WO2020108612A1 - 一种c-Met ADC在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途 - Google Patents

一种c-Met ADC在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途 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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French (fr)
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蒋家骅
廖成
张连山
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
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Priority to CN201980072269.1A priority Critical patent/CN112996540B/zh
Publication of WO2020108612A1 publication Critical patent/WO2020108612A1/zh
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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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], 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

本公开提供一种c-Met ADC在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途。具体而言，本公开提供了一种抗c-Met抗体药物偶联物在在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途，特别是经c-Met激酶抑制剂治疗后耐药的非小细胞肺癌，所述的抗c-Met抗体药物偶联物如说明书所述。

Description

一种c-Met ADC在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途
发明内容
本公开提供一种抗c-Met抗体药物偶联物(c-Met ADC)在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途。
背景技术
c-Met原癌基因位于人类第7号染色体长臂(7q31)，大小超过120kb，编码分子量约150kD的c-Met蛋白前体，经局部糖基化生成一个170kD的糖蛋白，该糖蛋白进一步剪切为α亚基(50kDa)和β亚基(140kDa)，以二硫键相连，形成成熟的c-Met蛋白受体。该异二聚体包含两条链，β链有胞外区、跨膜区(也称膜伸展片段)和胞内区(包含细胞内酪氨酸激酶结合位点)。α链只有胞外部分，但它是高度糖基化，通过二硫键附着于β链上。两个亚基的胞外区域是相应配体的识别部位，胞内区域具有酪氨酸激酶活性。
c-Met激活的机制分为三种：一是依赖HGF的激活机制，二是不依赖HGF激活机制，三是经过其他膜途径，例如通过透明质酸膜表面受体的CD44、粘附素以及RON信号传导途径等等。其中最常见的是依赖HGF的激活机制。HGF的N末端与c-Met结合，促进β链上Tyr1234和Tyr1235二聚化和自磷酸化，C-末端附近的Tyr1349和Tyr1356磷酸化产生多个接头蛋白的结合位点，这些接头蛋白诱导了P13K/Akt、Ras/Mapk、c-Src和STAT3/5介导的下游信号的激活，引发不同细胞反应，如细胞生存和活动(与P13K/Akt通路密切相关)，肿瘤转移和细胞增殖(主要由Ras/Mapk介导)。此外，c-Met与其它膜受体存在交联(cross-talk)，现已确知这种交联可促进肿瘤形成及转移，由于c-Met是导致肿瘤形成及转移的许多通路的交叉点，以c-Met为靶标可相对较容易地实现对许多通路的同时干扰，c-Met成为抗肿瘤生成和转移治疗的一个有希望的靶点。
抗体药物偶联物(antibody drug conjugate，ADC)把单克隆抗体或者抗体片段通过稳定的化学接头化合物与具有生物活性的细胞毒素相连，充分利用了抗体对肿瘤细胞特异或高表达抗原结合的特异性和细胞毒素的高效性，避免对正常细胞的毒副作用。这也就意味着，与以往传统的化疗药物相比，抗体药物偶联物能精准地结合肿瘤细胞并降低将对正常细胞的影响。
ADC药物由抗体(靶向部分)，接头和毒素三部分组成。其中，好的靶向部 分决定了ADC药物的特异性，这不仅包括特异靶向结合，还包括有效的内吞。
WO2016/165580A公开了一类c-Met抗体药物偶联物，可用于治疗胃癌、胰腺癌、肺癌、肠癌、肾癌、黑素瘤等，对于经过c-Met激酶抑制剂治疗后耐药的疾病是否有效并未提及，而c-Met激酶抑制剂耐药是该类药物的主要问题。
发明内容
本公开(The disclosure)提供一种抗c-Met抗体药物偶联物在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途。
本公开中所述的c-Met激酶抑制剂耐药的疾病，是指经c-Met激酶抑制剂治疗后耐药的疾病，包括但不限于胃癌、食道癌、肾癌包括乳突状肾细胞癌、肺癌、神经胶质瘤、头颈癌、上皮癌、皮肤癌、白血病、淋巴癌，骨髓瘤、脑癌、胰腺癌，结直肠癌、胃肠癌、肠癌、生殖器癌症、泌尿器癌症、黑色素瘤、前列腺癌，优选非小细胞肺癌。
本公开中所述的非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌。
本公开所述的抗c-Met抗体药物偶联物选自ABBV-399。
本公开所述的抗c-Met抗体药物偶联物中的抗c-Met抗体或其抗原结合片段，所述抗体包含如下所示的CDR：包含如下所示的CDR：
抗体重链可变区HCDR区序列：SEQ ID NO:1，SEQ ID NO:2和SEQ ID NO:3；
和抗体轻链可变区LCDR区序列：SEQ ID NO:4或SEQ ID NO:7，SEQ ID NO:5和SEQ ID NO:6。
本公开所述的抗c-Met抗体的CDR区如下表1所示：
表1
抗体 人c-Met单克隆抗体
重链CDR1 NYGVH(SEQ ID NO:1)
重链CDR2 VIWSGGSTNYAAAFVS(SEQ ID NO:2)
重链CDR3 NHDNPYNYAMDY(SEQ ID NO:3)
轻链CDR1 RANKSVSTSTYNYLH(SEQ ID NO:4)
轻链CDR2 LASNLAS(SEQ ID NO:5)
轻链CDR3 QHSRDLPPT(SEQ ID NO:6)
或者如下表2所示：
表2.
