WO2020108612A1 - Utilisation de conjugué anticorps-médicament de c-met dans la préparation d'un médicament destiné à traiter une maladie résistante aux inhibiteurs de la kinase c-met - Google Patents

Utilisation de conjugué anticorps-médicament de c-met dans la préparation d'un médicament destiné à traiter une maladie résistante aux inhibiteurs de la kinase c-met Download PDF

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WO2020108612A1
WO2020108612A1 PCT/CN2019/121943 CN2019121943W WO2020108612A1 WO 2020108612 A1 WO2020108612 A1 WO 2020108612A1 CN 2019121943 W CN2019121943 W CN 2019121943W WO 2020108612 A1 WO2020108612 A1 WO 2020108612A1
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antibody
met
cancer
seq
human
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PCT/CN2019/121943
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English (en)
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
苏州盛迪亚生物医药有限公司
上海恒瑞医药有限公司
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Priority to CN201980072269.1A priority Critical patent/CN112996540B/zh
Publication of WO2020108612A1 publication Critical patent/WO2020108612A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • 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
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure provides the use of an anti-c-Met antibody drug conjugate (c-Met ADC) in the preparation of a medicament for treating diseases resistant to c-Met kinase inhibitors.
  • c-Met ADC anti-c-Met antibody drug conjugate
  • the c-Met proto-oncogene is located on the long arm of human chromosome 7 (7q31), is over 120 kb in size, and encodes a precursor of c-Met protein with a molecular weight of about 150 kD. After local glycosylation, a 170 kD glycoprotein is generated. It is cleaved into ⁇ subunit (50kDa) and ⁇ subunit (140kDa), connected by disulfide bonds to form a mature c-Met protein receptor.
  • the heterodimer contains two chains, the ⁇ chain has an extracellular region, a transmembrane region (also called membrane stretch) and an intracellular region (including the intracellular tyrosine kinase binding site).
  • the alpha chain only has an extracellular part, but it is highly glycosylated and attaches to the beta chain through disulfide bonds.
  • the extracellular region of the two subunits is the recognition site of the corresponding ligand, and the intracellular region has tyrosine kinase activity.
  • the mechanism of c-Met activation is divided into three types: one is the HGF-dependent activation mechanism, the second is the HGF-independent activation mechanism, and the third is through other membrane pathways, such as CD44, adhesin, and surface receptors through hyaluronic acid membrane surface receptors. RON signaling pathway and so on. The most common of these is the HGF-dependent activation mechanism.
  • the N-terminus of HGF binds to c-Met, which promotes the dimerization and autophosphorylation of Tyr1234 and Tyr1235 on the ⁇ chain. Phosphorylation of Tyr1349 and Tyr1356 near the C-terminus produces multiple binding sites for linker proteins.
  • linker proteins induce Activation of downstream signals mediated by P13K/Akt, Ras/Mapk, c-Src, and STAT3/5 triggers different cellular responses, such as cell survival and activity (closely related to P13K/Akt pathway), tumor metastasis, and cell proliferation (mainly (Mediated by Ras/Mapk).
  • cell survival and activity closely related to P13K/Akt pathway
  • tumor metastasis mainly (Mediated by Ras/Mapk).
  • cell proliferation mainly (Mediated by Ras/Mapk).
  • cross-talk between c-Met and other membrane receptors It is now known that this cross-linking can promote tumor formation and metastasis. Since c-Met is a cross-point of many pathways that lead to tumor formation and metastasis With c-Met as the target, it is relatively easy to achieve simultaneous interference with many pathways, and c-Met has become a promising target for anti-tumor generation and metastasis therapy.
  • Antibody drug conjugates connect monoclonal antibodies or antibody fragments to biologically active cytotoxins through stable chemical linker compounds, making full use of the specificity of antibodies for tumor cell specific or highly expressed antigen binding And the high efficiency of cytotoxins, to avoid toxic and side effects on normal cells. This means that, compared with traditional chemotherapy drugs, antibody-drug conjugates can accurately bind tumor cells and reduce the impact on normal cells.
