[go: up one dir, main page]

CN105899236B - 表现出改进的体内抗肿瘤活性的倍癌霉素adc - Google Patents

表现出改进的体内抗肿瘤活性的倍癌霉素adc Download PDF

Info

Publication number
CN105899236B
CN105899236B CN201580003979.0A CN201580003979A CN105899236B CN 105899236 B CN105899236 B CN 105899236B CN 201580003979 A CN201580003979 A CN 201580003979A CN 105899236 B CN105899236 B CN 105899236B
Authority
CN
China
Prior art keywords
her2
cancer
breast cancer
purposes according
human solid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201580003979.0A
Other languages
English (en)
Other versions
CN105899236A (zh
Inventor
威廉·多克特
彼得·约翰内斯·戈耶丁斯
海斯贝特斯·弗朗西斯库斯·玛丽亚·费尔海登
帕特里克·亨利·伯斯克尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Byodes Private Limited
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of CN105899236A publication Critical patent/CN105899236A/zh
Application granted granted Critical
Publication of CN105899236B publication Critical patent/CN105899236B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6871—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting an enzyme
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明涉及含倍癌霉素的抗体‑药物缀合物(ADC)，其用于治疗表达HER2的人实体瘤和血液学恶性肿瘤，特别是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌、前列腺癌、胰腺癌、结直肠癌、头颈鳞状细胞癌或骨肉瘤，以及急性淋巴细胞白血病。特别地，本发明涉及用于治疗具有HER2 IHC2+或1+和HER2 FISH阴性组织状态的人实体瘤的含倍癌霉素的ADC。有利地，本发明涉及用于治疗三阴性乳腺癌(TNBC)的含倍癌霉素的ADC。

