WO2020259667A1 - Utilisation d'une combinaison d'un agoniste de tlr et d'un anticorps anti-ox40 ou d'un fragment de liaison à l'antigène de ceux-ci dans la préparation d'un médicament pour le traitement de tumeurs - Google Patents

Utilisation d'une combinaison d'un agoniste de tlr et d'un anticorps anti-ox40 ou d'un fragment de liaison à l'antigène de ceux-ci dans la préparation d'un médicament pour le traitement de tumeurs Download PDF

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WO2020259667A1
WO2020259667A1 PCT/CN2020/098409 CN2020098409W WO2020259667A1 WO 2020259667 A1 WO2020259667 A1 WO 2020259667A1 CN 2020098409 W CN2020098409 W CN 2020098409W WO 2020259667 A1 WO2020259667 A1 WO 2020259667A1
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cancer
antibody
amino acid
seq
once
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PCT/CN2020/098409
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Chinese (zh)
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蒋家骅
廖成
张连山
孙飘扬
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江苏恒瑞医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to the use of a TLR agonist combined with an anti-OX40 antibody or an antigen-binding fragment thereof in the preparation of a medicine for preventing or treating tumors.
  • Tumor immunotherapy is a continuing hot spot in the field of tumor treatment.
  • Recent studies have shown that enhancing the function of anti-tumor T cells can be used to fight cancer.
  • tumor cells “evade” the immune system by inducing active immune tolerance mediated mainly by regulatory T lymphocytes (Treg; Quezda et al. Immunol Rev 2011; 241:104-118). Therefore, the balance between effector T lymphocytes (Teff) and tolerogenic Treg is essential for effective anti-tumor immunotherapy.
  • an effective anti-tumor immune response can be obtained by enhancing the effector function of tumor-specific Teff and/or by reducing the inhibitory function of tumor-specific Treg.
  • the CD134 (OX40) receptor has been shown to be a key receptor that mediates these responses (Sugamura, K, Ishii, N, Weinberg, A. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nature Rev Imm 2004; 4:420-431).
  • TLRs Toll-like receptors
  • TLRs There are at least 10 different TLRs in mammals. Some ligands for these receptors and the corresponding signal cascades have been identified. Many diseases and obstacles are related to abnormalities of TLRs, such as melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma (basalcellcarcinoma), renal cell carcinoma, myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD) ), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV, SARS, HIV or influenza virus infection.
  • melanoma non-small cell lung cancer
  • hepatocellular carcinoma such as basal cell carcinoma (basalcellcarcinoma), renal cell carcinoma, myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD) ), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV
  • TLR7 is a member of the subgroup of TLRs (TLRs 3, 7, 8 and 9) and is limited to the endosomal compartment of cells that specialize in detecting non-hex nucleic acids. TLR7 plays a key role in antiviral defense by recognizing ssRNA (Diebold S.S. et al., Science, 2004:303, 1529-1531; and Lund J.M. et al., PNAS, 2004: 101, 5598-5603). Currently, the TLR7 inhibitors that have been marketed are mainly used for topical administration, such as imiquimod for the treatment of condyloma acuminatum.
  • WO2018095426A provides a TLR7 agonist, the structure is as follows:
  • OX40 (also known as CD134) is a member of the tumor necrosis factor receptor (TNFR) superfamily. It is a glycoprotein with a molecular weight of about 50kDa expressed on the cell surface.
  • the extracellular ligand binding domain of OX40 is composed of 4 cysteine-rich domains (CRD).
  • the natural ligand of OX40 is OX40L (CD252), and 3 OX40 correspond to the ligands that bind to the trimer to form an OX40-OX40L complex.
  • OX40 is mainly expressed on activated T cells, and OX40 is a secondary co-stimulatory molecule, which is expressed after 24-72 hours after activation.
  • the OX40 ligand OX40L is mainly expressed on activated antigen presenting cells.
  • T lymphocytes expressing OX40 have been confirmed to exist in the draining lymph nodes of various human malignant tumors and cancer patients.
  • SCID severe combined immunodeficiency
  • WO2017021912A discloses a combination of an antigen binding protein that binds to OX40 and a TRL7/8 modulator or a TRL4 modulator. Specific examples disclose the experimental data of the anti-OX40 antibody OX86 and TRL4 agonist in the CT-26 model, However, the combination of OX40 antibody and TRL7/8 modulator is not effective.
  • the present disclosure provides a use of a combination of a TLR agonist and an anti-OX40 antibody or an antigen-binding fragment thereof in the preparation of a drug for preventing or treating tumors.