  • ADC drugs are composed of antibody (targeting part), linker and toxin. Among them, a good targeting part determines the specificity of ADC drugs, which includes not only specific targeted binding, but also effective endocytosis.
  • WO2016/165580A discloses a class of c-Met antibody drug conjugates, which can be used to treat gastric cancer, pancreatic cancer, lung cancer, intestinal cancer, renal cancer, melanoma, etc., which are resistant to c-Met kinase inhibitor treatment Whether the disease is effective is not mentioned, and c-Met kinase inhibitor resistance is the main problem of this class of drugs.
  • the disclosure provides the use of an anti-c-Met antibody drug conjugate in the preparation of a medicament for treating diseases resistant to c-Met kinase inhibitors.
  • c-Met kinase inhibitor-resistant diseases mentioned in this disclosure refer to diseases that are drug-resistant after treatment with c-Met kinase inhibitors, including but not limited to gastric cancer, esophageal cancer, renal cancer including papillary kidney cells Cancer, lung cancer, glioma, head and neck cancer, epithelial cancer, skin cancer, leukemia, lymphoma, myeloma, brain cancer, pancreatic cancer, colorectal cancer, gastrointestinal cancer, intestinal cancer, genital cancer, urinary cancer, melanin Tumor and prostate cancer are preferably non-small cell lung cancer.
  • the non-small cell lung cancer described in this disclosure is selected from squamous cell carcinoma and non-squamous cell carcinoma.
  • the anti-c-Met antibody drug conjugate described in this disclosure is selected from ABBV-399.
  • the antibody includes the CDR shown below: includes the CDR shown below:
  • Antibody heavy chain variable region HCDR region sequence SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3;
  • Antibody Optimized humanized antibodies Heavy chain CDR1 NYGVH(SEQ ID NO: 1) Heavy chain CDR2 VIWSGGSTNYAAAFVS(SEQ ID NO: 2) Heavy chain CDR3 NHDNPYNYAMDY(SEQ ID NO: 3) Light chain CDR1 RADKSVSTSTYNYLH(SEQ ID NO: 7) Light chain CDR2 LASNLAS(SEQ ID NO:5) Light chain CDR3 QHSRDLPPT(SEQ ID NO: 6)
  • the anti-c-Met antibody or antigen-binding fragment thereof in the anti-c-Met antibody drug conjugate described in the present disclosure wherein the antibody is selected from a murine antibody, a chimeric antibody or a humanized antibody.
  • the heavy chain constant region of the humanized antibody comprises human-derived IgG1 Or a variant thereof, human IgG2 or a variant thereof, human IgG3 or a variant thereof or a constant region of human IgG4 or a variant thereof, preferably comprising human IgG1 or a variant thereof or human IgG2 or a variant thereof or
  • the constant region of human IgG4 or its variants more preferably the constant region of human IgG2 or its variants;
  • the light chain constant region of said humanized antibodies comprises those selected from human ⁇ or ⁇ chains or their variants Constant area.
  • the anti-c-Met receptor antibody or antigen-binding fragment thereof in the anti-c-Met antibody drug conjugate described in the present disclosure wherein the antibody comprises: heavy chain constant region amino acid sequence such as SEQ ID NO: 8 shows or has at least 85% sequence homology and the light chain constant region amino acid sequence is shown in SEQ ID NO: 9 or has at least 85% sequence homology with it, preferably the heavy chain constant region amino acid sequence is like SEQ ID NO :8 and the amino acid sequence of the light chain constant region are shown in SEQ ID NO:9.
  • the heavy chain of the anti-c-Met antibody in the anti-c-Met antibody drug conjugate of the present disclosure has 95% sequence homology with the Ab-10 antibody heavy chain amino acid sequence, the anti-c-Met antibody
  • the amino acid sequence of the light chain has 95% sequence homology with the antibody light chain of Ab-10, the heavy chain sequence of Ab-10 antibody is shown in SEQ ID NO: 10, and the light chain sequence of Ab-10 antibody is shown in SEQ ID NO: 11 shows.