Description

表现出改进的体内抗肿瘤活性的倍癌霉素ADC
技术领域
本发明涉及含倍癌霉素(duocarmycin)的抗体-药物缀合物(antibody-drugconjugate，ADC)，其用于治疗表达人表皮生长因子受体2(HER2)的人实体瘤和血液学恶性肿瘤，特别是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌、前列腺癌、胰腺癌、结直肠癌、头颈鳞状细胞癌、骨肉瘤和急性淋巴细胞白血病(acute lymphoblastic leukaemia)。
背景技术
抗体已经与多种细胞毒性药物缀合，包括使DNA烷基化或交联的小分子(例如，分别为倍癌霉素和加利车霉素(calicheamicin)或吡咯并-苯并二氮杂二聚体)，或者破坏微管的小分子(例如，美登素类化合物(maytansinoids)和澳瑞他汀(auristatin))或结合DNA的小分子(例如，蒽环类药。一种包含与加利车霉素缀合的人源化抗CD33抗体的这样的ADC——MylotargTM(吉妥珠单抗，Wyeth)——在2000年被批准用于急性骨髓性白血病。2011年，美国食品与药物管理局(FDA)批准将AdcetrisTM(brentuximab vedotin，SeattleGenetics)——一种包含针对与单甲基澳瑞他汀E(monomethyl auristatin E，MMAE)缀合之CD30的嵌合抗体的ADC——用于治疗霍奇金淋巴瘤和间变性大细胞淋巴瘤。
倍癌霉素最初由链霉菌属(Streptomyces)物种的培养液中分离，是抗肿瘤抗生素家族(包括倍癌霉素A、倍癌霉素SA和CC-1065)的成员。据称这些极有效的药剂的生物活性来源于其在小沟中腺嘌呤的N3位置处序列选择性地使DNA烷基化的能力，这启动了导致肿瘤细胞死亡的事件级联。
WO2011/133039A公开了DNA烷基化剂CC-1065的一系列新类似物及其HER2靶向性ADC。在实施例15中，在裸小鼠中针对N87(即，HER2IHC(免疫组织化学)3+胃肿瘤)异种移植物测试了若干曲妥珠单抗(trastuzumab)-倍癌霉素缀合物。结果示出在图4A、4B和4C中。在用12mg/kg的单剂量静脉内治疗后，与抗体曲妥珠单抗自身和对照载剂相比，所有六种ADC降低了肿瘤体积并且改善了存活，而没有不利地影响体重。推断含相对短接头的缀合物比具有相对长接头的相应缀合物具有更好的(抗肿瘤)效力，并且证明了接头的性质和药物的性质二者同样对效力具有影响。
乳腺癌依然是世界范围内女性中最常见的恶性肿瘤。乳腺癌是异质性疾病，其表现出多种多样的临床行为(clinical behaviour)和预后。乳腺癌是乳腺乳小叶或乳腺导管的上皮细胞的异常恶性生长。癌组织可以仅位于原始位置(原位癌)或可以通过基底膜侵入周围组织(侵袭性癌症)。一旦癌细胞通过淋巴管和血管扩散到其他器官，就发生转移癌。使用生物标志物进行乳腺癌细胞的组织学分化和表征。
用于治疗决策的乳腺癌的分子分类主要由对雌激素受体(ER)、孕酮受体(PR)和人表皮生长因子受体2(HER2)表达状态的评估组成。这意味着可以辨别全部三种乳腺癌：(1)表达激素受体(ER或PR)而不过表达HER2的乳腺癌组织，(2)过表达HER2，表达或不表达激素受体(HR)的乳腺癌组织，以及(3)无治疗相关激素受体或HER2受体表达的乳腺癌组织，所谓的三阴性乳腺癌(triple negative breast cancer，TNBC)。
具有激素受体(HR)阳性癌组织状态的乳腺癌患者(全部乳腺癌患者中的约60-70％)比不具有或具有最低激素受体状态的那些患者表现出更好的预后。相反地，与其肿瘤具有较低等级HER2膜表达或FISH阴性扩增率的乳腺癌患者相比，其肿瘤具有IHC 3+或IHC2+/FISH(荧光原位杂交)阳性状态的患者(发生在所有乳腺癌病例的约20％中)具有更差预后。现在具有激素受体阳性和HER2过表达乳腺癌组织的患者具有靶向治疗这一选择，所以三阴性乳腺癌意味着最差的预后，因为仅具有有限疗效的化学治疗可用于其肿瘤为ER、PR和HER2阴性的这些患者。
在美国，1998年FDA批准将HerceptinTM(曲妥珠单抗)——抗HER2的重组人源化IgG1单克隆抗体——用于HER2过表达乳腺癌的辅助治疗以及用于治疗转移性HER2过表达乳腺癌和胃癌，即，HER2 IHC 3+或HER2 IHC 2+/FISH阳性。在欧洲，2000年EMA批准了该药物。
对患有转移性乳腺癌疾病的患者进行的临床研究已经证明，如果患者具有HER2IHC过表达或FISH阳性基因扩增的肿瘤，则仅曲妥珠单抗治疗有临床相关效力。由于该原因，目前HER2测试算法旨在鉴定最可能从HER2靶向获得显著益处的那些患者。尽管HER2膜表达在生物学上是从低到高过表达的连续集(continuum)，但是经批准的IHC测试如HercepTestTM(Dako，Glostrup，Denmark)在半定量量度上将HER2状态以0至3+分类。如果＞10％癌细胞中具有强的圆周膜染色，则分配3+的IHC评分。如果相对于着丝粒的扩增速率≥2.0，则分配FISH阳性基因扩增。这鉴定可能受益于曲妥珠单抗或其他HER2靶向剂的治疗的患者。6,556例乳腺癌的综述表明，约92％的HER2评分为3+的肿瘤具有FISH阳性基因扩增。相反地，在评分为2+(23.3％)、1+(7.4％)和0(4.1％)的肿瘤中，观察到较低速率的HER2扩增。将HER2扩增作为确定的对HER2靶向药剂应答的指示剂，当前的算法需要HER2 IHC评分为2+的肿瘤的FISH测试。
Ado-曲妥珠单抗emtansine或曲妥珠单抗emtansine(KadcylaTM，T-DM1)是其中曲妥珠单抗与细胞毒性美登素抗微管蛋白剂DM1缀合的ADC。在不响应于利用曲妥珠单抗作为单一药剂的治疗的肿瘤异种移植物模型中，T-DM1具有抗肿瘤活性。在3期EMILIA试验中，将之前利用曲妥珠单抗和紫杉烷治疗的患有HER2阳性晚期乳腺癌的患者随机分配以接受T-DM1或拉帕替尼(lapatinib)联合卡培他滨。与对照组的治疗相比，T-DM1治疗导致了显著更长的无进展和总存活时间。
在美国，2013年2月FDA批准将KadcylaTM(T-DM1)用于治疗之前接受曲妥珠单抗和紫杉烷治疗的具有HER2阳性转移性乳腺癌的患者。该药物于2013年9月在日本被MHLW(厚生劳动省(Ministry of Health，Labour and Welfare))批准，2013年11月在欧洲被EMA批准。当前经批准的方案包括静脉内3.6mg/kg体重的剂量，每三周一次。在正在进行的III期研究中以及在利用T-DM1和卡培他滨的组合作为患有乳腺癌和胃癌的患者的2线治疗的正在进行的II期研究中研究了每周静脉内2.4mg/kg体重的剂量，以相对于作为胃癌患者之2线治疗的紫杉烷来研究T-DM1。对于具有HER2阳性、局部晚期或转移性乳腺癌的患者的治疗，还针对T-DM和帕妥珠单抗(pertuzumab)的组合进行着III期研究。
对于HER2阳性转移性乳腺癌的治疗，尽管在临床实践中T-DM1的引入带来超过曲妥珠单抗的改善，但是T-DM1的使用与若干严重副作用有关，最重要的是血小板减少、肝毒性和神经病(不可逆的轴突变性)。另外，曲妥珠单抗和T-DM1均未被批准用于治疗具有中等或低HER2表达(即，IHC 2+或1+)和/或FISH阴性HER2扩增状态的癌组织的人实体瘤和血液学恶性肿瘤。
类似于乳腺癌，对于患有卵巢癌的患者，HER2表达指示了差的预后(A.Berchuck等，1990，Cancer Res.，50，4087-4091；H.Meden和W.Kuhn，1997，Eur.J.Obstet.&Gynecol.Reprod.Biol.，71，173-179)。SKOV3细胞来源于患有卵巢腺癌的患者的腹水。这种细胞系过表达HER2，并且经常用于HER2靶向药剂的体外和体内探索性研究。在这种细胞系中，曲妥珠单抗和帕妥珠单抗具有多种抗癌效果(N.Gaborit等，2011，J.Biol.Chem.，286，13，11337-11345)。利用抗HER2抗体曲妥珠单抗和帕妥珠单抗的单一治疗迄今具有适中效力(G.M.Mantia-Smaldone等，2011，Cancer Management Res.3，25-38；S.P.Langdon等，2010，Expert Opin.Biol.Ther.10：7，1113-1120)。如果HER2靶向抗体与化学治疗组合，抗肿瘤效果显著提高(S.Makhija等，2010，J.Clin.Oncol.，28：7，1215-1223；I.Ray-Coquard等，2008，Clin.Ovarian Cancer，1：1，54-59)。
此外，对于晚期膀胱癌疾病的治疗，存在高医疗需求。对于晚期或转移性膀胱癌，化学治疗(例如顺铂和吉西他滨的组合)具有有限的效力，因为其导致低于50％的平均响应率，而患者的总存活时间为6至12个月。在对化学治疗抵抗的情况下，完全没有标准的治疗选择。在化学辐射后，HER2阳性与完全响应率降低显著相关(50％对比于81％，p＝0.026)(A.Chakravarti等，2005，Int.J.Radiation Oncology Biol.Phys.，62：2，309-317)。在II期研究中，向紫杉醇和顺铂的方案中加入曲妥珠单抗的HER2阳性晚期膀胱癌的一线疗法表现出70％的总响应率和14.1个月的总存活时间(M.H.A.Hussain等，2007，J.Clin.Oncol.，25：16，2218-24)。在病案讨论应用中，在标准化学治疗后具有肿瘤复发的患者响应于曲妥珠单抗、紫杉醇和卡铂的组合(D.Amsellem-Ouazana等，2004，Ann.Oncol.，15，3，538)。
在侵袭性非小细胞肺癌腺癌的情况下，HER2突变和扩增与不利结果有关(M.Suzuki等，2014，Lung Cancer，http://dx.doi.org/10.1016/j.lungca.2014.10.014)。在具有HER2突变的肺癌患者中，可以利用基于曲妥珠单抗的疗法实现93％的疾病控制率(J.Mazieres等，2013，J.Clin.Oncol.，31：16，1997-2004)。肺癌的化学抗性通常与增强的HER2表达相关(C.-M.Tsai等，1993，J.Natl.Cancer Inst.，85：11，897-901；Z.Calikusu等，2009，J.Exp.Clin.Cancer Res.，28：97)，对于酪氨酸激酶抑制剂的抗性与增强的HER2扩增相关(K.Takezawa等，2012，Cancer Discov.2(10)，922-33)。
患有早期或晚期前列腺癌的患者大部分接受雄激素受体靶向治疗。在雄激素受体和HER2的信号传导功能中存在相互关联(cross-talk)(F.-N.Hsu等，2011，Am.J.Physiol.Endocrinol.Metab.，300：E902-E908；L.Chen等，2011，Clin.Cancer Res.，17(19)，6218-28)。HER2活化抑制雄激素受体的表达(C.Cai等，2009，Cancer Res.，69(12)，5202-5209)，提高的HER2表达与PSA进展、迅速增殖和差的预后有关(S.Minner等，2010，Clin.Cancer Res.，16(5)，1553-60；S.F.Shariat等，2007，Clin.Cancer Res.，13(18)，5377-84)。在约四分之一的前列腺癌病例中，提高的HER2表达似乎独立于雄激素参与进展(J.M.S.Bartlett等，2005，J.Pathol.，205，522-529)。
由于其起病隐袭和对于治疗的抗性，胰腺癌是最致命的人实体瘤之一。吉西他滨或者5-FU、甲酰四氢叶酸、伊立替康和奥沙利铂的组合可帮助延长患有晚期疾病的患者的生命(H.Burris和A.M.Storniolo，1997，Eur.J.Cancer 33(1)：S18-S22；T.Conroy等，2011，N.Engl.J.Med.364(19)：1817-25)。最近，据报道在胰腺癌患者中HER2表达也很普遍，等同10％的比例被认定为HER2 2+和3+。基于该事实，基于在临床前模型中观察到的效果，认为包含曲妥珠单抗的HER2靶向治疗是这种患者群体中可行的选择(C.Larbouret等，2012，Neoplasia 14(2)，121-130)。
