve tumor suppression and/or prolong survival.
  • Figure 1 is the mouse tumor growth curve in Example 2.
  • Figure 2 is the mouse survival curve in Example 2.
  • Figure 3 is the mouse tumor growth curve in Example 3.
  • Figure 4 is the mouse survival curve in Example 3.
  • an entity refers to one or more such entities, e.g. "an antibody” should be understood to mean one or more antibodies, therefore, the term “a” (or “an” ), “one or more” and “at least one” may be used interchangeably herein.
  • polypeptide is intended to encompass the singular “polypeptide” as well as the plural “polypeptide” and refers to a molecule composed of amino acid monomers linearly linked 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 specific length of the product.
  • the definition of “polypeptide” includes peptide, dipeptide, tripeptide, oligopeptide, "protein,” “amino acid chain” or any other term used to refer to two or more amino acid chains, and the term “polypeptide” may Used instead of or 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-natural Amino acid modifications that occur.
  • a polypeptide may be derived from natural biological sources or produced by recombinant techniques, but it does not have to be translated from a specified nucleic acid sequence and 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 may be encoded by a nucleic acid directly or in the form of a precursor.
  • a single amino acid is encoded by a nucleic acid consisting of three nucleotides (so-called codons or base triplets). Each amino acid is encoded by at least one codon. The fact that the same amino acid is encoded by different codons is called the "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 Acid (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I ), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y) and valine (val, V).
  • a “conservative amino acid substitution” refers to the replacement of one amino acid residue with another amino acid residue containing a side chain (R group) with similar chemical properties (eg, charge or hydrophobicity). Generally speaking, conservative amino acid substitutions are unlikely to materially 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.
  • Amide-containing side chains asparagine and glutamine
  • Aromatic side chains phenylalanine, tyrosine and tryptophan
  • Basic side chains lysine, Arginine and histidine
  • Acidic side chains aspartic acid and glutamic acid.
  • the number of amino acids of "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 between any two of these values (inclusive of the endpoints) or any one thereof What value.
  • the number of amino acids of "conservative amino acid substitutions of heavy or light chain” may be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10 about 11, about 13, about 14, about 15, about 18, about 19, about 22, about 24, about 25, about 29, about 31, about 35, About 38, about 41, about 45 conservative amino acid substitutions, or a range between any two of these values, inclusive, or any value therein.
  • encoding when applied to a polynucleotide, refers to a polynucleotide that is said to "encode” a polypeptide that, in its native state or when manipulated by methods well known to those skilled in the art, is transcribed and/or Or translation can produce the polypeptide and/or fragments thereof.
  • the antibodies, antigen-binding fragments or derivatives disclosed in the present invention include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single-chain antibodies, and antigen-binding fragments. (eg Fab, Fab', F(ab') 2 , scFv).
  • recombinant refers to a polypeptide or polynucleotide and means a form of the polypeptide or polynucleotide that does not occur in nature, and non-limiting examples may be combined to produce polynucleotides that do not normally exist or Peptides.
  • 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. When a position in the compared sequences is occupied by the same base or amino acid, the molecules are homologous at that position. 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 means about 80% identity, about 81% identity, about 82% identity, about 83% identity, about 85% identity, about 86% identity, about 87% identity, About 88% identical, about 90% identical, about 91% identical, about 92% identical, about 94% identical, about 95% identical, about 98% identical, about 99% identical, or these The range between any two values in a numeric value, including endpoints, or any value within it.
  • a nucleic acid or polynucleotide sequence is "identical” or “sequence identical” to another sequence by a certain percentage (eg, 90%, 95%, 98% or 99%). When sequences are aligned, this percentage of bases (or amino acids) in the two sequences being compared are identical.
  • the alignment percent identity or sequence identity can be determined using visual inspection or software programs known in the art, such as those described in Ausubel et al. eds. (2007), Current Protocols in Molecular Biology. It is preferred to use the default parameters for comparison.
  • Biologically equivalent polynucleotides are polynucleotides that share the percentage identity specified above and encode a polypeptide with the same or similar biological activity.
  • Antibody and antigen-binding fragment refer to polypeptides or polypeptide complexes that specifically recognize and bind to antigens. Antibodies can be complete antibodies, any antigen-binding fragments thereof, or single chains thereof. The term “antibody” thus includes any protein or peptide whose molecule contains at least a portion of an immunoglobulin molecule that has the biological activity of binding to an antigen.