  • the "Ab-10” described in the present disclosure is the c-Met antibody Ab-10 disclosed in WO2016/165580A1, and Ab-10 humanized antibody:
  • the anti-c-Met antibody drug conjugate in this disclosure is ADC-12 and has the structure shown below:
  • the range of y is 1-8, including 1, 2, 3, 4, 5, 6, 7, and 8, preferably 2-5, and the Ab-10 is a c-Met antibody.
  • the antibody in the anti-c-Met antibody drug conjugate contains at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93 with the amino acid sequence SEQ ID NO: 10 %, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of the heavy chain sequence, and the amino acid sequence SEQ ID NO: 11 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of the light chain sequence.
  • the anti-c-Met kinase inhibitors described in this disclosure are selected from Merestinib, Cabozantinib S-malate, Crizotinib, Sitravatinib, S-49076, Tepotinib, PLB-1001, BPI-9016M, MP-0250, Savolitinib, Sym-015, AMC -303, OMO-1, Capmatinib, TAS-115, HH-SCC-244, Ningetinib, CM-118, HQP-8361, TQ-B3139, BMS-817378, HS-10241, Altiratinib, ASLAN-002 and AL-2846 , Preferably Crizotinib.
  • the dosage of the anti-c-Met antibody drug conjugate described in the present disclosure is selected from 0.05-10 mg/kg, preferably 0.1-5 mg/kg, 0.2-5 mg/kg, 0.3-3.0 mg/kg and 0.6-2.0 mg /kg; including but not limited to 0.05mg/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, 1.1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg, 1.7mg/kg, 1.8mg/ kg, 1.9mg/kg, 2.0mg/kg, 2.1mg/kg, 2.2mg/kg, 2.3mg/kg, 2.4mg/kg, 2.5mg/kg, 2.6mg/kg,
  • the dosing regimen of the anti-c-Met antibody drug conjugate described in the present disclosure is: the administered dose is selected from 0.05 mg/kg to 3.3 mg/kg, and the administered frequency is selected from every two weeks Once or every three weeks.
  • the dosing regimen of the anti-c-Met antibody drug conjugate described in this disclosure is: the administered dose is selected from 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg /kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg and 1.0mg/kg, the frequency of administration is selected from once every two weeks or every three Once a week.
  • the dosing regimen of the anti-c-Met antibody drug conjugate described in the present disclosure is: the administered dose is selected from 0.05 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, 0.8 mg/kg, 0.9 mg/kg and 1.0 mg/kg, the frequency of administration is selected once every three weeks.
  • the dosing regimen of the anti-c-Met antibody drug conjugate described in this disclosure is: the administered dose is selected from 1.6 mg/kg or 1.9 mg/kg, and the administered frequency is selected from every two weeks Once; or the dosage is selected from 2.7mg/kg or 3.0mg/kg, the frequency of administration is selected once every three weeks.
  • the present disclosure provides a method for treating diseases resistant to c-Met kinase inhibitors, and provides a therapeutically effective amount of c-Met antibody drug conjugates to patients.
  • the diseases resistant to c-Met kinase inhibitors are selected from gastric cancer, esophageal cancer, renal cancer including papillary renal cell carcinoma, lung cancer, Glioma, head and neck cancer, epithelial cancer, skin cancer, leukemia, lymphoma, myeloma, brain cancer, pancreatic cancer, colorectal cancer, gastrointestinal cancer, intestinal cancer, genital cancer, urinary cancer, melanoma, prostate cancer , Preferably non-small cell lung cancer.
  • the present disclosure provides a method of treating non-small cell lung cancer by intravenously administering a therapeutically effective amount of c-Met antibody drug conjugate to a patient with Crizotinib resistance.
  • the present disclosure provides a method for treating non-small cell lung cancer by intravenously administering 1-1000 mg of c-Met antibody drug conjugate in Crizotinib-resistant patients once every two weeks or once every three weeks.