抗体 优化的人源化抗体
重链CDR1 NYGVH(SEQ ID NO:1)
重链CDR2 VIWSGGSTNYAAAFVS(SEQ ID NO:2)
重链CDR3 NHDNPYNYAMDY(SEQ ID NO:3)
轻链CDR1 RADKSVSTSTYNYLH(SEQ ID NO:7)
轻链CDR2 LASNLAS(SEQ ID NO:5)
轻链CDR3 QHSRDLPPT(SEQ ID NO:6)
本公开所述的抗c-Met抗体药物偶联物中的抗c-Met抗体或其抗原结合片段，其中所述抗体选自鼠源抗体、嵌合抗体或人源化抗体。
本公开中所述的抗c-Met抗体药物偶联物中的抗c-Met受体的抗体或其抗原结合片段，其中所述的人源化抗体的重链恒定区包含源自人源IgG1或其变体、人源IgG2或其变体、人源IgG3或其变体或人源IgG4或其变体的恒定区，优选包含人源IgG1或其变体或人源IgG2或其变体或人源IgG4或其变体的恒定区，更优选人源IgG2或其变体的恒定区；所述的人源化抗体的轻链恒定区包含选自人源κ或λ链或其变体的恒定区。
本公开所述的所述的抗c-Met抗体药物偶联物中的抗c-Met受体的抗体或其抗原结合片段，其中所述抗体包含：重链恒定区氨基酸序列如SEQ ID NO:8所示或与其具有至少85％序列同源性和轻链恒定区氨基酸序列如SEQ ID NO:9所示或与其具有至少85％序列同源性，优选重链恒定区氨基酸序列如SEQ ID NO:8所示和轻链恒定区氨基酸序列如SEQ ID NO:9所示。
重链恒定区：
Figure PCTCN2019121943-appb-000001
轻链恒定区：
Figure PCTCN2019121943-appb-000002
本公开所述的抗c-Met抗体药物偶联物中的抗c-Met抗体的重链与Ab-10的抗体重链氨基酸序列具有95％的序列同源性，所述抗c-Met抗体的轻链氨基酸序 列与Ab-10的抗体轻链具有95％的序列同源性，所述Ab-10抗体重链序列如SEQ ID NO：10所示，Ab-10抗体轻链序列如SEQ ID NO：11所示。
本公开中所述的“Ab-10”为WO2016/165580A1所公开的c-Met抗体Ab-10，Ab-10人源化抗体：
重链：
Figure PCTCN2019121943-appb-000003
轻链：
Figure PCTCN2019121943-appb-000004
本公开中抗c-Met抗体药物偶联物为ADC-12，具有如下所示的结构：
Figure PCTCN2019121943-appb-000005
其中y的范围为1-8，包括1、2、3、4、5、6、7和8，优选2-5，所述Ab-10为c-Met抗体。
所述抗c-Met抗体药物偶联物中的抗体包含与氨基酸序列SEQ ID NO：10具有至少85％，86％，87％，88％，89％，90％，91％，92％，93％，94％，95％，96％，97％，98％，或99％序列一致性的重链序列，和氨基酸序列SEQ ID NO：11具有至少85％，86％，87％，88％，89％，90％，91％，92％，93％，94％，95％，96％，97％，98％，或99％序列一致性的轻链序列。
本公开中所述抗c-Met激酶抑制剂选自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和AL-2846，优选Crizotinib。
本公开中所述抗c-Met抗体药物偶联物的给药剂量选自0.05-10mg/kg，优选0.1-5mg/kg、0.2-5mg/kg、0.3-3.0mg/kg和0.6-2.0mg/kg；包括但不限于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、2.7mg/kg、2.8mg/kg、2.9mg/kg、3.0mg/kg、3.1mg/kg、3.2mg/kg、3.3mg/kg、3.4mg/kg、3.5mg/kg、3.6mg/kg、3.7mg/kg、3.8mg/kg、3.9mg/kg、4.0mg/kg、4.1mg/kg、4.2mg/kg、4.3mg/kg、4.4mg/kg、4.5mg/kg、4.6mg/kg、4.7mg/kg、4.8mg/kg、4.9mg/kg、5.0mg/kg、5.1mg/kg、5.2mg/kg、5.3mg/kg、5.4mg/kg、5.5mg/kg、5.6mg/kg、5.7mg/kg、5.8mg/kg、5.9mg/kg、6.0mg/kg、6.1mg/kg、6.2mg/kg、6.3mg/kg、6.4mg/kg、6.5mg/kg、6.6mg/kg、6.7mg/kg、6.