  • the TLR agonists provided in the present disclosure can be selected from TLR1 agonists, TLR2 agonists, TLR3 agonists, TLR4 agonists, TLR5 agonists, TLR6 agonists, TLR7 agonists, TLR8 agonists, TLR9 agonists, preferably TLR7 agonists or TLR9 agonists, most preferably TLR7 agonists.
  • the TLR agonists provided by the present disclosure can be selected from Heplisav, resiquimod, SD-101, Dynavax, DV-281, imiquimod, cobitolimod, entolimod, lemonolimod, Poly-ICLC, Grass MATA MPL, G-100, AST-008, GSK-1795091 , Tilsotolimod, KMRC-011, CMB-305, rintatolimod, AZD-1419, influenza-PAL, SAR-439794, MIS-416, MGN-1601, GSK-2245035, VTX-1463, motolimod, GS-9688, LHC-165 , BDB-001, PGV-001, AV-7909, DSP-0509, DPX-E7, RG-7854, telratolimod, vesatolimod, poly-ICLC adjuvanted vaccines, MVAME-03, Riboxxim, G-305, PUL-042, litenimod , DR
  • the anti-OX40 antibody or antigen-binding fragment thereof described in the present disclosure is selected from MEDI6469, PF-04518600, KHK4083, BMS986178, MEDI0562, MOXR0916, MEDI6383, INCAGN01949.
  • the anti-OX40 antibody described in the present disclosure specifically binds to human OX40, and contains the CDRs shown below: heavy chain HCDR1, HCDR2, HCDR3 shown in the amino acid sequence of SEQ ID NO: 1, 2, and 3, or with SEQ ID
  • the HCDR1, HCDR2, and HCDR3 shown in NO: 1, 2, and 3 respectively have HCDR variants with 3, 2 or 1 amino acid difference; and the light chain LCDR1 shown in the amino acid sequence of SEQ ID NO: 6, 7, and 8 respectively , LCDR2, LCDR3 or LCDR1, LCDR2, LCDR3 shown in SEQ ID NO: 6, 7, 8 with 3, 2 or 1 amino acid difference, respectively, preferably containing SEQ ID NO: 3, 4, 5
  • the CDR (including 3 heavy chain CDRs and 3 light chain CDRs) of the monoclonal antibody or antigen-binding fragment has 3, 2 or 1 amino acid difference
  • CDR variants are screened by affinity maturation methods. Obtained CDR variants with 3, 2 or 1 amino acid difference.
  • the heavy chain HCDR2 variant of the OX40 antibody is shown in the amino acid sequence of SEQID NO: 12.
  • the anti-OX40 antibody described in the present disclosure is a murine antibody, a chimeric antibody or a humanized antibody, preferably a humanized antibody.
  • the humanized antibody comprises the heavy chain variable region shown in the amino acid sequence of SEQ ID NO: 11 or has at least 95% sequence identity with the heavy chain variable region, preferably comprising the amino acid sequence shown in SEQ ID NO: 11 The variable region of the heavy chain shown in the sequence.
  • the anti-OX40 antibody or antigen-binding fragment thereof comprises: the light chain variable region shown in the amino acid sequence of SEQ ID NO: 10 or having at least 95% sequence identity with it, preferably comprising the light chain variable region shown in SEQ ID NO: 10 ID NO: The variable region of the light chain shown in the 10 amino acid sequence.
  • the humanized antibody includes the heavy chain variable region shown in the amino acid sequence of SEQ ID NO: 11 and the light chain variable region shown in the amino acid sequence of SEQ ID NO: 10.
  • the anti-OX40 antibody includes a constant region; preferably, the antibody is a chimeric antibody or a humanized antibody, and the heavy chain constant region of the antibody is derived from human IgG1, IgG2, and IgG3 or IgG4 or its mutant sequence.
  • the light chain constant region is derived from human ⁇ , ⁇ chain or its mutant sequence.
  • the amino acid sequence of the heavy chain constant region is shown in SEQ ID NO: 13 or has at least 95% sequence thereof Identity
  • the amino acid sequence of the constant region of the light chain is shown in SEQ ID NO: 14 or has at least 95% sequence identity with it
  • most preferably the amino acid sequence of the constant region of the heavy chain is shown in SEQ ID NO: 13
  • the amino acid sequence of the light chain constant region is shown in SEQ ID NO: 14.
  • IgG1 heavy chain constant region 1 + IgG1 heavy chain constant region:
  • the anti-OX40 antibody comprises: the heavy chain amino acid sequence is shown in SEQ ID NO: 15 or has at least 85% sequence identity with it and the light chain amino acid sequence is shown in SEQ ID NO: 16 or It has at least 85% sequence identity; preferably, the heavy chain amino acid sequence is shown in SEQ ID NO: 15 and the light chain amino acid sequence is shown in SEQ ID NO: 16.