使用接受的染色和评分方法，在约6％的结直肠癌(CRC)患者中观察到了HER2的过表达(A.N.Seo等，2014，PLoS ONE，9(5)：e98528)。基于此，HER2靶向治疗在这一亚类CRC患者中可能有效。两个临床试验研究了含曲妥珠单抗的联合疗法在晚期或转移性CRC中的益处，在这些试验中观察到的临床响应提供了治疗效力的证据(R.K.Ramanathan等，2004，Cancer Invest.22(6)：858-865；J.Clark等，2003，Proc.Am.Soc.Clin.Oncol.22：abstr3584)。另外，一个研究提出引入曲妥珠单抗疗法来作为用于(抗EGFR单克隆抗体)西妥昔单抗抗性CRC患者的治疗方案的一部分(A.Bertotti等，2011，Cancer Discov.1(6)：508-523)。
晚期头颈鳞状细胞癌(HNSCC)的管理由利用手术、辐射和化学治疗的多种形式的治疗组成。Beckhardt等报道了在16％的细胞系样品中具有高HER2过表达，分别在31％和35％样品中具有中等和低HER2表达(R.N.Beckhardt等，1995，Arch.Otolaryngol.HeadNeck SurR.121：1265-1270)。这说明了曲妥珠单抗治疗在HNSCC中潜在的治疗潜力。
1999年，Gorlick等报道了在47个骨肉瘤样品的20个中HER2过表达，并且表明与不过表达这种抗原的肿瘤患者相比，这些患者对治疗具有差的响应，并且具有降低的存活率(R.Gorlick等，1999，J.Clin.Oncol.17：2781-8)。因此，HER2作为在这种适应症中的靶向生物治疗的有希望的候选者脱颖而出。最近来自使用曲妥珠单抗的临床研究的发现指示，抗HER2治疗可以与基于蒽环类药的化学疗法以及右雷佐生一起安全地组合递送(D.Ebb等，2012，J.Clin.Oncol.30(20)，2545-2551)。
此外，在约三分之一的急性淋巴细胞白血病(ALL)患者中发现HER2过表达，在费城染色体易位(Philadelphia translocation)的存在下甚至更频繁。HER2的抑制诱导了体外白血病细胞凋亡(M.E.Irwin等，2013，PLoS ONE，8：8，e70608)。在II期研究中证明，在恶性B细胞中具有HER2过表达的难治性或复发性成年B-ALL患者的曲妥珠单抗治疗导致13％的总体响应率，这表明这种疾病对HER2靶向药剂的响应(P.Chevalier等，Blood，2012，DOI10.1182/blood-2011-11-390781)。
因此，需要新的HER2靶向疗法，尤其是用于治疗具有(i)中等或低IHC状态，和/或(ii)阴性FISH状态，和/或(iii)激素受体(HR)阴性状态之癌组织的肿瘤和恶性肿瘤的患者。特别地，需要用于靶向治疗三阴性乳腺癌(TNBC)的管理部门批准的新疗法。
发明内容
本发明涉及含倍癌霉素的抗体-药物缀合物(ADC)，其用于治疗表达HER2的人实体瘤和血液学恶性肿瘤，特别是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌、前列腺癌、胰腺癌、结直肠癌、头颈鳞状细胞癌、骨肉瘤和急性淋巴细胞白血病。
附图简述
图1.MAXF-1162 PDX模型(乳腺癌，腺癌，HER2 IHC 3+，HER2 FISH阳性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图2.HBCx-34 PDX模型(乳腺癌，导管癌，HER2 IHC 2+，HER2 FISH阴性，ER和PR阳性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：XenTech)。
图3.MAXF 449 PDX模型(乳腺癌，侵袭性导管癌，HER2 IHC 1+，HER2 FISH阴性，ER和PR阴性，即三阴性乳腺癌)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图4.HBCx-10 PDX模型(乳腺癌，导管腺癌，HER2 IHC 1+，HER2 FISH阴性，ER和PR阴性，即三阴性乳腺癌)中与T-DM1相比SYD985的抗肿瘤活性(CRO：XenTech)。
图5.MAXF-MX1 PDX模型(乳腺癌，侵袭性导管癌，HER2 IHC 1+，HER2 FISH阴性，ER和PR阴性，即三阴性乳腺癌)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图6.ST313 PDX模型(乳腺癌，HER2 IHC 2+，HER2 FISH阴性，ER和PR阳性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Start)。
图7.GXA3057 PDX模型(胃癌，HER2 IHC 1+，HER2 FISH阴性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图8.GXA3067 PDX模型(胃癌，HER2 IHC 2+，HER2 FISH阳性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图9.GXA3054 PDX模型(胃癌，HER2 IHC 3+，HER2 FISH阳性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图10.GXA3038 PDX模型(胃癌，HER2 IHC 2+，HER2 FISH阴性)中与T-DM1相比SYD985的抗肿瘤活性(CRO：Oncotest)。
图11.BXF439 PDX模型(膀胱癌，HER2 IHC 3+，HER2 FISH阳性)中SYD985的抗肿瘤活性(CRO：Oncotest)。
图12.SKOV3细胞系衍生的异种移植物模型(卵巢癌，HER2 IHC 2+，HER2 FISH阳性)中SYD983的抗肿瘤活性(CRO：Piedmont)。
发明详述
本发明涉及含倍癌霉素的ADC，其用于治疗表达HER2的人实体瘤和血液学恶性肿瘤。
在一个实施方案中，本发明提供了式(I)的化合物
其中
抗HER2 Ab是抗HER2抗体或抗体片段，
n是0至3，优选0至1，
m表示1至4的平均DAR(药物抗体比，drug-to-antibody ratio)，
R1选自
y是1至16，并且
R2选自
其用于治疗表达HER2的人实体瘤和血液学恶性肿瘤，特别是用于治疗人实体瘤。
在另一个实施方案中，本发明涉及式(I)的化合物，其中抗HER2 Ab是抗HER2抗体或抗体片段，n是0至1，m表示1至4、优选2至3的平均DAR，R1选自
y是1至16，优选1至4，并且R2选自
在另一个实施方案中，本发明涉及式(I)的化合物，其中抗HER2 Ab是抗HER2单克隆抗体，n是0至1，m表示2至3、优选2.5至2.9的平均DAR，R1选自
y是1至4，并且R2选自
在又一个实施方案中，本发明涉及式(I)的化合物，其中抗HER2 Ab是曲妥珠单抗或其生物类似物(biosimilar)，n是0至1，m表示2至3、优选2.5至2.9的平均DAR，R1选自
y是1至4，并且R2选自
在一个优选实施方案中，本发明涉及式(II)的化合物，所述化合物包含曲妥珠单抗或其生物类似物
在本说明书中被称为SYD985的式(II)化合物的平均DAR为2.6至2.9。式(II)的SYD983的平均DAR为2.0。
在本说明书中示出的结构式中，n表示0至3的整数，而m表示1至4的平均药物抗体比(DAR)。本领域中周知，可以例如使用疏水作用色谱(HIC)或反向高效液相色谱(RP-HPLC)确定DAR和药物负载分布。HIC特别适于确定平均DAR。
可以根据本发明治疗的人实体瘤的实例是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌、前列腺癌、胰腺癌、结直肠癌、头颈鳞状细胞癌和骨肉瘤，特别是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌和前列腺癌，更特别地是乳腺癌、胃癌和膀胱癌(还参见S.Scholl等，2001，Ann.Oncol.，12(1)：S81-S87)。可以根据本发明治疗的血液学恶性肿瘤的实例是急性淋巴细胞白血病(ALL)。但是，本发明的范围不限于这些特定实例。
在一个实施方案中，本发明提供了式(I)或(II)的化合物，其用于治疗乳腺癌、胃癌或膀胱癌，特别是乳腺癌或胃癌，尤其是乳腺癌。所述乳腺癌是激素受体(ER和/或PR)阳性或阴性的，有利地为ER和PR阴性的。
在另一个实施方案中，本发明提供了式(I)或(II)的化合物，其用于治疗表现出中等或低的HER2表达(即，HER2IHC 2+或1+)的人实体瘤。
在又一个实施方案中，本发明提供了式(I)或(II)的化合物，其用于治疗不具有HER2基因扩增(即，HER2 FISH阴性)的人实体瘤。
出乎意料的，本发明人发现，本发明的含倍癌霉素的ADC化合物特别可用于治疗具有中等或低的HER2表达(即，HER2 IHC 2+或1+)和/或不具有HER2基因扩增(即，HER2 FISH阴性)的人实体瘤，特别是乳腺癌和胃癌。曲妥珠单抗或T-DM1均未获得用于治疗患这样的肿瘤之患者的销售许可。另外，如下文实施例和附图所示，T-DM1在这样的肿瘤中缺乏效力。因此，本发明的含倍癌霉素的ADC化合物可用于治疗目前没有可用的HER2靶向治疗的患者群体。在WO2011/133039A的实施例15中在具有N87(即，HER2 IHC 3+胃肿瘤)异种移植物的小鼠中测试的含倍癌霉素的ADC化合物在12mg/kg的单静脉内剂量后确实表现出了效力。然而，该文献没有任何内容提示本领域技术人员在较低级HER2表达的肿瘤(即，HER2 IHC 2+或1+)和/或不具有HER2基因扩增(即，HER2 FlSH阴性)的肿瘤中测试，更不用说预期找到疗效，即使已经处在3mg/kg的剂量。
本发明人进一步出乎意料地发现，与T-DM1(参见实施例和附图)和曲妥珠单抗相比，在以相同剂量施用时，式(I)或(II)的含倍癌霉素的ADC化合物在动物肿瘤模型中表现出改善的体内抗肿瘤活性。显著地，发现在具有最低级HER2表达(即，IHC HER2 1+)的肿瘤模型中，特别是在(三阴性)乳腺癌和胃癌中，改善最明显。
在本发明的一个有利的实施方案中，人实体瘤是表现出中等或低HER2表达(即，HER2 IHC 2+或1+)的不具有HER2基因扩增(即，HER2 FISH阴性)的乳腺癌或胃癌。
在本发明一个特别有利的实施方案中，人实体瘤是三阴性乳腺癌(即，HER2 IHC 2+或1+，HER2 FISH阴性，以及ER和PR阴性)。
通常，首先在体外(人)肿瘤细胞系中评估抗肿瘤活性，然后在体内评估。有利地在动物模型中评估落入本发明范围的ADC的抗肿瘤活性，所述模型通常为具有皮下异种移植物的免疫缺陷小鼠。异种移植物可以是(人)肿瘤细胞系或来源于患者的(原发性)肿瘤。优选地，动物模型是来源于患者的肿瘤异种移植物(PDX)模型。
PDX模型中的人肿瘤保持原始肿瘤的生物学特性，如通过显微镜检查评估的。目前PDX模型在许多学术机构中常规使用，并且在商业上由包括Jackson Lab(USA)、Oncotest(Germany)、Molecular Response(USA)、Charles River(USA)、Oncodesign(France)、XenTech(France)、Champions Oncology(USA)和Start(USA)的若干合同研究组织(Contract Research Organization，CRO)提供。许多显示出在异种移植物中保持了原始人肿瘤的特征性形态和免疫组织化学特征。除了关于生物学特性的密切关系外，PDX模型对于治疗临床结果具有非常好的预测价值。总之，可以声称，在灵敏度以及肿瘤对治疗的抗性二者方面，来自不同来源的报道指出PDX中对于治疗的响应与患者中的响应相比有至少90％正确重复。(Website Champions Oncology，http://www.championsoncology.com/translational-oncology-solutions/predictive-value；Fiebig等，1984，BehringInst.Mitt.74：343-352；Hidalgo等，2011，Mol.Cancer Ther.10：1311-1316)。