8mg/kg、6.9mg/kg、7.0mg/kg、7.1mg/kg、7.2mg/kg、7.3mg/kg、7.4mg/kg、7.5mg/kg、7.6mg/kg、7.7mg/kg、7.8mg/kg、7.9mg/kg、8.0mg/kg、8.1mg/kg、8.2mg/kg、8.3mg/kg、8.4mg/kg、8.5mg/kg、8.6mg/kg、8.7mg/kg、8.8mg/kg、8.9mg/kg、9.0mg/kg、9.1mg/kg、9.2mg/kg、9.3mg/kg、9.4mg/kg、9.5mg/kg、9.6mg/kg、9.7mg/kg、9.8mg/kg、9.9mg/kg和10.0mg/kg，优选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、1.6mg/kg、1.9mg/kg、2.7mg/kg和3.0mg/kg；或者所述抗c-Met抗体药物偶联物的给药剂量选自1-1000mg，优选3mg-500mg，优选6mg-200mg，包括但不限于3mg、6mg、12mg、18mg、20mg、36mg、40mg、60mg、80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、320mg、340mg、360mg、380mg、400mg、420mg、440mg、460mg、480mg、500mg、520mg、540mg、560mg、580mg、600mg、620mg、640mg、660mg、680mg、700mg、720mg、740mg、760mg、780mg、800mg、820mg、840mg、860mg、880mg、900mg、920mg、940mg、960mg、980mg、1000mg，优选3mg、6mg、12mg、18mg、20mg和36mg； 给药频次选自每周一次，每两周一次，每三周一次，每四周一次，优选每两周一次或每三周一次。
在一些实施方案中，本公开中所述的抗c-Met抗体药物偶联物的给药方案为：给药剂量选自0.05mg/kg-3.3mg/kg，给药频次选自每两周一次或每三周一次。
在另一些实施方案中，本公开中所述的抗c-Met抗体药物偶联物的给药方案为：给药剂量选自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和1.0mg/kg，给药频次选自每两周一次或每三周一次。
在一些实施方案中，本公开中所述的抗c-Met抗体药物偶联物的给药方案为：给药剂量选自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和1.0mg/kg，给药频次选自每三周一次。
在一些实施方案中，本公开中所述的抗c-Met抗体药物偶联物的给药方案为：给药剂量选自1.6mg/kg或1.9mg/kg，给药频次选自每两周一次；或者给药剂量选自2.7mg/kg或3.0mg/kg，给药频次选自每三周一次。
本公开提供一种治疗c-Met激酶抑制剂耐药的疾病的方法，给与患者治疗有效量的c-Met抗体药物偶联物。
本公开提供的治疗c-Met激酶抑制剂耐药的疾病的方法，所述的c-Met激酶抑制剂耐药的疾病选自胃癌、食道癌、肾癌包括乳突状肾细胞癌、肺癌、神经胶质瘤、头颈癌、上皮癌、皮肤癌、白血病、淋巴癌，骨髓瘤、脑癌、胰腺癌，结直肠癌、胃肠癌、肠癌、生殖器癌症、泌尿器癌症、黑色素瘤、前列腺癌，优选非小细胞肺癌。
本公开提供一种治疗非小细胞肺癌的方法，静脉给予Crizotinib耐药患者治疗有效量的c-Met抗体药物偶联物。
本公开提供一种治疗非小细胞肺癌的方法，每两周一次或者每三周一次静脉给予Crizotinib耐药患者1-1000mg的c-Met抗体药物偶联物。
可以将本公开中所述的c-Met抗体药物偶联物构成在组合物中，例如，含有c-Met抗体药物偶联物和药学上可接受的载体的药物组合物。
本文中使用的“药学上可接受的载体”包括生理学上相容的任意的和所有的溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。在一 个实施方案中，用于含有抗体的组合物的载体适合静脉、肌肉、皮下、胃肠外、腹腔、脊柱或表皮施用(例如，通过注射或输注)，本披露的药物组合物可以包括一种或多种药学上可接受的盐、抗氧化剂、水性和非水性载体，和/或佐剂，诸如防腐剂、润湿剂、乳化剂和分散剂。