  • anti- Body and antigen-binding fragments include, but are not limited to, complementarity determining regions (CDRs) of heavy or light chains or their ligand-binding portions, heavy chain variable regions (VH), light chain variable regions (VL), heavy chain constant regions (CH), light chain constant region (CL), framework region (FR) or any part thereof, or at least part of a binding protein.
  • CDR region includes the CDR region of the light chain (L CDR1-3) and the CDR region of the heavy chain (HCDR1-3).
  • antibodies includes a wide variety of biochemically distinguishable polypeptides. Those skilled in the art will understand that classes of heavy chains include gamma, mu, alpha, delta or epsilon (gamma, mu, alpha, delta, epsilon), of which there are also subclasses (eg ⁇ 1- ⁇ 4). The nature of this chain determines the "class" of the antibody: IgG, IgM, IgA, IgG, or IgE. Immunoglobulin subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgG5, etc. are well characterized and the functional specificities conferred are known. All immunoglobulin species are within the scope of the invention. In some embodiments, the immunoglobulin molecule is of the IgG class.
  • Light chains can be classified as kappa ( ⁇ ) or lambda ( ⁇ ). Each heavy chain can be combined with a kappa or lambda light chain.
  • ⁇ kappa
  • ⁇ lambda
  • the amino acid sequence extends from the N-terminus at the fork end of the Y configuration to the C-terminus at the bottom of each chain.
  • the variable region of the immunoglobulin kappa light chain is V ⁇ ; the variable region of the immunoglobulin lambda light chain is V ⁇ .
  • 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 binding, etc. By convention, the numbering of constant regions increases as they become farther away from the antibody's antigen-binding site, or amino terminus.
  • the N-terminal part is the variable region and the C-terminal part is the constant region; for example, the CH3 and CL domains of IgG1 actually contain the carboxyl termini of the heavy and light chains respectively.
  • CDR complementarity determining region
  • CDRs defined according to Kabat and Chothia include overlapping 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 numbering comprising 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 CDR contains based on the amino acid sequence of the variable region of the antibody.
  • Kabat et al. also defined a numbering system applicable to the variable region sequences of any antibody.
  • One of ordinary skill in the art can apply this "Kabat numbering" system to any variable region sequence without relying on experimental data other than the sequence itself.
  • “Kabat numbering” refers to the numbering system proposed by Kabat et al., USDept. of Health and Human Services in "Sequence of Proteins of Immunological Interest” (1983).
  • Antibodies can also use the EU or Chothia numbering system.
  • Treatment means therapeutic treatment and preventive or preventative measures designed to prevent, slow down, ameliorate and halt adverse physiological changes or disorders such as the progression of a disease, including but not limited to the following whether detectable or undetectable
  • the results include alleviation of symptoms, reduction in disease severity, stabilization of disease status (i.e. no worsening), delay or slowdown of disease progression, improvement or alleviation of disease status, reduction or disappearance (whether partial or complete), prolongation and Expected survival without treatment, etc.
  • Patients in need of treatment include patients who already have a condition or disorder, are susceptible to a condition or disorder, or are in need of prevention of a condition or disorder from which an antibody or composition disclosed herein can be or is expected to result from administration of an antibody or composition disclosed herein for detection, Patients who benefit from diagnostic procedures and/or treatments.
  • Patient refers to any mammal for whom diagnosis, prognosis or treatment is required, including humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, etc.
  • Effective amount refers to an amount of an active compound or agent that causes a biological or medical response in a tissue, system, animal, individual, or human.
  • in need means that a patient has been identified as needing a particular method or treatment. In some embodiments, identification can be by any diagnostic means.
  • DNA encoding the antibody can be designed and synthesized according to the antibody amino acid sequence described herein according to conventional methods, placed into an expression vector, and then transfected into host cells, and the transfected host cells are cultured in culture medium to produce monoclonal antibodies.
  • an expression antibody 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 through the early and late promoters of SV40, the long terminal repeat sequences from retroviruses such as RSV, HTLV1, HIVI, and the early promoter of cytomegalovirus, and other cellular promoters such as muscle can also 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 host cells include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells and CHO cells.
  • the antibody heavy chain and light chain DNA sequences are cloned into expression vectors, then transferred into host cells, cultured and purified to obtain antibodies.