根据本发明，抗HER2抗体或抗体片段可以是能够与HER2结合的任何抗体或抗体片段，例如，具有曲妥珠单抗的互补决定区(CDR)的IgG1抗体或与曲妥珠单抗表现出竞争性结合的抗体。优选的抗体是抗HER2单克隆抗体。特别优选的单克隆抗体是曲妥珠单抗或其生物类似物。
根据本发明的式(I)和(II)的抗体-药物缀合物(ADC)化合物具有通过半胱氨酸残基的S原子与抗体缀合的接头-药物，即，其为半胱氨酸连接的抗体-药物缀合物。半胱氨酸残基可以是抗体(Ab)的重链和/或轻链中存在的天然半胱氨酸残基并且形成链间二硫键，或者在重链和/或轻链的一个或更多个合适的位置处引入到Ab中的工程化半胱氨酸残基。本发明特别涉及其中接头-药物通过Ab(更特别地单克隆Ab(mAb))的链间二硫键缀合的ADC化合物。不同抗体类别的抗体包含了不同数目的链间二硫键。例如，IgG1抗体通常具有4个链间二硫键，所有这四个位于铰链区，并且在二硫键(部分)还原后，接头-药物随机连接至游离巯基。
根据本发明应用的式(I)和(II)的化合物可根据本领域技术人员周知的方法和程序获得。通过链间二硫键的缀合可以在所述二硫键完全或部分还原后发生。制备这样的化合物的合适的方法可以在申请人的WO2011/133039A的描述和实施例中找到。特别地，WO2011/133039A的实施例15描述了部分地还原曲妥珠单抗以使得每个mAb产生2个游离巯基，并且与若干接头-药物缀合以产生平均DAR为约2的ADC。本领域技术人员容易理解如何获得平均DAR为1至4的ADC。WO2005/084390A的实施例7和8描述了用于(部分)负载具有接头-药物的抗体vcMMAE的部分还原、部分还原/部分再氧化和完全还原策略。
使用已知测试、程序和设备确定肿瘤组织的IHC和FISH状态。根据本发明，可以使用荧光(FISH)或产色(CISH)或任何其他原位杂交测试测量HER2基因扩增。用于确定肿瘤组织的HER2膜表达状态的合适的测试如HercepTestTM(Dako Denmark)是市售可得的。另外，HER2 IHC测试由Ventana Medical Systems(PATHWAY anti-HER2/neu)、BiogenexLaboratories(InSiteTM HER2/neu)和Leica Biosystems(Bond OracleTM HER2 IHC)销售。FISH/CISH测试可以从Abbott Molecular(PathVysion HER2 DNA Probe Kit)、LifeTechnologies(HER2 CISH Kit)、Dako Denmark(HER2 CISH PharmDxTMKit)、Dako Denmark(HER2 FISH PharmDxTM Kit)和Ventana Medical Systems(INFORMHER2 Dual ISH DNA Probe Cocktail)获得。FISH阳性意味着FISH扩增率≥2.0(例如，通过使用Dako HER2 FISH PharmDXTM测试试剂盒)。FISH阴性意味着FISH扩增率＜2.0。
可以根据本发明有利地治疗的表达HER2的肿瘤是乳腺癌和胃癌，特别是乳腺癌，最特别地三阴性乳腺癌。出乎意料地，本发明人发现，根据本发明的ADC化合物在HER2 IHC2+或1+并且FISH阴性的乳腺癌PDX模型中、在三阴性乳腺癌PDX模型中以及在HER2 IHC 2+或1+并且FISH阴性的胃癌PDX模型中显著有效，如下文实施例和附图所示。鉴于PDX模型对于治疗临床结果具有非常好的预测价值的这个事实，这些发现特别为目前没有可用的此类经批准治疗选择的乳腺癌和胃癌提供了新的HER2靶向治疗选择。
本发明还涉及式(I)或(II)的化合物用于治疗具有表达HER2的人实体瘤或血液学恶性肿瘤，特别是上文所述HER2 IHC 2+或1+和/或HER2 FISH阴性的人实体瘤之患者的用途。
本发明还涉及式(I)或(II)的化合物与治疗性抗体和/或化学治疗剂的组合用于治疗表达HER2的人实体瘤和血液学恶性肿瘤，特别是人实体瘤的用途，最特别地是用于治疗三阴性乳腺癌的用途。
在本发明的一个实施方案中，治疗性抗体是帕妥珠单抗、贝伐珠单抗、雷莫芦单抗(ramucirumab)或曲妥珠单抗，化学治疗剂是i)紫杉烷类，特别是多西他赛、紫杉醇、白蛋白结合型紫杉醇(nab-paclitaxel)或卡巴他赛(cabazitaxel)，ii)有丝分裂抑制剂，特别是艾日布林(eribulin)、长春瑞滨或长春花碱，iii)DNA损伤剂，特别是5-氟-尿嘧啶、卡培他滨、吉西他滨、替莫唑胺、顺铂、卡铂、奥沙利铂、环磷酰胺或异环磷酰胺(ifosfamide)，iv)抗叶酸，特别是培美曲塞(pemetrexed)或甲氨喋呤，v)蒽环类药，特别是米托蒽醌、阿霉素、脂质体阿霉素、表柔比星、柔红霉素或戊柔比星，更特别地阿霉素，vi)mTOR(哺乳动物雷帕霉素靶点)抑制剂，特别是替西罗莫司(temsirolimus)或依维莫司(everolimus)，vii)拓扑异构酶抑制剂，特别是伊立替康或拓扑替康，viii)酪氨酸激酶抑制剂，特别是吉非替尼、埃罗替尼(erlotinib)、帕唑帕尼(pazopanib)、克唑替尼(crizotinib)、拉帕替尼(lapatinib)或阿法替尼(afatinib)，ix)雄激素受体调节剂，特别是恩杂鲁胺(enzalutamide)或醋酸阿比特龙，x)类固醇激素，特别是强的松，xi)激素治疗剂，特别是他莫昔芬，xii)芳香化酶抑制剂或类固醇改性剂，特别是阿那曲唑、来曲唑、氟维司群或依西美坦，或xiii)PARP抑制剂，特别是奥拉帕尼(olaparib)。本领域技术人员在选择用于治疗表达HER2的人实体瘤和血液学恶性肿瘤的合适的联合疗法方面没有困难。
在本发明的另一个实施方案中，治疗性抗体是帕妥珠单抗，化学治疗剂是紫杉烷，特别是多西他赛或紫杉醇，或者蒽环类药，特别是阿霉素、表柔比星、柔红霉素或戊柔比星，更特别地阿霉素。
本发明还涉及式(I)或(II)的化合物与另一种ADC(例如T-DM1)的组合用于治疗表达HER2的人实体瘤和血液学恶性肿瘤，特别是表达HER2的人实体瘤的用途。
本发明还涉及药物组合物，所述组合物包含式(I)或(II)的化合物或者上述其与治疗性抗体和/或化学治疗剂的组合，以及一种或更多种可药用赋形剂。
通常，治疗性蛋白质如单克隆抗体和(单克隆)抗体-药物缀合物的典型药物制剂采用冻干粉末或饼的形式(其需要在静脉内输注之前(水)溶解(即，重构))或者冻结(水)溶液形式(其需要在使用之前融化)。特别地，根据本发明，药物组合物以冻干饼的形式提供。
用于包含到根据本发明的药物组合物(冻干前)中的合适的可药用赋形剂包括缓冲溶液(例如，在水中包含柠檬酸盐、组氨酸或琥珀酸盐的盐)、冻干保护剂(例如，蔗糖、海藻糖)、张力调节剂(例如，氯化钠)、表面活性剂(例如，聚山梨醇酯)和填充剂(例如，甘露醇、甘氨酸)。为了使其在冻干过程中以及储存期间具有防止蛋白质变性的能力，选择用于冻干蛋白质制剂的赋形剂。
HerceptinTM的无菌冻干粉末多剂量制剂包含440mg曲妥珠单抗、400mgα，α-海藻糖二水合物、9.9mg L-组氨酸盐酸盐、6.4mg L-组氨酸和1.8mg聚山梨醇酯20，USP。利用20ml抑茵或无菌注射用水(BWFI或SWFI)重构产生pH约6的包含21mg/ml曲妥珠单抗的多剂量溶液。KadcylaTM的无菌冻干粉末单次使用制剂在重构后包含20mg/ml ado-曲妥珠单抗emtansine、0.02％w/v聚山梨醇酯20、10mM琥珀酸钠和6％w/v蔗糖，pH为5.0。
用于根据本发明应用的式(I)或(II)化合物的治疗有效量为约0.01mg/kg体重至约15mg/kg体重，特别为约0.1mg/kg体重至约10mg/kg体重，更特别约0.3mg/kg体重至约10mg/kg体重。后一个范围大致对应于20至800mg ADC化合物的平剂量(flat dose)。本发明化合物每周一次、每周两次、每周三次或每月一次施用，例如前12周每周一次，然后每三周一次直到疾病进展。可以根据疾病的严重程度、患者的年龄、施用的化合物以及主治医生认为合适的类似的其他因素使用替代治疗方案。
实施例
PDX HER2基因扩增测试
通过原位杂交(ISH)，在福尔马林固定、石蜡包埋的人乳腺癌组织试样中使用FAD批准的来自Ventana Medical Systems(INFORM HER2 Dual ISH DNA Probe Cocktail)或Abbott Molecular(PathVysion HER2 DNA Probe Kit)的测试确定HER2基因的扩增。所使用的方案由测试供应商详细说明。
PDX HER2 IHC染色
制备福尔马林固定、石蜡包埋的肿瘤异种移植物样品的组织切片。使用合适的Ab如多克隆兔抗人HER2(DAKO Cat#A0485)抗体结合HER2，并且通过合适的二抗如生物素化山羊抗兔IgG(JackSonlmmuno research，Cat#111-065-04)和Biozol(Cat#VEC-PK-4000)ABC试剂盒对其进行检测。在合适的显微镜上(如使用Zeiss Axiovert 35显微镜)对染色进行半定量评估。基于染色的肿瘤细胞的数目以及膜染色的完整性和强度，将染色解读为免疫反应性。
0：＜10％的肿瘤细胞表现出膜染色。
1：＞10％的肿瘤细胞表现出膜染色，但是表面不完全染色。
2：＞10％的肿瘤细胞表现出遍布于全部表面的弱或中等的膜染色。
3：＞30％的肿瘤细胞表现出遍布于全部表面的强的膜染色。
在每个HER2染色程序中包括已知的HER2阳性(IHC 3+)和HER2阴性(IHC 0)对照肿瘤切片。
PDX和细胞系衍生的异种移植物动物研究
所有动物研究经地方动物伦理委员会批准并且根据地方动物实验伦理规范进行。使用来自专业动物饲养者如Harlan或Charles River的雌性免疫缺陷nu/nu小鼠(4-6周龄)或SCID小鼠，并且根据各自CRO的详细方案进行随机化，如Fiebig等在Cancer Genomics&Proteomics 4：197-210，1997中所述。
进行所有乳腺和胃PDX研究，与T-DM1一一对应地(head-to-head)测试SYD985，因为前者ADC已经被批准用于治疗患有HER2阳性转移性乳腺癌的患者，并且正在寻求批准T-DM1用于HER2阳性胃癌。仅使用SYD985进行其他适应症(膀胱和卵巢)中的研究，因为T-DM1在这些适应症中不是经批准药物。在所有乳腺PDX模型中用载剂、3mg/kg SYD985或3mg/kgT-DM1处理小鼠(图1-6)，并且在所有胃PDX模型中用载剂、10mg/kg SYD985或10mg/kg T-DM1处理小鼠(图7-10)。在膀胱PDX模型中，用载剂或10mg/kg SYD985处理小鼠(图11)，并且在细胞系衍生的卵巢异种移植物模型中用载剂或15mg/kg SYD983处理小鼠(图12)。所有处理在第0天通过单剂量静脉内注射到尾静脉中来进行。表示为平均肿瘤体积±S.D.的数据由每个实验组的6-8只动物组成。体重和肿瘤大小每周测量两次。肿瘤体积通过利用卡尺的二维测量确定。终止标准包括肿瘤体积＞2000mm或体重损失＞30％等情况。使用GraphPadPrism处理各个动物的肿瘤大小。结果示出在图1至12中。
首次人体(first-in-human)临床研究
利用抗体-药物缀合物SYD985(曲妥珠单抗vc-seco-DUBA)进行二部分首次人体I期研究(two-part first-in-human phase I study)(利用扩大的人群)以评估在具有局部晚期或转移性实体瘤的患者中的安全性、药代动力学和效力(即，NCT02277717)。I部分是剂量递增的部分，其中给予三位癌症患者(具有任何来源的实体瘤的女性或男性)低剂量的SYD985。如果良好耐受，给予另三位癌症患者更高剂量的SYD985。持续该过程直到进一步提高剂量不再安全。在研究的II部分中，具有特定类型癌症(包括乳腺肿瘤和胃肿瘤)的数组患者接受所选择的SYD985剂量用于进一步研发。来自研究的两个部分的所有患者(估计总共登记76位患者)将接受每三周一次的SYD985(静脉内)输注，直到癌症进展或不可接受的毒性出现。