本公开提供的用途中，所述c-Met抗体药物偶联物组合物包含c-Met抗体药物偶联物，及其他赋形剂，所述赋形剂选自缓冲剂、糖、表面活性剂，所述缓冲剂优选为琥珀酸盐或柠檬酸盐缓冲剂，更优选琥珀酸盐缓冲剂；所述糖包括单糖，二糖，三糖，多糖，糖醇，还原性糖，非还原性糖等，优选海藻糖或蔗糖所述表面活性剂选自聚山梨醇酯20、聚山梨醇酯80、聚羟亚烃、Triton、十二烷基磺酸钠、月桂基磺酸钠、辛基糖甙钠、月桂基-、肉豆蔻基-、亚油基-、硬脂基-磺基甜菜碱、月桂基-、肉豆蔻基-、亚油基-、硬脂基-肌氨酸、亚油基-、肉豆蔻基-、鲸蜡基-甜菜碱、月桂酰胺基丙基-、柯卡酰胺基丙基-、亚油酰胺基丙基-、肉豆蔻酰胺基丙基-、棕榈酰胺基丙基-、异硬脂酰胺基丙基-甜菜碱、肉豆蔻酰胺基丙基-、棕榈酰胺基丙基-、异硬脂酰胺基丙基-二甲基胺、甲基可可酰基钠、甲基油基牛磺酸钠、聚乙二醇、聚丙二醇、乙烯与丙烯二醇的共聚物等，优选的表面活性剂是聚山梨醇酯80或聚山梨醇酯20。
本公开中所述c-Met抗体药物偶联物的给药途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。所述“胃肠外施用”是指，通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，所述所述c-Met抗体药物偶联物通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，例如，鼻内地、阴道地、直肠地、舌下地或局部地。
发明详述
一、术语
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
本公开所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
术语“c-Met”或“c-Met多肽”或“c-Met受体”是指结合细胞生长因子(HGF)的受体酪氨酸激酶。本公开中如非特指，比如鼠c-Met(m-c-Met)或猴c-Met(cyno-c-Met)，均指人的c-Met(h-c-Met)。本公开中所用的人、鼠、食蟹猴c-Met均通过GenBank提供的核苷酸序列或多肽序列进行编码，例如GenBank登录号NM_000245中提供的核苷酸序列编码的人多肽，或由GenBank登录号NP_000236中提供的多肽序列编码的人蛋白质或其细胞外结构域。原始的单链前体蛋白质在翻译后被剪切以产生α和β亚基，其通过二硫键连接以形成成熟受体。受体酪氨酸激酶c-Met参与细胞过程包括，例如伴随胚胎发生的组织再生的迁移、侵入和形态发生的过程。
本公开所述的抗体指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM，IgD，IgG，IgA和IgE，其相应的重链分别为μ链，δ链，γ链，α链，ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1，IgG2，IgG3，IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中第每类Ig都可以有κ链或λ链。
抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大，为可变区(V区)；靠近C端的其余氨基酸序列相对稳定，为恒定区(C区)。可变区包括3个高变区(HVR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性，又称为互补性决定区(CDR)。每条轻链可变区(LCVR)和重链可变区(HCVR)由3个CDR区4个FR区组成，从氨基端到羧基端依次排列的顺序为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。轻链的3个CDR区指LCDR1，LCDR2，和LCDR3；重链的3个CDR区指HCDR1，HCDR2和HCDR3。发明所述的抗体或抗原结合片段的LCVR区和HCVR区的CDR氨基酸残基在数量和位置符合已知的Kabat编号规则。
术语“鼠源抗体”在本公开中为根据本领域知识和技能用小鼠制备的抗人c-Met的单克隆抗体。制备时用c-Met抗原注射试验对象，然后分离表达具有所 需序列或功能特性的抗体的杂交瘤。在本公开一个优选的实施方案中，所述的鼠源c-Met抗体或其抗原结合片段，可进一步包含鼠源κ、λ链或其变体的轻链恒定区，或进一步包含鼠源IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区。
术语“嵌合抗体(chimeric antibody)”，是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体，可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体，要先建立分泌鼠源性特异性单抗的杂交瘤，然后从小鼠杂交瘤细胞中克隆可变区基因，再克隆到人抗体的恒定区基因，进行重组表达。