  • the c-Met antibody drug conjugate described in the present disclosure may be constituted in a composition, for example, a pharmaceutical composition containing the c-Met antibody drug conjugate and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, spinal or epidermal administration (eg, by injection or infusion), and 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, emulsifying agents, and dispersing agents.
  • the c-Met antibody drug conjugate composition includes a c-Met antibody drug conjugate, and other excipients selected from buffers, sugars, and surfactants
  • the buffer is preferably a succinate or citrate buffer, more preferably a succinate buffer
  • the sugar includes monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars Sugar, etc., preferably trehalose or sucrose.
  • the surfactant is selected from polysorbate 20, polysorbate 80, polyhydroxyalkylene, Triton, sodium dodecyl sulfonate, sodium lauryl sulfonate, octyl Sodium glycosides, lauryl-, myristyl-, linoleyl-, stearyl-sulfobetaine, lauryl-, myristyl-, linoleyl-, stearyl-sarcosine, Oleyl-, myristyl-, cetyl-betaine, lauramidopropyl-, cocaamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmitoyl Propyl-, isostearamidopropyl-betaine, myristamidopropyl-, palmitoylpropyl-, isostearamidopropyl-dimethylamine, sodium methylcocoyl
  • the route of administration of the c-Met antibody drug conjugate described in this disclosure includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.
  • the "parenteral administration” refers to modes of administration 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, subepidermal, intraarticular, subcapsular, subarachnoid, intraspine, epidural, and intrasternal injection and infusion, as well as in vivo electrical perforation.
  • the c-Met antibody drug conjugate is administered by a non-parenteral route, and in certain embodiments, is administered orally.
  • Other non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasally, vaginally, rectally, sublingually or locally.
  • c-Met or "c-Met polypeptide” or “c-Met receptor” refers to a receptor tyrosine kinase that binds to cell growth factor (HGF).
  • HGF cell growth factor
  • m-c-Met murine c-Met
  • cyno-c-Met monkey c-Met
  • the human, mouse, and cynomolgus monkey c-Met used in this disclosure are all encoded by the nucleotide sequence or polypeptide sequence provided by GenBank, for example, the human polypeptide encoded by the nucleotide sequence provided in GenBank accession number NM_000245, or by GenBank The human protein or its extracellular domain encoded by the polypeptide sequence provided in accession number NP_000236.
  • GenBank GenBank accession number NM_000245
  • GenBank GenBank
  • the original single-chain precursor protein is cleaved after translation to produce alpha and beta subunits, which are connected by disulfide bonds to form mature receptors.
  • Receptor tyrosine kinase c-Met is involved in cellular processes including, for example, migration, invasion and morphogenesis of tissue regeneration accompanying embryogenesis.
  • immunoglobulin which is a tetrapeptide chain structure formed by connecting two identical heavy chains and two identical light chains through interchain disulfide bonds.
  • the immunoglobulin heavy chain constant region has different amino acid composition and arrangement order, so its antigenicity is also different.
  • immunoglobulins can be divided into five categories, or isotypes called immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, the corresponding heavy chains are ⁇ chain, ⁇ chain, ⁇ chain , ⁇ chain, ⁇ chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • the light chain is divided into a kappa chain or a lambda chain by different constant regions.
  • Each of the five types of Ig can have a ⁇ chain or a ⁇ chain.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly and is a variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and are constant regions (C region).
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences.
  • the three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR).
  • CDR complementarity determining region
  • Each light chain variable region (LCVR) and heavy chain variable region (HCVR) are composed of 3 CDR regions and 4 FR regions, and the sequence from the amino terminal to the carboxy terminal is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the number and position of the CDR amino acid residues in the LCVR region and HCVR region of the antibody or antigen-binding fragment of the invention conform to the known Kabat numbering rules.
  • murine antibody in this disclosure is a monoclonal antibody against human c-Met prepared with mice according to the knowledge and skills in the art. During preparation, the test subject is injected with c-Met antigen, and then the hybridoma expressing the antibody having the desired sequence or functional characteristics is isolated.