  • TLR agonists can be used with a uniform dose or a weight-based dose. In other embodiments, the TLR agonist is administered as a uniform dose. In some embodiments, the TLR agonist is administered as a weight-based dose.
  • the dosage may be within the following range of 0.1-1000 ⁇ g/kg, 0.5-500 ⁇ g/kg, 1-500 ⁇ g/kg; specifically, it may be 0.10 ⁇ g/kg, 0.20 ⁇ g/kg, 0.30 ⁇ g/kg, 0.40 ⁇ g/kg, 0.50 ⁇ g/kg, 0.60 ⁇ g/kg, 0.70 ⁇ g/kg, 0.80 ⁇ g/kg, 0.90 ⁇ g/kg, 1.00 ⁇ g/kg, 5 ⁇ g/kg, 10 ⁇ g/kg, 15 ⁇ g/kg, 20 ⁇ g/kg , 25 ⁇ g/kg, 30 ⁇ g/kg, 35 ⁇ g/kg, 40 ⁇ g/kg, 45 ⁇ g/kg, 50 ⁇ g/kg, 55 ⁇ g/kg, 60 ⁇ g/kg, 65 ⁇ g/kg, 70 ⁇ g/kg, 75 ⁇ g/kg, 80 ⁇ g/kg, 85 ⁇ g /kg, 90 ⁇ g/kg, 95 ⁇ g/kg, 100 ⁇ g/kg, 105 ⁇ g/kg,
  • the dose of the TLR agonist is selected from 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.40 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.60 mg, 0.65 mg, 0.70mg, 0.75mg, 0.80mg, 0.85mg, 0.90mg, 0.95mg, 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10mg, 11mg, 12mg , 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg.
  • the dose of the TLR agonist is selected from 0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10 mg, 11 mg, 12 mg, 13mg, 14mg, 15mg.
  • the dose of the TLR agonist is selected from 0.5 mg, 1 mg, 2.0 mg, 3 mg, 4.0 mg, 6.0 mg, 8 mg, 9 mg, and 12 mg.
  • the frequency of administration of TLR agonists is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, weekly Once, once every 2 weeks, once every 3 weeks, once every 4 weeks; preferably once a week, once every 2 weeks.
  • the frequency of administration of the TLR agonist is once a week.
  • the frequency of TLR agonist administration is once every 2 weeks.
  • the frequency of administration of the TLR agonist is once every 3 days.
  • the combined use provided by the present disclosure can be used with a uniform dose or a weight-based dose.
  • the anti-OX40 antibody or antigen binding portion thereof is administered as a uniform dose.
  • the anti-OX40 antibody or antigen binding portion thereof is administered as a weight-based dose.
  • the dosage may be in the following range: 0.01-10.0 mg/kg, 0.1-5 mg/kg, 0.1-2 mg/kg, for example, the dosage may be 0.01 mg/kg, 0.02 mg/kg, 0.03 mg /kg, 0.04mg/kg, 0.05mg/kg, 0.06mg/kg, 0.07mg/kg, 0.08mg/kg, 0.09mg/kg, 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg /kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg /kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg
  • the dose of the anti-OX40 antibody is selected from 0.03 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4 mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4 mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg.
  • the anti-OX40 antibody dose is selected from 0.03 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 1 mg/kg, 3 mg/kg , 5mg/kg.
  • the anti-OX40 antibody dose is selected from 0.03 mg/kg.
  • the anti-OX40 antibody dose is selected from 0.1 mg/kg.
  • the anti-OX40 antibody dose is selected from 0.3 mg/kg.
  • the anti-OX40 antibody dose is selected from 1 mg/kg.
  • the anti-OX40 antibody dose is selected from 3 mg/kg.
  • the anti-OX40 antibody dose is selected from 5 mg/kg.
  • the frequency of administration of anti-OX-40 antibody in the present disclosure is 3 times a week, 2 times a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, every 3 times. -6 months once, preferably 3 times a week or once every 4 weeks, most preferably once every 3 weeks.
  • the tumor described in the present disclosure is selected from squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma Cancer, gastric cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer , Endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, soft tissue sarcoma, neuroblastoma, penile cancer, melanoma, superficial spreading melanoma Tumors, lentigo melanoma, acral melanoma, nodular melanoma, multiple mye
  • the present disclosure provides a use of a compound represented by formula (I) or a complex or a pharmaceutically acceptable salt thereof in combination with the above-mentioned anti-OX40 antibody or antigen-binding fragment in the preparation of a medicine for preventing or treating tumors.