术语“人源化抗体(humanized antibody)”，也称为CDR移植抗体(CDR-grafted antibody)人源化，是指将小鼠的CDR序列移植到人的抗体可变区框架，即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量小鼠蛋白成分，从而诱导的强烈的抗体可变抗体反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com.ac.uk/vbase可获得)，以及在Kabat，E.A.等人，1991Sequences of Proteins of Immunological Interest，第5版中找到。在本公开一个的实施方案中，所述的c-Met人源化抗体小鼠的CDR序列选自SEQ ID NO:6，7，8，9，10，11(please check the#s,in case just copy from sost draft)。人的抗体可变区框架经过设计选择，其中所述抗体轻链可变区上的轻链FR区序列，选自人种系轻链序列，优选人种系轻链IGKV085或IGKV 4-1*01，包含人种系轻链IGKV085和IGKV 4-1*01的FR1，FR2，FR3区和FR4区；其中所述抗体重链可变区上的重链FR区序列，来源于人种系重链序列，优选人种系重链IGHV 3-33*01；包含人种系重链IGHV 3-33*01的FR1，FR2，FR3区和FR4区。为避免免疫原性下降的同时，引起的活性下降，可对所述的人抗体可变区可进行最少反向突变，以保持活性。
在CDR编码序列移植到所选人框架编码序列上之后，然后表达编码人源化可变重链和可变轻链序列的所得DNA序列，以产生结合c-Met的人源化抗体。可将人源化HCVR和LCVR表达为整个抗硬骨素抗体分子的部分，即表达为与人恒定域序列的融合蛋白。然而，HCVR和LCVR序列也可在不存在恒定序列的情况下进行表达，以产生人源化抗c-Met scFv。
进一步描述参与人源化可使用小鼠抗体的方法的文献包括，例如Queen等， Proc.，Natl.Acad.Sci.USA，88，2869，1991和Winter及其同事的方法[Jones等，Nature，321，522(1986)，Riechmann，等，Nature，332，323-327(1988)，Verhoeyen，等，Science，239，1534(1988)]。
本公开中所述的“抗原结合片段”，指具有抗原结合活性的Fab片段，Fab’片段，F(ab’) 2片段，以及与人c-Met结合的Fv片段scFv片段。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv(scFv)。scFv还可以和其它抗体，例如抗EGFR抗体构建双特异抗体(bispecific antibody)本公开的术语“与c-Met结合”，指能与人c-Met相互作用。本公开的术语“抗原结合位点”指抗原上不连续的，由本公开抗体或抗原结合片段识别的三维空间位点。本公开中所述的“ADCC”，即antibody-dependent cell-mediated cytotoxicity，抗体依赖的细胞介导的细胞毒作用，是指表达Fc受体的细胞通过识别抗体的Fc段直接杀伤被抗体包被的靶细胞。可通过对IgG上Fc段的修饰，降低或消除抗体的ADCC效应功能。所述的修饰指在抗体的重链恒定区进行突变，如选自IgG1的N297A，L234A，L235A；IgG2/4chimera，IgG4的F235E,或L234A/E235A突变。
“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。
“治疗”意指给予患者内用或外用治疗剂，诸如包含本公开的任一种结合化合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，无论是通过诱导这类症状退化还是抑制这类症状发展到任何临床右测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状 的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽本公开的实施方案(例如治疗方法或制品)在缓解每个患都有的目标疾病症状方面可能无效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者中应当减轻目标疾病症状。