  • the murine c-Met antibody or antigen-binding fragment thereof may further comprise the light chain constant region of murine ⁇ , ⁇ chain or a variant thereof, or further comprise murine IgG1 , IgG2, IgG3 or IgG4 or its heavy chain constant region.
  • chimeric antibody is an antibody obtained by fusing the variable region of a murine antibody and the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
  • To build a chimeric antibody we must first build a hybridoma that secretes murine specific monoclonal antibodies, and then clone the variable region gene from the mouse hybridoma cells, and then clone the human antibody constant region gene for recombinant expression.
  • humanized antibody also known as CDR-grafted antibody (CDR-grafted antibody) humanization
  • CDR-grafted antibody refers to the transplantation of mouse CDR sequences into the framework of human antibody variable regions, that is, different types of Antibodies produced in human germline antibody framework sequences. It can overcome the strong antibody variable antibody reaction induced by the chimeric antibody due to carrying a large amount of mouse protein components.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, EA People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the c-Met humanized antibody mouse CDR sequence is selected from SEQ ID NO: 6, 7, 8, 9, 10, 11 (please check the #s, in case just copy from sosdraft).
  • the human antibody variable region framework has been designed and selected, wherein the light chain FR region sequence on the antibody light chain variable region is selected from human germline light chain sequences, preferably human germline light chain IGKV085 or IGKV 4-1* 01, including FR1, FR2, FR3 and FR4 regions of human germline light chains IGKV085 and IGKV 4-1*01; wherein the heavy chain FR region sequence on the antibody heavy chain variable region is derived from human germline heavy
  • the chain sequence is preferably the human germline heavy chain IGHV 3-33*01; it contains the FR1, FR2, FR3 and FR4 regions of the human germline heavy chain IGHV 3-33*01.
  • the variable region of the human antibody can be subjected to the least reverse mutation to maintain the activity.
  • the resulting DNA sequence encoding the humanized variable heavy chain and variable light chain sequences is then expressed to produce a humanized antibody that binds c-Met.
  • the humanized HCVR and LCVR can be expressed as part of the entire anti-sclerostin antibody molecule, ie expressed as a fusion protein with human constant domain sequences. However, the HCVR and LCVR sequences can also be expressed in the absence of constant sequences to generate humanized anti-c-Met scFv.
  • the "antigen-binding fragment” in the present disclosure refers to a Fab fragment having an antigen-binding activity, a Fab' fragment, an F(ab') 2 fragment, and an Fv fragment scFv fragment that binds to human c-Met.
  • the Fv fragment contains the antibody heavy chain variable region and light chain variable region, but has no constant region, and has the smallest antibody fragment with all antigen binding sites.
  • Fv antibodies also contain a polypeptide linker between the VH and VL domains, and are capable of forming the structure required for antigen binding. Different linkers can also be used to connect the variable regions of two antibodies into a single polypeptide chain, called single chain antibody (single chain antibody) or single chain Fv (scFv).
  • the scFv can also be used to construct bispecific antibodies with other antibodies, such as anti-EGFR antibodies.
  • binding to c-Met in the present disclosure refers to the ability to interact with human c-Met.
  • antigen binding site of the present disclosure refers to a discontinuous three-dimensional site on the antigen recognized by the antibody or antigen-binding fragment of the present disclosure.
  • the "ADCC” described in this disclosure namely antibody-dependent cell-mediated cytotoxicity, refers to antibody-dependent cell-mediated cytotoxicity, which means that cells expressing the Fc receptor directly kill the antibody coating by recognizing the Fc segment of the antibody Target cells. The ADCC effect function of the antibody can be reduced or eliminated by modifying the Fc segment on IgG.
  • the modification refers to mutation in the constant region of the heavy chain of the antibody, such as N297A, L234A, L235A selected from IgG1; F235E from IgG2/4chimera, IgG4, or L234A/E235A mutation.
  • administering when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids refer to exogenous drugs, therapeutic agents, diagnostic agents or compositions and animals, humans, subjects Subjects, cells, tissues, organs or biological fluids.
  • administering and “treatment” may refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental methods.