Claims (14)

1.式(I)的化合物
用于制造用于治疗表达HER2的人实体瘤之药物的用途，
其中
抗HER2Ab是抗HER2抗体或抗体片段，
n是0至3，
m表示1至4的平均DAR，
R1选自
y是1至16，并且
R2选自
其中所述表达HER2的人实体瘤是HER2 IHC 2+或1+。
2.根据权利要求1所述的用途，其中
抗HER2 Ab是抗HER2抗体或抗体片段，
n是0至1，
m表示1至4的平均DAR，
R1选自
y是1至16，并且
R2选自
3.根据权利要求1所述的用途，其中所述化合物是式(II)的化合物
4.根据权利要求1至3中任一项所述的用途，其中所述表达HER2的人实体瘤是乳腺癌、胃癌、膀胱癌、卵巢癌、肺癌、前列腺癌、胰腺癌、结直肠癌、头颈鳞状细胞癌或骨肉瘤。
5.根据权利要求4所述的用途，其中所述表达HER2的人实体瘤是乳腺癌或胃癌。
6.根据权利要求5所述的用途，其中所述表达HER2的人实体瘤是激素受体阳性或阴性乳腺癌。
7.根据权利要求1至3中任一项所述的用途，其中所述人实体瘤是HER2 FISH阴性。
8.根据权利要求1至3中任一项所述的用途，其中所述人实体瘤是三阴性乳腺癌。
9.根据权利要求1至3中任一项所述的用途，其中所述化合物与治疗性抗体和/或化学治疗剂组合使用。
10.根据权利要求9所述的用途，其中所述表达HER2的人实体瘤是乳腺癌。
11.根据权利要求10所述的用途，其中所述乳腺癌是三阴性乳腺癌。
12.根据权利要求9所述的用途，其中所述治疗性抗体是帕妥珠单抗，所述化学治疗剂是紫杉烷或者蒽环类药。
13.根据权利要求12所述的用途，其中所述紫杉烷是多西他赛或紫杉醇。
14.根据权利要求12所述的用途，其中所述蒽环类药是阿霉素、表柔比星、柔红霉素或戊柔比星。
CN201580003979.0A 2014-01-10 2015-01-09 表现出改进的体内抗肿瘤活性的倍癌霉素adc Active CN105899236B (zh)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP14150791 2014-01-10
EP14150791.3 2014-01-10
EP14188450 2014-10-10
EP14188450.2 2014-10-10
PCT/EP2015/050350 WO2015104385A2 (en) 2014-01-10 2015-01-09 Duocarmycin adcs showing improved in vivo antitumor activity