“有效量或有效剂量”包含足以改善或预防医字病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
人与动物对同一药物的耐受性相差较大，一般来说，动物的耐受性要比人大。一般可按下列比例换算：人用药量为1，小白鼠、大白鼠为25-50，兔、豚鼠为15-20，狗、猫为5-10。此外，可以采用人与动物表面积计算法来换算，1)人体表面积计算法，一般认为如许文氏公式(中国生理学杂志，12,327,1937)、Mech-Rubner氏公式。上述方法可适用于本公开中人与不同种类动物之间药物剂量的换算。
“同源性”是指两个多核苷酸序列之间或两个多肽之间的序列相似性。当两个比较序列中的位置均被相同碱基或氨基酸单体亚基占据时，例如如果两个DNA分子的每一个位置都被腺嘌呤占据时，那么所述分子在该位置是同源的。两个序列之间的同源怀百分率是两个序列共有的匹配或同源位置数除以比较的位置数×100的函数。例如，在序列最佳比对时，如果两个序列中的10个位置有6个匹配或同源，那么两个序列为60％同源。一般而言，当比对两个序列而得到最大的同源性百分率时进行比较。
偶联物是与如上所述的治疗剂偶联的抗体组分或其他靶向部分。本文所用的术语“偶联物”和“免疫偶联物”可交换地使用。
附图说明
图1：
Figure PCTCN2019121943-appb-000006
肺癌异种移植模型LU1902荷瘤鼠在药物A和Crizotinib单药治疗中的体重变化曲线；
图2：
Figure PCTCN2019121943-appb-000007
肺癌异种移植模型LU1902荷瘤鼠在药物A和Crizotinib单药治疗中的肿瘤体积变化曲线。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例1、在皮下
Figure PCTCN2019121943-appb-000008
肺癌异体移植模型LU1902在Balb/c裸小鼠体内的药效学研究。
1、实验设计
采用维持中的种子肿瘤LU1902，接种于6-7周龄雌性Balb/C nude裸小鼠右侧肩胛骨。接种9天后选取36只状态良好、平均肿瘤大小为132mm 3的小鼠，随机分为6组，每组6只。6个剂量组分别为：溶剂对照组(IgG1)、药物A 1mg/kg组、药物A 3mg/kg组、药物A 10mg/kg组、裸抗10mg/kg组、Crizotinib 30mg/kg组。药物A每周尾静脉给药两次，Crizotinib每天灌胃给药一次。实验全部给药周期为11天，注射用药物A共给药三次，Crizotinib共给药十一次。第1，5和6组分别在分组后第13天和15天结束实验，测试药物A及裸抗组给药组后续观察4周，于分组给药后42天结束实验。
表3.
Figure PCTCN2019121943-appb-000009
备注：药物A：c-Met抗体药物偶联物；i.v.静脉注射；p.o.口服给药。
2、实验材料
实验动物：雌性BALB/C裸小鼠；供应商为上海灵畅生物科技有限公司；年龄：8-9周(给药起始)；实验动物数量：36只小鼠加上60只富余。
模型信息：非小细胞肺癌模型
Figure PCTCN2019121943-appb-000010
源自于一名65岁女性病人，该患者的病理诊断为大细胞未分化癌，基因学诊断为c-Met扩增(HGF非依赖)。肺癌
Figure PCTCN2019121943-appb-000011
系LU1901经过Crizotinib(30mg/kg,每天一次)长期治疗后所产生的Crizotinib耐药的非小细胞肺癌异体移植模型。
受试药和对照药
受试药：c-Met抗体药物偶联物(药物A)
制备方法：参考WO2016/165580A实施例24。
对照品：Ab-10裸抗，重链氨基酸序列如SEQ ID NO:10所示，轻链序列如SEQ ID NO:11所示。
对照药：Crizotinib，提供者：Selleck。
上述药物A、对照品裸抗Ab-10包装和保存条件为-20℃。
3、实验方法
表4.受试药和对照药的配置方法
Figure PCTCN2019121943-appb-000012
Figure PCTCN2019121943-appb-000013
备注：根据体重调整给药量(给药体积＝10μL/g)
实验过程中每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：TV＝0.5a×b 2测量肿瘤，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。