  • the tumor is preferably colon cancer.
  • the pharmaceutically acceptable salts of TLR agonists in the present disclosure can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valeric acid Salt, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate , Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonate, etc. , Maleate and hydrochloride are preferred, and dihydrochloride is most preferred.
  • the present disclosure provides a method for treating tumors, comprising administering to a patient a therapeutically effective amount of the above-mentioned TLR agonist and a therapeutically effective amount of the above-mentioned anti-OX40 antibody or antigen-binding fragment.
  • the present disclosure provides a method for treating colon cancer, which comprises administering to a patient a therapeutically effective amount of compound dihydrochloride represented by formula (I) and a therapeutically effective amount of the OX40 antibody or antigen-binding fragment.
  • the administration route of the anti-OX40 antibody or antigen-binding fragment in the present disclosure includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration routes, such as by injection or infusion.
  • the "parenteral administration” refers to administration modes other than enteral and local administration by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, Intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, intralesional, And electroporation in vivo.
  • the anti-OX40 antibody or antigen-binding fragment is administered by a non-parenteral route, in certain embodiments, orally.
  • non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical.
  • the route of administration of TLR agonists in the present disclosure may be the same as or different from the above-mentioned immune checkpoint inhibitors, specifically including oral, nasal, topical, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, intralesional or other gastric Parenteral administration route, the administration route of the TLR agonist in the present disclosure is preferably intratumoral administration in the lesion.
  • the present disclosure provides a method for treating tumors, comprising administering to a patient a therapeutically effective amount of the above-mentioned TLR agonist and a therapeutically effective amount of the above-mentioned anti-OX40 antibody or antigen-binding fragment.
  • the present disclosure provides a method for treating tumors, which includes intratumorally administering to a patient a therapeutically effective amount of the above-mentioned TLR agonist and tumor or intravenously administering to the patient a therapeutically effective amount of the above-mentioned anti-OX40 antibody or antigen-binding fragment.
  • the present disclosure provides a method for treating tumors, which comprises intratumorally administering a therapeutically effective amount of compound dihydrochloride of formula (I) to a patient and intravenously administering a therapeutically effective amount of the above-mentioned OX40 antibody or antigen-binding fragment to the patient.
  • the anti-OX40 antibody or antigen-binding fragment of the present disclosure can be constituted in a composition, for example, a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing an antibody and a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delaying agents that are physiologically compatible.
  • the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, spinal or epidermal administration (e.g., by injection or infusion),
  • the pharmaceutical composition of the present disclosure may include One or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifiers and dispersants.
  • TLR agonist provided by the present disclosure and the anti-OX40 antibody or the antigen-binding fragment thereof has unexpected remote effects.
  • uniform dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (e.g., 240 mg of anti-OX40 antibody).
  • BSA body surface area
  • weight-based dose refers to the dose calculated based on the weight of the patient and administered to the patient.
  • 10.0mg/kg means that 10.0mg per kg is administered based on the body weight of the subject.
  • the "combination" described in the present disclosure is a mode of administration, which means that at least an anti-OX40 antibody and a TLR agonist are administered within a certain period of time, and both drugs show pharmacological effects.
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the anti-OX40 antibody and TLR agonist can be administered simultaneously or sequentially. This period includes treatments in which the anti-OX40 antibody and the TLR agonist are administered via the same route of administration or different routes of administration.
  • anti-OX40 antibody and "antibody that binds to OX40” refer to antibodies that can bind to OX40 with sufficient affinity so that the antibody can be used as a diagnostic and/or therapeutic agent for targeting OX40.
  • antibody refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, and their antigenicity is also different.
  • immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain, and ⁇ chain respectively. , ⁇ chain and ⁇ chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • the light chain is divided into ⁇ chain or ⁇ chain by the difference of the constant region.
  • Each of the five Ig types can have ⁇ chain or ⁇ chain.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), and antibody fragments, as long as they exhibit The desired antigen binding activity can be obtained.
  • the antibody light chain variable region described in the present disclosure may further comprise a light chain constant region, and the light chain constant region comprises human or murine ⁇ , ⁇ chains or variants thereof, preferably ⁇ constant Area.
  • the antibody heavy chain variable region of the present disclosure may further comprise a heavy chain constant region, and the heavy chain constant region comprises human or murine IgG1, IgG2, IgG3, IgG4 or variants thereof,
  • the IgG1 constant region is preferred.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly and is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region (C region).
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conservative sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDR).
  • CDR complementarity determining regions
  • Each light chain variable region (VL) and heavy chain variable region (VH) is composed of 3 CDR regions and 4 FR regions.