Publications (2)

Publication Number Publication Date
CN105899236A CN105899236A (zh) 2016-08-24
CN105899236B true CN105899236B (zh) 2019-07-26

Family

ID=52396655

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201580003979.0A Active CN105899236B (zh) 2014-01-10 2015-01-09 表现出改进的体内抗肿瘤活性的倍癌霉素adc

Country Status (23)

Country Link
US (4) US9421278B2 (zh)
EP (2) EP3069735B1 (zh)
JP (2) JP6342517B2 (zh)
KR (2) KR102323302B1 (zh)
CN (1) CN105899236B (zh)
AU (2) AU2015205509B2 (zh)
BR (1) BR112016015848A2 (zh)
CA (1) CA2935433C (zh)
CL (1) CL2016001760A1 (zh)
CY (2) CY1117687T1 (zh)
DK (2) DK2948184T3 (zh)
ES (2) ES2575508T3 (zh)
HR (2) HRP20160697T1 (zh)
HU (2) HUE029255T2 (zh)
LT (1) LT3069735T (zh)
MX (2) MX374126B (zh)
NO (1) NO3069735T3 (zh)
PL (2) PL2948184T3 (zh)
PT (2) PT3069735T (zh)
RU (2) RU2769700C2 (zh)
SG (2) SG11201605602XA (zh)
WO (1) WO2015104385A2 (zh)
ZA (2) ZA201604535B (zh)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9901567B2 (en) 2007-08-01 2018-02-27 Syntarga B.V. Substituted CC-1065 analogs and their conjugates
MX2011004625A (es) 2008-11-03 2011-07-20 Syntarga Bv Analogos cc-1065 novedosos y sus conjugados.
AU2011243294C1 (en) 2010-04-21 2015-12-03 Syntarga B.V. Novel conjugates of CC-1065 analogs and bifunctional linkers
US9943610B2 (en) 2012-12-21 2018-04-17 Bioalliance C.V. Hydrophilic self-immolative linkers and conjugates thereof
PT2948183T (pt) 2014-01-10 2016-07-13 Univ Yale Conjugados anticorpo-fármaco de duocarmicina para utilização no tratamento de cancro do endométrio
PT3069735T (pt) 2014-01-10 2018-05-18 Synthon Biopharmaceuticals Bv Adc de duocarmicina para utilização no tratamento de cancro da bexiga
PT3092010T (pt) 2014-01-10 2018-09-28 Synthon Biopharmaceuticals Bv Método para purificação de conjugados anticorpo-fármaco ligados por cys
SG10201913977TA (en) 2014-05-22 2020-03-30 Synthon Biopharmaceuticals Bv Site-specific conjugation of linker drugs to antibodies and resulting adcs
TWI695011B (zh) 2014-06-18 2020-06-01 美商梅爾莎納醫療公司 抗ｈｅｒ２表位之單株抗體及其使用之方法
US9808528B2 (en) 2014-06-18 2017-11-07 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates and methods of using same
JP2017528418A (ja) 2014-06-20 2017-09-28 バイオアライアンス コマンディテール フェンノートシャップ 抗葉酸受容体アルファ（ｆｒａ）抗体−薬物コンジュゲート及びその使用方法
SG11201610468XA (en) * 2014-06-20 2017-01-27 Abgenomics Internat Inc Her2 antibody-drug conjugates
AU2016292759B2 (en) 2015-07-10 2021-05-20 Byondis B.V. Compositions comprising antibody-duocarmycin drug conjugates
BR112018005494A2 (pt) * 2015-09-22 2018-10-09 Synthon Biopharmaceuticals Bv composto, composição farmacêutica, e, método de tratamento de um paciente com uma doença.
CN106729743B (zh) * 2015-11-23 2021-09-21 四川科伦博泰生物医药股份有限公司 抗ErbB2抗体-药物偶联物及其组合物、制备方法和应用
PT3380525T (pt) * 2015-11-25 2024-02-05 Immunogen Inc Formulações farmacêuticas e métodos que as utilizam
WO2017120534A1 (en) 2016-01-08 2017-07-13 Bioalliance C.V. Tetravalent anti-psgl-1 antibodies and uses thereof
BR112018071105A2 (pt) 2016-04-15 2019-02-26 Macrogenics, Inc. conjugado de droga e anticorpo, molécula de ligação, composição farmacêutica e uso
GB201708909D0 (en) * 2017-06-05 2017-07-19 Orthox Ltd Implantable tissue repair devices and methods for manufacturing the same
EP3866785A1 (en) 2018-10-15 2021-08-25 Merck Patent GmbH Combination therapy utilizing dna alkylating agents and atr inhibitors
SG11202104413TA (en) * 2018-11-09 2021-05-28 Byondis Bv Filterable duocarmycin-containing antibody-drug conjugate compositions and related methods
BR112022015062A2 (pt) * 2020-02-06 2022-09-20 Byondis Bv Conjugado anticorpo-fármaco para uso no tratamento de um tumor, composição, uso de um conjugado anticorpo-fármaco, produto compreendendo um conjugado anticorpo-fármaco, e, método para prevenção ou redução da toxicidade associada à administração de um conjugado anticorpo-fármaco