相对肿瘤增殖率T/C(％)＝T RTV/C RTV(T RTV：治疗组RTV的平均值；C RTV：阴性对照组RTV的平均值)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即D 0)测量所得肿瘤体积，V t为某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]*100％。
实验中使用Study Director(版本号3.1.399.19，供应商Studylog System,Inc)软件收集数据，包括小鼠体重的称量，原始数据由天平和游标卡尺测量后直接导入软件，数据的任何变动都将被记录在此软件中。
4、实验结果
各治疗组和溶剂处理组荷瘤鼠的体重见下表5。
表5.各治疗组和溶剂处理组荷瘤鼠的体重
Figure PCTCN2019121943-appb-000014
Figure PCTCN2019121943-appb-000015
注释：数据以“平均值±标准误差”表示
各治疗组和溶剂处理组荷瘤鼠的体重变化曲线及体重改变百分比曲线分别见图1和图2。
各治疗组和溶剂处理组荷瘤鼠在不同时间点的肿瘤体积见表6。
表6.各治疗组和溶剂处理组荷瘤鼠的肿瘤体积
Figure PCTCN2019121943-appb-000016
Figure PCTCN2019121943-appb-000017
注释：数据以“平均值±标准误差”表示
各治疗组荷瘤鼠的肿瘤生长抑制情况见表7。
表7.药物A和Crizotinib在
Figure PCTCN2019121943-appb-000018
肺癌异种移植模型LU1902中的抑瘤效果
Figure PCTCN2019121943-appb-000019
注释：a.数据以“平均值±标准误差”表示；n＝5；
b.p值运用单因素方差分析(one way ANOVA)肿瘤体积所得，F值有显著性差异(p<0.05)，应用Dunnett’s T3法进行分析；
c.第2,3,4组与第5组运用T test检验分析，p＝0.001均具有显著性差异。
各治疗组和溶剂处理组荷瘤鼠的肿瘤体积变化曲线见图2。
表8.各治疗组和溶剂处理组荷瘤鼠的瘤重数据及统计分析
Figure PCTCN2019121943-appb-000020
Figure PCTCN2019121943-appb-000021
注释：a.数据以“平均值±标准误差”表示；
b.p值运用单因素方差分析(one way ANOVA)肿瘤瘤重所得，F值有显著性差异(p<0.05)，应用Dunnett’s T3法进行分析。
c.第2,3,4组与第5组运用T test检验分析，p<0.001均具有显著性差异。
5、讨论
在分组治疗后第13天，第1组、第2组、第3组、第4组、第5组和第6组的荷瘤鼠体重改变百分比分别为17.47％、9.07％、5.63％、5.78％、16.90％和11.03％。
在分组治疗后第13天，对照组小鼠(第1组)的平均肿瘤体积达到3383.07mm 3。与溶媒对照组相比，测试药药物A 1mg/kg治疗组(第2组)，药物A 3mg/kg治疗组(第3组)，药物A 10mg/kg治疗组(第4组)的平均瘤体积均缩小并消退为0mm 3，TGI分别达到99.13％，99.83％和99.91％，与对照组相比较，测试药药物A 1mg/kg治疗组(第2组)，药物A 3mg/kg治疗组(第3组)，药物A 10mg/kg治疗组(第4组)，都具有统计学显著的抗皮下
Figure PCTCN2019121943-appb-000022
肺癌异体移植模型LU1902肿瘤生长的作用(P<0.05)。而裸抗10mg/kg(第5组)和Crizotinib 30mg/kg治疗组(第6组)的平均肿瘤体积为2388.69mm 3和2261.81mm 3，TGI分别为27.42％和31.93％，与对照组相比，均不有统计学显著的抗皮下
Figure PCTCN2019121943-appb-000023
肺癌异体移植模型LU1902肿瘤生长的作用(P>0.05)。
在分组治疗后第13天，对照组小鼠(第1组)的平均瘤重达到3.8376g。与溶媒对照组相比，测试药药物A 1mg/kg治疗组(第2组)，药物A 3mg/kg治疗组(第3组)，药物A 10mg/kg治疗组(第4组)的平均瘤重都达到0.0000g。与对照组相比较，测试药药物A 1mg/kg治疗组(第2组)，药物A 3mg/kg治疗组(第3组)，药物A 10mg/kg治疗组(第4组)，都具有统计学显著的抗皮下