  • the treatment of cells includes the contact of reagents with cells and the contact of reagents with fluids, wherein the fluids are in contact with cells.
  • Treatment means administration of a therapeutic agent for internal or external use to a patient, such as a composition comprising any of the binding compounds of the present disclosure, the patient has one or more symptoms of the disease, and the therapeutic agent is known to have Therapeutic effect.
  • the therapeutic agent is administered in an amount effective to relieve one or more symptoms of the disease in the treated patient or population, whether by inducing regression of such symptoms or inhibiting the development of such symptoms to the extent of any clinical measurement.
  • the amount of therapeutic agent effective to relieve the symptoms of any specific disease can vary based on various factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce a desired therapeutic effect in the patient.
  • the embodiments of the present disclosure may be ineffective in relieving the symptoms of the target disease that each patient has, but according to any statistical test methods known in the art such as Student test, chi-square test, and evidence Mann and Whitney's U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test determined that they should alleviate the target disease symptoms in a statistically significant number of patients.
  • Effective amount or effective dose contains an amount sufficient to ameliorate or prevent the symptoms or conditions of medical conditions.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of the method of administration, and the severity of side effects.
  • the effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • the human and animal surface area calculation method can be used for conversion. 1) The human body surface area calculation method is generally regarded as Xu Wen's formula (Chinese Journal of Physiology, 12,327, 1937) and Mech-Rubner's formula. The above method can be applied to the conversion of drug doses between humans and different kinds of animals in this disclosure.
  • “Homology” refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When the positions in the two compared 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 matched or homologous positions shared by the two sequences divided by the number of compared positions ⁇ 100. For example, when the sequences are optimally aligned, if there are 6 matches or homology at 10 positions in the two sequences, then the two sequences are 60% homologous. In general, the comparison is made when the two sequences are aligned to obtain the maximum percentage of homology.
  • Conjugates are antibody components or other targeting moieties conjugated to therapeutic agents as described above. As used herein, the terms “conjugate” and “immunoconjugate” are used interchangeably.
  • figure 1 Lung cancer xenograft model LU1902 tumor-bearing mice body weight change curve during drug A and Crizotinib monotherapy;
  • FIG. 1 Lung cancer xenograft model LU1902 tumor-bearing mice tumor volume change curve in drug A and Crizotinib monotherapy.
  • Example 1 under the skin Pharmacodynamic study of lung cancer allograft model LU1902 in Balb/c nude mice.
  • the maintained seed tumor LU1902 was used to inoculate the right scapula of 6-7 week old female Balb/C nude nude mice.
  • mice in good condition with an average tumor size of 132 mm 3 were randomly divided into 6 groups, with 6 mice in each group.
  • the six dose groups were: solvent control group (IgG1), drug A 1 mg/kg group, drug A 3 mg/kg group, drug A 10 mg/kg group, naked anti-10 mg/kg group, Crizotinib 30 mg/kg group.
  • Drug A was given twice a week through the tail vein, and Crizotinib was given by gavage once a day.
  • the total administration period of the experiment was 11 days.
  • Drug A for injection was administered three times, and Crizotinib was administered eleven times.
  • the first, fifth and sixth groups ended the experiment on the 13th and 15th days after grouping respectively.
  • the test drug A and the naked anti-drug group were followed up for 4 weeks, and ended the experiment 42 days after the grouping.
  • Drug A c-Met antibody drug conjugate; i.v. intravenous injection; p.o. oral administration.
  • mice female BALB/C nude mice; supplier is Shanghai Lingchang Biotechnology Co., Ltd.; age: 8-9 weeks (start of administration); number of experimental animals: 36 mice plus 60 surpluses.
  • Non-small cell lung cancer model It originated from a 65-year-old female patient with a pathological diagnosis of large cell undifferentiated carcinoma and a genetic diagnosis of c-Met expansion (HGF-independent).
  • Lung cancer It is a non-small cell lung cancer xenograft model of Crizotinib resistance after long-term treatment with Crizotinib (30mg/kg, once a day).