  • the sequence from the amino terminal to the carboxy terminal is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2 and HCDR3.
  • the number and position of the CDR amino acid residues of the LCVR region and the HCVR region of the antibody or antigen-binding fragment described in the present disclosure comply with the known Kabat numbering rules.
  • the antibodies of the present disclosure include murine antibodies, chimeric antibodies, and humanized antibodies, preferably humanized antibodies.
  • antibody framework (FR) refers to a part of the variable domain VL or VH, which serves as a scaffold for the antigen binding loop (CDR) of the variable domain. Essentially, it is a variable domain without CDRs.
  • amino acid difference refers to the difference between a polypeptide and its variants, in a certain or certain amino acid positions on the polypeptide fragment, wherein the variants can be replaced, inserted or inserted into certain positions or positions on the polypeptide. Obtained by missing amino acids.
  • the "mutated sequence” mentioned in the present disclosure means that the nucleotide sequence and amino acid sequence of the present disclosure are different from the nucleotide sequence and amino acid sequence of the present disclosure under the condition that the nucleotide sequence and amino acid sequence of the present disclosure are modified by mutation, such as insertion or deletion. Nucleotide sequence and amino acid sequence in percent sequence identity.
  • the sequence identity described in the present disclosure may be at least 85%, 90% or 95%, non-limiting examples include 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%. Sequence comparison and determination of the percent identity between the two sequences can be performed through the default settings of the BLASTN/BLASTP algorithm available on the National Center For Biotechnology Institute website.
  • Homology and “identity” herein refer to the sequence similarity between two polynucleotide sequences or between two polypeptides. When positions in two comparison sequences are occupied by the same base or amino acid monomer subunit, for example, if each position of two DNA molecules is occupied by adenine, then the molecules are homologous at that position . The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared ⁇ 100.
  • the two sequences are 60% homologous; if there are 95 matches in 100 positions in the two sequences Or homology, then the two sequences are 95% homologous.
  • the comparison is made when two sequences are aligned to obtain the maximum percent homology.
  • Figure 3 Body weight change curve of tumor-bearing mice during treatment with test compound.
  • the experimental methods without specific conditions in the examples of the present disclosure usually follow conventional conditions, such as Cold Spring Harbor's antibody technology experimental manual, molecular cloning manual; or according to the conditions recommended by the raw material or commodity manufacturer.
  • Reagents without specific sources are conventional reagents purchased on the market.
  • the anti-human OX40 monoclonal antibody library is generated by immunizing mice.
  • Experimental mice of BalB/C and A/J strains Comparative Medicine Center of Yangzhou University, Animal Production License Number: SCXK ( ⁇ )2017-007), female, 10 weeks old.
  • the immune antigen is human OX40 recombinant protein with Fc tag (OX40-Fc: OX40 Leu 29-Ala 216 (Accession#NP_003318) fused with Fc), purchased from Acro Biosystems, catalog number #OX40-H5255, expressed in HEK293 as usual Method purification.
  • the ratio of antigen to adjuvant is 1:1, and 25 ⁇ g protein/200 ⁇ l/mouse is injected per immunization. See Table 1 below for details.
  • the mouse serum was detected by the following ELISA method to determine the antibody titer of the mouse serum and the neutralizing activity of blocking OX40/OX40L binding.
  • the mice with strong serum titer, affinity and ligand binding blocking ability were selected for a final immunization and then sacrificed.
  • the target hybridomas are selected by the following indirect ELISA, capture ELISA, and cell-based functional screening, and monoclonal antibodies are established by the limiting dilution method.
  • the 19 established strains of OX40 mouse monoclonal antibodies were produced by serum-free expression, and purified mouse monoclonal antibodies were obtained by protein A affinity chromatography technology.
  • the brief steps of functional screening are as follows: culture GS-H2/OX40 stable cell line (purchased from genscript, cat#M00608). Prepare diluted test antibody and OX40L (Sino Biological, 13127-H04H) solution and add them to GS-H2/OX40 cells in the logarithmic growth phase. After culture, the cell supernatant is collected and the IL-8 content in the supernatant is determined ( Use human IL-8 kit, cisbio, cat#62IL8PEB).
  • RNA can be obtained by conventional RNA extraction technology, and then the PCR product of the variable region of the monoclonal antibody can be obtained by reverse transcription polymerase chain reaction (RT-PCR).
  • RT-PCR reverse transcription polymerase chain reaction
  • the PCR products were separated and recovered by agarose gel, then cloned into gene vector and transformed into E. coli.
  • Several transformed colonies were randomly selected, and the variable regions of monoclonal antibodies were amplified by PCR for gene sequencing.