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2380909A1 (en) * 2010-04-26 2011-10-26 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. PTK-7 protein involved in breast cancer
CN103118679A (zh) * 2010-04-21 2013-05-22 辛塔佳有限公司 Cc-1065类似物和双功能接头的新型缀合物

Family Cites Families (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1238907A (en) 1984-02-21 1988-07-05 Robert C. Kelly 1,2,8,8a-tetrahydrocyclopropa¬c|pyrrolo(3,2-e)- indol-4(5h)-ones and related compounds
US4771128A (en) 1986-10-10 1988-09-13 Cetus Corporation Method of purifying toxin conjugates using hydrophobic interaction chromatography
MX9203460A (es) 1988-09-12 1992-09-01 Upjohn Co Nuevos analogos cc-1065 que tienen dos subunidades cpi.
CA2078118C (en) 1990-04-25 1999-11-16 Paul A. Aristoff Cc-1065 analogs
JPH05268205A (ja) 1992-03-19 1993-10-15 Fujitsu Ltd クロック切換え回路
ES2149768T3 (es) 1992-03-25 2000-11-16 Immunogen Inc Conjugados de agentes enlazantes de celulas derivados de cc-1065.
JP3514490B2 (ja) 1992-08-21 2004-03-31 杏林製薬株式会社 トリフルオロメチルピロロインドールカルボン酸エステル誘導体及びその製造方法
GB9307491D0 (en) 1993-04-08 1993-06-02 Sandoz Ltd Organic compounds
KR960702463A (ko) 1994-04-01 1996-04-27 나까무라 간노스께 Dc-89 유도체[dc-89 derivative]
US5502068A (en) 1995-01-31 1996-03-26 Synphar Laboratories, Inc. Cyclopropylpyrroloindole-oligopeptide anticancer agents
DE19503320A1 (de) 1995-02-02 1996-08-08 Boehringer Mannheim Gmbh Neue Benzodiazepinkonjugate
US5843937A (en) 1996-05-23 1998-12-01 Panorama Research, Inc. DNA-binding indole derivatives, their prodrugs and immunoconjugates as anticancer agents
NZ334344A (en) 1996-09-12 2000-08-25 Cancer Res Campaign Tech benzo[e]indole and pyrrolo[3,2-e]indole compounds and their use as prodrugs
WO1998025900A1 (fr) 1996-12-13 1998-06-18 Shionogi & Co., Ltd. Composes presentant une activite antitumorale
US20030036629A1 (en) 1997-12-12 2003-02-20 Barry Foster Novel tgf-beta protein purification methods
US7214685B2 (en) 2000-05-02 2007-05-08 Lutz F. Tietze Prodrugs for a selective cancer therapy
ATE310724T1 (de) 2000-09-19 2005-12-15 Taiho Pharmaceutical Co Ltd Zusammensetzungen und verfahren zur verwendung achirale analoge von cc1065 und den duocarmycinen
US7064117B2 (en) 2001-01-24 2006-06-20 Auckland Uniservices Limited Anti-cancer 2,3-dihydro-1H-pyrrolo[3,2-f]quinoline complexes of cobalt and chromium
ATE327750T1 (de) 2001-02-22 2006-06-15 Univ London Pharmacy Benz-indol- und benzo-chinolin-derivate als prodrugs zur tumorbehandlung
NZ529788A (en) * 2001-05-31 2003-12-19 Medarex Inc Cytotoxins, prodrugs, linkers and stabilizers useful therefor
US7514078B2 (en) 2001-06-01 2009-04-07 Cornell Research Foundation, Inc. Methods of treating prostate cancer with anti-prostate specific membrane antigen antibodies
JP2005502703A (ja) 2001-09-07 2005-01-27 ザ スクリプス リサーチ インスティテュート Ｃｃ−１０６５およびデュオカルマイシンのｃｂｉ類似体
WO2003026577A2 (en) * 2001-09-24 2003-04-03 Seattle Genetics, Inc. P-amidobenzylethers in drug delivery agents
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
US7235578B2 (en) 2002-05-17 2007-06-26 Auckland Uniservices Limited Processes for preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl-(amine-derived)] compounds and analogues thereof, and to products obtained therefrom
EP1575514A2 (en) * 2002-07-31 2005-09-21 Seattle Genetics, Inc. Anti-cd20 antibody-drug conjugates for the treatment of cancer and immune disorders
EP1560599A1 (en) 2002-11-14 2005-08-10 Syntarga B.V. Prodrugs built as multiple self-elimination-release spacers
EP1592457B1 (en) 2003-01-27 2012-07-25 Endocyte, Inc. Folate-vinblastine conjugate as medicament
WO2004069201A2 (en) 2003-02-03 2004-08-19 Medlogics Device Corporation Compounds useful in coating stents to prevent and treat stenosis and restenosis
EP2100619B1 (en) 2003-02-20 2014-02-12 Seattle Genetics, Inc. Anti-CD70 antibody-drug conjugates and their use for the treatment of immune disorders
US20050026987A1 (en) 2003-05-13 2005-02-03 The Scripps Research Institute CBI analogues of the duocarmycins and CC-1065
WO2005032594A2 (en) 2003-10-03 2005-04-14 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Alkylators linked to polyamides as dna binding agents
AU2005218642B2 (en) 2004-03-02 2011-04-28 Seagen Inc. Partially loaded antibodies and methods of their conjugation
US7517903B2 (en) 2004-05-19 2009-04-14 Medarex, Inc. Cytotoxic compounds and conjugates
ES2579805T3 (es) 2004-09-23 2016-08-16 Genentech, Inc. Anticuerpos y conjugados modificados por ingeniería genética con cisteína
AU2005289453A1 (en) 2004-09-27 2006-04-06 Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services, National Institutes of Health Modulating MxA expression
NZ536107A (en) 2004-10-22 2007-06-29 Auckland Uniservices Ltd Nitrobenzindoles and their use in cancer therapy
CA2598956A1 (en) 2005-02-24 2006-08-31 Pfizer Products Inc. Bicyclic heteroaromatic derivatives useful as anticancer agents
ES2416136T3 (es) 2005-09-26 2013-07-30 Medarex, Inc. Conjugados de anticuerpo-fármaco y su uso
CN101365679B (zh) 2005-10-26 2012-11-14 梅达莱克斯公司 制备cc-1065类似物的方法和化合物
BRPI0707426A2 (pt) 2006-02-02 2011-05-03 Syntarga Bv composto, conjugado, uso de um composto, composição farmacêutica, processo para preparar uma composição farmacêutica, e, métodos de tratamento de um mamìfero estando em necessidade do mesmo, e de tratamento ou prevenção de um tumor em um mamìfero
EP1832577A1 (en) 2006-03-07 2007-09-12 Sanofi-Aventis Improved prodrugs of CC-1065 analogs
EP3276349B1 (en) 2006-11-01 2019-08-07 Ventana Medical Systems, Inc. Haptens, hapten conjugates, compositions thereof and method for their preparation and use
WO2008074004A2 (en) 2006-12-14 2008-06-19 Medarex, Inc. Human antibodies that bind cd70 and uses thereof
TW200900059A (en) 2007-02-21 2009-01-01 Medarex Inc Chemical linkers with single amino acids and conjugates thereof
ES2433379T3 (es) 2007-08-01 2013-12-10 Syntarga B.V. Análogos de CC-1065 sustituidos y sus conjugados
US9901567B2 (en) 2007-08-01 2018-02-27 Syntarga B.V. Substituted CC-1065 analogs and their conjugates
US8377981B2 (en) 2007-11-13 2013-02-19 The Scripps Research Institute CBI derivatives subject to reductive activation
US20090162372A1 (en) 2007-11-30 2009-06-25 Medarex, Inc. Fibronectin ed-b antibodies, conjugates thereof, and methods of use
NZ571028A (en) 2008-09-03 2011-01-28 Auckland Uniservices Ltd Nitrobenzindole compounds and their use in cancer treatment
EP2349274A4 (en) 2008-09-17 2014-12-17 Endocyte Inc CONJUGATES OF ANTIFOLATES BINDING THE FOLATE RECEPTOR
EP2165710A1 (en) * 2008-09-19 2010-03-24 Institut Curie Tyrosine kinase receptor Tyro3 as a therapeutic target in the treatment of a bladder tumor
MX2011004625A (es) 2008-11-03 2011-07-20 Syntarga Bv Analogos cc-1065 novedosos y sus conjugados.
WO2010070117A1 (en) * 2008-12-18 2010-06-24 Universite Libre De Bruxelles Treatment method by the administration of anti-her2 targeted active compounds to patients with early breast cancer and her2-negative primary tumor
WO2011022316A1 (en) * 2009-08-20 2011-02-24 The Regents Of The University Of Colorado, A Body Corporate Mirnas dysregulated in triple-negative breast cancer
EP2575880B1 (en) * 2010-05-27 2019-01-16 Genmab A/S Monoclonal antibodies against her2 epitope
CN103796678B (zh) * 2011-04-20 2018-02-27 健玛保 针对her2的双特异性抗体
ES2708699T3 (es) 2011-09-29 2019-04-10 Seattle Genetics Inc Determinación de la masa intacta de compuestos de agentes conjugados con proteínas
PL4241849T3 (pl) * 2011-10-14 2025-01-13 F. Hoffmann-La Roche Ag Zastosowania i wyrób przemysłowy zawierający pertuzumab, inhibitor dimeryzacji HER2
US11147852B2 (en) 2011-12-23 2021-10-19 Pfizer Inc. Engineered antibody constant regions for site-specific conjugation and methods and uses therefor
US10010623B2 (en) 2012-02-16 2018-07-03 Ucl Business Plc Lysosome-cleavable linker
PT2948183T (pt) 2014-01-10 2016-07-13 Univ Yale Conjugados anticorpo-fármaco de duocarmicina para utilização no tratamento de cancro do endométrio
PT3092010T (pt) 2014-01-10 2018-09-28 Synthon Biopharmaceuticals Bv Método para purificação de conjugados anticorpo-fármaco ligados por cys
PT3069735T (pt) 2014-01-10 2018-05-18 Synthon Biopharmaceuticals Bv Adc de duocarmicina para utilização no tratamento de cancro da bexiga
SG10201913977TA (en) 2014-05-22 2020-03-30 Synthon Biopharmaceuticals Bv Site-specific conjugation of linker drugs to antibodies and resulting adcs
PL3152191T3 (pl) 2014-06-05 2019-10-31 Synthon Biopharmaceuticals Bv Ulepszony sposób wytwarzania proleków duokarmycyny
WO2016046173A1 (en) 2014-09-22 2016-03-31 Synthon Biopharmaceuticals B.V. Pan-reactive antibodies to duocarmycins
AU2016292759B2 (en) 2015-07-10 2021-05-20 Byondis B.V. Compositions comprising antibody-duocarmycin drug conjugates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103118679A (zh) * 2010-04-21 2013-05-22 辛塔佳有限公司 Cc-1065类似物和双功能接头的新型缀合物
EP2380909A1 (en) * 2010-04-26 2011-10-26 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. PTK-7 protein involved in breast cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Antibody Drug Conjugates as Cancer Therapeutics;Pamela A. Trail;《Antibodies》;20130227;第2卷(第1期);第113-119页
Wim Dokter et al.Abstract 4329: Novel HER2 targeting antibody-drug conjugates based on DNA-interacting duocarmycin and an unique linker technology with great potential in breast cancer and NSCLC.《American Association for Cancer Research》.2013,第73卷(第4期),