  • Test drug c-Met antibody drug conjugate (Drug A)
  • Preparation method refer to Example 24 of WO2016/165580A.
  • Control Ab-10 naked antibody, the heavy chain amino acid sequence is shown in SEQ ID NO: 10, and the light chain sequence is shown in SEQ ID NO: 11.
  • Control drug Crizotinib
  • provider Selleck.
  • the packaging and storage conditions of the above drug A and the control naked anti-Ab-10 are -20°C.
  • the diameter of the tumor was measured with vernier calipers twice a week.
  • the compound's antitumor efficacy was evaluated by TGI (%) or relative tumor proliferation rate T/C (%).
  • T/C (%) T RTV /C RTV (T RTV : average value of RTV in treatment group; C RTV : average value of RTV in negative control group).
  • RTV relative tumor volume
  • TGI (%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment of the solvent control group-treatment of the solvent control group Mean tumor volume)]*100%.
  • the Study Director version number 3.1.399.19, supplier Studylog System, Inc
  • the original data was directly imported into the software after being measured by the balance and vernier calipers. Recorded in this software.
  • the weight of tumor-bearing mice in each treatment group and solvent treatment group is shown in Table 5 below.
  • the body weight change curves and percentage body weight change curves of tumor-bearing mice in each treatment group and solvent treatment group are shown in Figure 1 and Figure 2, respectively.
  • the p value is obtained by using one-way ANOVA (one-way ANOVA) tumor volume, and the F value is significantly different (p ⁇ 0.05). Dunnett’s T3 method is used for analysis
  • the tumor volume change curves of tumor-bearing mice in each treatment group and solvent treatment group are shown in Figure 2.
  • the average tumor volume of the mice in the control group reached 3383.07 mm 3 .
  • the mean tumors of the test drug Drug A 1 mg/kg treatment group (Group 2), drug A 3 mg/kg treatment group (Group 3), drug A 10 mg/kg treatment group (Group 4)
  • the volume was reduced and disappeared to 0mm 3 , and the TGI reached 99.13%, 99.83% and 99.91% respectively.
  • the role of tumor growth in lung cancer xenograft model LU1902 (P ⁇ 0.05).
  • the role of tumor growth in lung cancer xenograft model LU1902 P>0.05.
  • the average tumor weight of the control group reached 3.8376 g.
  • the mean tumors of the test drug Drug A 1 mg/kg treatment group (Group 2), drug A 3 mg/kg treatment group (Group 3), drug A 10 mg/kg treatment group (Group 4) The weight reaches 0.0000g.
  • the test drug A 1mg/kg treatment group (group 2), drug A 3mg/kg treatment group (group 3), drug A 10mg/kg treatment group (group 4) all have statistics Learn significant anti-subcutaneous The role of tumor growth in lung cancer xenograft model LU1902 (P ⁇ 0.05).
  • the injection drug A can significantly inhibit the subcutaneous lung when treated with 1mg/kg, 3mg/kg and 10mg/kg respectively.

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Abstract

La présente invention concerne l'utilisation d'un conjugué anticorps-médicament (CAM) de c-Met dans la préparation d'un médicament destiné à traiter une maladie résistante aux inhibiteurs de la kinase c-Met. L'invention concerne en particulier l'utilisation d'un conjugué anticorps-médicament anti-c-Met dans la préparation d'un médicament destiné au traitement d'une maladie résistante aux inhibiteurs de la kinase c-Met, en particulier du cancer du poumon non à petites cellules, traité par inhibiteur de kinase c-Met et résistant à celui-ci. Le conjugué anticorps-médicament anti-c-Met selon l'invention est tel que présenté dans la description.
PCT/CN2019/121943 2018-11-30 2019-11-29 Utilisation de conjugué anticorps-médicament de c-met dans la préparation d'un médicament destiné à traiter une maladie résistante aux inhibiteurs de la kinase c-met WO2020108612A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022048521A1 (fr) * 2020-09-01 2022-03-10 荣昌生物制药(烟台)股份有限公司 Conjugué médicament-anticorps anti c-met et ses applications
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