  • the corresponding sequence of the obtained exemplary murine monoclonal antibody is shown below.
  • the heavy and light variable region sequences of the murine monoclonal antibody m2G3 are as follows:
  • the heavy chain vector is designed as follows: signal peptide + heavy chain variable region sequence + human IgG1 constant region sequence.
  • the light chain vector is designed as follows: signal peptide + light chain variable region sequence + human Kappa constant region sequence. The above sequences were inserted into pCEP4 vector (Thermofisher, V04450).
  • the plasmid is drawn out, and the plasmid is sent to sequencing for verification.
  • the qualified plasmid was transfected into human 293F cells with PEI and cultured continuously, and the 293F cells were cultured with serum-free medium (Shanghai Optima Biotech, OPM-293CD03) to the logarithmic growth phase for cell transfection.
  • serum-free medium Shanghai Optima Biotech, OPM-293CD03
  • Cell culture conditions 5% CO 2 , 37°C, 125 rpm/min. During the culture period, feed was added on the 1st and 3rd day until the cell viability was less than 70%, and the cell supernatant was collected and centrifuged. Load the cell culture fluid after centrifugation and filtration on the antibody purification affinity column, wash the column with phosphate buffer, elution with glycine hydrochloric acid buffer (pH 2.7 0.1M Gly-HCl), neutralize with 1M Tris hydrochloric acid pH 9.0, and After dialysis with phosphate buffer, purified chimeric antibody Ch2G3 was finally obtained.
  • glycine hydrochloric acid buffer pH 2.7 0.1M Gly-HCl
  • the mouse antibody and chimeric antibody were tested for the affinity of human OX40 (the method steps are the same as the ELISA identification and screening method of 2 antibodies). Among them, m2G3-NC and ch2G3-NC are negative controls. The results show that the chimeric antibody Ch2G3 has high affinity with human OX40.
  • the EC50 (nM) of the Ch2G3 antibody is 0.6371, showing that the chimeric antibody Ch2G3 effectively activates the reporter gene.
  • the murine antibody was humanized.
  • the heavy chain variable region (VH) and the light chain variable region (VL) of the chimeric antibody were respectively used for site-specific amino acid mutations in the FR (framework region) region. According to different combinations of amino acid mutations, different humanized antibody weights were designed.
  • Humanized antibodies can be produced by transfecting cells with plasmids that combine different light and heavy chains. The brief description is as follows. First design the expression vector: the heavy chain vector is designed as follows: signal peptide + mutant heavy chain variable region sequence + human IgG1 constant region sequence.
  • the light chain vector is designed as follows: signal peptide + mutated light chain variable region sequence + human Kappa constant region sequence.
  • the above sequences were inserted into pCEP4 vector (Thermofisher, V04450). Ask a third-party gene synthesis company to synthesize the expression vector according to the above design, and after obtaining the vector plasmid, the plasmid will be large-scaled and sent to sequence verification.
  • the qualified plasmid was transfected into human 293F cells with PEI and cultured continuously, and the 293F cells were cultured with serum-free medium (Shanghai Optima Biotech, OPM-293CD03) to the logarithmic growth phase for cell transfection.
  • the sequence of the humanized variable region is as follows:
  • the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, the italic in the sequence is the FR sequence, and the underline is the CDR sequence.
  • the heavy chain variable region hu2G3 VH1.1 and the light chain variable region hu2G3 VL1 are combined to form a new optimized humanized antibody, see Table 4.
  • the aforementioned humanized antibody was subjected to affinity evaluation (refer to the capture ELISA in Example 2), and the experimental results showed that the humanized molecule can bind to OX40.
  • the light chain variable region and the light chain constant region sequence are combined to form the final light chain sequence, and each heavy chain variable region and the heavy chain constant region (for example, SEQ ID NO: 13) combined to form the final heavy chain sequence.
  • the specific light and heavy chain constant regions are not limited to the constant regions of the antibodies of the present disclosure, and other light and heavy chain constant regions and their mutants known in the art can also be used to increase the performance of the antibody.
  • An exemplary constant region is as follows:
  • IgG1 heavy chain constant region 1 + IgG1 heavy chain constant region:
  • the full-length amino acid sequence of an exemplary 2G3 antibody is as follows:
  • the Biacore method is a recognized method for objectively detecting mutual affinity and kinetics of proteins.
  • GE Biacore T200
  • the recombinant anti-OX40 antibody to be tested of the present disclosure was covalently connected to the CM5 (GE) chip using the NHS standard amino coupling method. Then, a series of concentration gradients of human OX40-His protein (Yiqiao Shenzhou #10481-H08H) diluted in the same buffer were injected into each cycle at a flow rate of 30 ⁇ L/min. After injection, all were regenerated in the kit Reagent regeneration. Track the antigen-antibody binding kinetics for 3 minutes and track the dissociation kinetics for 10 minutes.