Figure PCTCN2019121943-appb-000024
肺癌异体移植模型LU1902肿瘤生长的作用(P<0.05)。而裸抗10 mg/kg(第5组)和Crizotinib 30mg/kg治疗组(第6组，与对照组相比，均不有统计学显著的抗皮下
Figure PCTCN2019121943-appb-000025
肺癌异体移植模型LU1902肿瘤生长的作用(P>0.05)。
综上所示，注射用药物A分别在1mg/kg，3mg/kg和10mg/kg治疗时，均能显著抑制肺皮下
Figure PCTCN2019121943-appb-000026
肺癌异体移植模型LU1902的肿瘤生长。

Claims (13)

  1. 一种抗c-Met抗体药物偶联物在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于所述c-Met激酶抑制剂耐药的疾病选自胃癌、食道癌、肾癌、肺癌、神经胶质瘤、头颈癌、上皮癌、皮肤癌、白血病、淋巴癌，骨髓瘤、脑癌、胰腺癌，结直肠癌、胃肠癌、肠癌、生殖器癌症、泌尿器癌症、黑色素瘤、前列腺癌，优选非小细胞肺癌。
  3. 根据权利要求2所述的用途，其特征在于所述非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌。
  4. 根据权利要求1-3任一项所述的用途，其特征在于所述抗c-Met抗体药物偶联物选自ABBV-399。
  5. 根据权利要求1-3任一项所述的用途，其特征在于所述抗c-Met抗体药物偶联物中的抗c-Met抗体或其抗原结合片段，包含如下所示的CDR：
    抗体重链可变区HCDR区序列：SEQ ID NO:1，SEQ ID NO:2和SEQ ID NO:3；
    和抗体轻链可变区LCDR区序列：SEQ ID NO:4或SEQ ID NO:7，SEQ ID NO:5和SEQ ID NO:6。
  6. 根据权利要求5所述的用途，其特征在于所述抗c-Met抗体选自鼠源抗体、嵌合抗体或人源化抗体。
  7. 根据权利要求6所述的用途，其特征在于所述人源化抗体的重链恒定区包含源自人源IgG1或其变体、人源IgG2或其变体、人源IgG3或其变体或人源IgG4或其变体的恒定区，优选包含人源IgG1或其变体或人源IgG2或其变体或人源IgG4或其变体的恒定区，更优选人源IgG2或其变体的恒定区；所述人源化抗体的轻链恒定区包含选自人源κ或λ链或其变体的恒定区。
  8. 根据权利要求5-7任一项所述的用途，其特征在于所述抗体包含：重链恒定区氨基酸序列如SEQ ID NO:8所示或与其具有至少85％序列同源性和轻链恒定区氨基酸序列如SEQ ID NO:9所示或与其具有至少85％序列同源性，优选重链恒定区氨基酸序列如SEQ ID NO:8所示和轻链恒定区氨基酸序列如SEQ ID NO:9所示。
  9. 根据权利要求8所述的用途，其特征在于所述抗体的重链与Ab-10的抗体重链氨基酸序列具有95％的序列同源性，所述抗体的轻链氨基酸序列与Ab-10的抗体轻链具有95％的序列同源性，所述Ab-10抗体重链序列如SEQ ID NO：10所示，Ab-10抗体轻链序列如SEQ ID NO：11所示。
  10. 根据权利要求5-9任一项所述的用途，其特征在于所述抗c-Met抗体药物偶联物为ADC-12，具有如下所示的结构：
    Figure PCTCN2019121943-appb-100001
    其中y的范围为1-8，优选2-5，所述Ab-10为c-Met抗体。
  11. 根据权利要求1-10任一项所述的用途，其特征在于所述c-Met激酶抑制剂选自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和AL-2846，优选Crizotinib。
  12. 根据权利要求5-11任一项所述的用途，其特征在于所述抗c-Met抗体药物偶联物的给药剂量选自0.05-10mg/kg或1mg-1000mg；给药频次选自每周一次、 每两周一次、每两周一次、每三周一次和每四周一次，优选每两周一次或每三周一次。
  13. 一种药物组合物，其包含权利要求1-12任一项所述的抗c-Met抗体药物偶联物以及一种或多种可药用赋形剂。
PCT/CN2019/121943 2018-11-30 2019-11-29 一种c-Met ADC在制备治疗c-Met激酶抑制剂耐药的疾病的药物中的用途 Ceased WO2020108612A1 (zh)

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