  • the amino acid sequences of antibody h10D8OF, antibody h10D8OFKF, antibody 1, antibody Anti-mCTLA4, antibody Anti-mTIGIT and control antibody IgG1 are shown in Table 1-5. Among them, the amino acid sequences of antibodies h10D8OF and h10D8OFKF are the same.
  • the host cells expressing antibody h10D8OFKF and antibody 1 are CHO-K1 cells with ⁇ -(1,6)-fucosyltransferase gene (Fut-8) knockout, and the resulting fucosylation level of antibody h10D8OFKF Approximately 0%, Antibody 1 fucosylation level is approximately 0%, total high mannose glycoforms ⁇ 2%, and total sialylated glycoforms ⁇ 1%.
  • the host cells expressing antibody h10D8OF are CHO-K1 cells.
  • the host cells expressing antibody Anti-mCTLA4, antibody Anti-mTIGIT and control antibody IgG1 are HEK293F cells.
  • mice were subcutaneously inoculated with CT26 colon cancer cells (inoculation number: 1 ⁇ 10 6 /mouse).
  • the day of grouping was recorded as day 0, which is the start.
  • the first administration, administration mode (administration frequency, cycle, route) and specific group administration regimen are shown in Table 6.
  • the mouse body weight and tumor volume were recorded twice a week, and the tumor inhibition rate TGI% and p value were calculated. The results were expressed as mean ⁇ standard error. Mice were euthanized when their tumor volume was greater than 3000 mm 3 .
  • mice tumor growth curve is shown in Figure 1, and the mouse survival curve is shown in Figure 2.
  • both the single-drug group (Group 2 and Group 3) and the combined administration group (Group 4) inhibited tumor growth to a certain extent, and no significant difference was shown between the groups 14 days after administration.
  • mice whose tumor volume reached the euthanasia standard were all euthanized. From the survival curve of the mice, it can be seen that the survival time of the mice in the combined administration group (group 4) was significantly longer than that in the negative control group ( Group 1) and single drug group (Group 2 and Group 3).
  • Example 3 Efficacy test of combined administration of antibody h10D8OFKF and antibody 1
  • mice were subcutaneously inoculated with CT26 cells at an inoculation number of 1 ⁇ 10 6 /mouse.
  • the average tumor volume of the mice was 88.33 mm 3 , they were divided into groups and administered drugs.
  • the day of grouping was recorded as day 0, that is, the first administration was started.
  • the administration method administration frequency, cycle, route
  • the specific group administration scheme are shown in Table 7.
  • the mouse body weight and tumor volume were recorded twice a week, and the tumor inhibition rate TGI% and p value were calculated. The results were expressed as mean ⁇ standard error. Mice were euthanized when their tumor volume was greater than 3000 mm 3 .
  • the mouse tumor growth curve is shown in Figure 3, and the mouse survival curve is shown in Figure 4.
  • the results of the study showed that compared with the control antibody IgG1, the test antibody 1, antibody h10D8OFKF, and the combination of antibody 1 and antibody h10D8OFKF all showed significant tumor inhibitory effects (see Figure 3) and could significantly extend the survival time of mice. (See Figure 4).
  • the group administered antibody 1 in combination with antibody h10D8OFKF group Compared with the group administered with antibody h10D8OFKF alone (group 3), the group administered antibody 1 in combination with antibody h10D8OFKF (group 4) showed significant tumor inhibition (*, p ⁇ 0.05) and could significantly prolong the survival of mice ( **, p ⁇ 0.01).

Abstract

La présente invention concerne une polythérapie, comprenant un anticorps anti-TIGIT ou un fragment de liaison à l'antigène de celui-ci et un anticorps anti-CTLA -4 ou un fragment de liaison à l'antigène de celui-ci. La présente invention concerne également l'utilisation combinée d'un anticorps anti-TIGIT et d'un anticorps anti-CTLA-4 dans le traitement d'une tumeur.
PCT/CN2023/115904 2022-08-31 2023-08-30 Utilisation combinée d'un anticorps anti-tigit et d'un anticorps anti-ctla-4 dans le traitement d'une tumeur WO2024046389A1 (fr)

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WO2021043206A1 (fr) * 2019-09-03 2021-03-11 百奥泰生物制药股份有限公司 Immunosuppresseur anti-tigit et son application
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WO2021238932A1 (fr) * 2020-05-26 2021-12-02 百奥泰生物制药股份有限公司 Anticorps multi-spécifique et son application
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