  • Isolate CD4+ memory T cells add the antibody to be tested to a 96-well plate coated with anti-CD3 antibody (Chempartner, A05-001), incubate at 37°C for 72 hours, take the supernatant to detect IFN- ⁇ , the result is shown in Figure 2. .
  • GPX4 and 2G3 can significantly enhance the release of IFN- ⁇ , and 2G3 can achieve the maximum stimulation effect at 10ng/mL.
  • Anti-OX40 antibody inhibits tumor cell growth
  • B-hTNFRSF4 (OX40) humanized mouse B-hTNFRSF4 (OX40) humanized mouse, Biocytogen Jiangsu Gene Biotechnology Co., Ltd.), female, 17-20g, 6-7 weeks.
  • Collect logarithmic growth phase MC38 tumor cells 7 purchased from Nanjing Yinhe Biomedicine Co., Ltd.
  • PBS buffer PBS buffer
  • the average tumor volume on the flank of the tumor-bearing mice reached 102.5mm 3.
  • Grouping and drug administration observations were made according to the tumor size.
  • the specific grouping information is as follows:
  • the average tumor volume of the Vehicle (IgG1) control group reached 1732.593 mm 3
  • the average tumor volume of the mice in the low-dose administration group (0.3 mg/kg) of the test compound 2G3 reached 930.37 mm 3
  • the average tumor volume of tumor-bearing mice in the middle-dose administration group (2G3 1mg/kg) and the high-dose administration group (2G3 3mg/kg) were 303.49mm 3 and 155.79mm 3 , respectively.
  • the middle and high-dose groups inhibited tumor growth compared with the control group The difference was obvious (**P ⁇ 0.01), and showed a preliminary dose-dependent relationship.
  • the tumor growth inhibition rate reached 49%, 88% and 97.0%, respectively.
  • the average tumor volume of GPX4 3mg/kg tumor-bearing mice was 362.47mm 3 , which was significantly different from the Vehicle group. It also showed significant tumor growth inhibition (*P ⁇ 0.05), and its tumor growth inhibition rate reached 84. %
  • mice were euthanized, and the subcutaneous transplanted tumor mass of the tumor-bearing mice was stripped and weighed.
  • the vehicle group had an average tumor mass weight of 1.568g, and the test compound 2G3 in the low-dose group (0.3mg/kg), medium-dose group (1mg/kg) and high-dose group (3mg/kg), the average tumor weight was 0.926, respectively g, 0.251g and 0.181g, among which the high-dose group and the control group are significantly different, and the tumor growth inhibition effect is obvious (**P ⁇ 0.01).
  • the average tumor weight of GPX4 3mg/kg in the administration group was 0.372g, which was significantly different from that in the Vehicle group, and also showed a significant inhibitory effect on the growth of MC38 tumor cells (**P ⁇ 0.01).
  • Example 2 Preclinical evaluation of anti-OX40 antibody (drug A) and compound dihydrochloride (drug B) represented by formula (I) and single or combined drugs on the growth of hOX40 transgenic mice MC38 colon cancer xenografts .
  • MC38 tumor cells were purchased from Nanjing Yinhe Biomedical Co., Ltd. The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, and the cells were digested and passaged with EDTA-containing trypsin as usual, passaged twice a week, and placed in a 37°C, 5% CO 2 incubator for continued cultivation. Tumor cells in the logarithmic growth phase are used for the establishment of transplanted tumor models in vivo.
  • mice 75 humanized B-hTNFRSF4 (OX40) mice, female, 4-5 weeks, weighing 14-19g, provided by Biocytogen Jiangsu Gene Biotechnology Co., Ltd.
  • mice All the mice were raised in an SPF animal room IVC constant temperature and pressure system, where the temperature was 20-26°C, the humidity was 40-70%, and the light cycle was 12 hours bright and 12 hours dark. 6 mice were raised in each cage, the size of the cage was 325mmx210mmx180mm, and the litter in the cage was changed twice a week.
  • Drug A The preparation method is as in Example 1, specifically 2G3.
  • Mouse TLR9 agonist ODN-1826, purchased from Suzhou Hongxun Biotechnology Co., Ltd.
  • N Number of animals used
  • intratumoral injection intravascular injection only on the right side
  • intratumoral injection volume is 0.1mL/mouse
  • intraperitoneal injection is adjusted according to the weight of tumor-bearing mice (0.1mL/10g).
  • the first and fourth groups of this experiment ended on the 18th day after grouping, and the second, third, and fifth to tenth groups ended on the 21st day after grouping.
  • the first group is the vehicle group.
  • the main purpose is to detect the growth inhibitory effect of (OX40) humanized mouse MC38 colon cancer cell transplantation tumor.
  • RTV T/C Relative Tumor Volume
  • V o is the tumor volume of each mouse in the group at the beginning of the administration
  • V t is the measurement after each administration Tumor volume.
  • TRTV average relative tumor volume RTV of tumor-bearing mice in the test drug group
  • CRTV average relative tumor volume of mice in the control group
  • TGI (%) [1-T/C] ⁇ 100
  • BWL(%) (BW i -BW 0 )/BW 0 ⁇ 100
  • BW i is the average body weight after the start of administration
  • BW 0 is the average at the first administration body weight.
  • Table 14 Shows the tumor volume on the right side of the mouse after treatment
  • Table 15 Shows the tumor volume on the left side of the mouse after treatment
  • the average tumor volume on the right side of the tumor-bearing mice in group 2, group 3, group 5, group 6, group 7, group 8, 9 and group 10 was 649.96mm 3 , 768.28mm 3 , 1013.28mm 3 , 824.27mm 3 , 334.23mm 3 , 536.72mm 3 , 231.48mm 3 and 239.03mm 3 , which are significantly different from the Vehicle group, and have a significant inhibitory effect on tumor growth (*P ⁇ 0.05,* *P ⁇ 0.01) (see Figure 1, Table 14, Table 16), the tumor growth inhibition rate reached 76.83%, 73.75%, 63.42%, 70.48%, 88.03%, 81.63%, 92.0% and 91.69% (see Table 16).
  • the average tumor volume on the left side of the tumor-bearing mice were 1084.84mm 3 , 917.22mm 3 , 1470.54mm 3 , 947.32mm 3 , 490.11mm 3 , 644.32mm 3 , 498.02mm 3 and 349.66mm 3 , respectively, and the Vehicle group
  • the difference is significant, and it has a significant effect of inhibiting tumor growth (*P ⁇ 0.05, **P ⁇ 0.01), and its tumor growth inhibition rate reached 48.48%, 69.09%, 43.51%, 62.62%, 76.66%, 77.28%, respectively , 79.44% and 90.22% (see Figure 2, Table 15, Table 17).

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Abstract

L'invention concerne l'utilisation d'une combinaison d'un agoniste de TLR et d'un anticorps anti-OX40 ou d'un fragment de liaison à l'antigène de ceux-ci dans la préparation du médicament pour le traitement de tumeurs. Spécifiquement, l'agoniste de TLR est le composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/098409 2019-06-28 2020-06-28 Utilisation d'une combinaison d'un agoniste de tlr et d'un anticorps anti-ox40 ou d'un fragment de liaison à l'antigène de ceux-ci dans la préparation d'un médicament pour le traitement de tumeurs WO2020259667A1 (fr)

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CN112957475A (zh) * 2021-02-04 2021-06-15 李文峰 一种预防和或治疗肿瘤的组合物及应用
WO2023001118A1 (fr) * 2021-07-19 2023-01-26 百奥泰生物制药股份有限公司 Application d'anticorps anti-ox40 dans un médicament combiné

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WO2013038191A2 (fr) * 2011-09-16 2013-03-21 Bioceros B.V. Anticorps anti-cd134 (ox40) et leurs utilisations
WO2015153513A1 (fr) * 2014-03-31 2015-10-08 Genentech, Inc. Anticorps anti-ox40 et procédés d'utilisation correspondants
WO2016179517A1 (fr) * 2015-05-07 2016-11-10 Agenus Inc. Anticorps anti-ox40 et procédés d'utilisation de ceux-ci
WO2017021912A1 (fr) * 2015-08-06 2017-02-09 Glaxosmithkline Intellectual Property Development Limited Modulateurs de tlr combinés avec anticorps anti-ox40
WO2017096182A1 (fr) * 2015-12-03 2017-06-08 Agenus Inc. Anticorps anti-ox40 et leurs procédés d'utilisation
WO2018045058A1 (fr) * 2016-08-30 2018-03-08 Dana-Farber Cancer Institute, Inc. Compositions d'administration de médicament et leurs utilisations
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112957475A (zh) * 2021-02-04 2021-06-15 李文峰 一种预防和或治疗肿瘤的组合物及应用
WO2023001118A1 (fr) * 2021-07-19 2023-01-26 百奥泰生物制药股份有限公司 Application d'anticorps anti-ox40 dans un médicament combiné

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