Also Published As

Publication number Publication date
LT3069735T (lt) 2018-06-11
CA2935433C (en) 2019-04-02
CA2935433A1 (en) 2015-07-16
JP6430603B2 (ja) 2018-11-28
HRP20160697T1 (hr) 2016-07-15
AU2019264575A1 (en) 2019-12-05
HUE037250T2 (hu) 2018-08-28
RU2019114963A3 (zh) 2021-09-28
CY1117687T1 (el) 2017-05-17
CN105899236A (zh) 2016-08-24
KR20210130826A (ko) 2021-11-01
HUE029255T2 (en) 2017-02-28
DK3069735T3 (en) 2018-05-22
RU2019114963A (ru) 2019-07-17
EP3069735B1 (en) 2018-03-14
SG10201911860VA (en) 2020-02-27
US20180140711A1 (en) 2018-05-24
AU2015205509B2 (en) 2019-08-15
US11382982B2 (en) 2022-07-12
MX374126B (es) 2025-03-05
US20170014525A1 (en) 2017-01-19
RU2016132759A (ru) 2018-02-16
RU2016132759A3 (zh) 2018-08-14
PL2948184T3 (pl) 2016-11-30
PT3069735T (pt) 2018-05-18
EP2948184A2 (en) 2015-12-02
US9421278B2 (en) 2016-08-23
HRP20180876T1 (hr) 2018-07-13
EP3069735A1 (en) 2016-09-21
ES2668984T3 (es) 2018-05-23
CY1120288T1 (el) 2019-07-10
MX2016009070A (es) 2016-09-09
AU2015205509A1 (en) 2016-07-07
ES2575508T3 (es) 2016-06-29
CL2016001760A1 (es) 2017-06-09
US10603387B2 (en) 2020-03-31
ZA201800350B (en) 2019-07-31
EP2948184B1 (en) 2016-03-23
WO2015104385A3 (en) 2015-08-27
DK2948184T3 (en) 2016-06-27
RU2769700C2 (ru) 2022-04-05
MX2019011494A (es) 2019-11-01
JP2018039809A (ja) 2018-03-15
JP2017503858A (ja) 2017-02-02
PL3069735T3 (pl) 2018-08-31
SG11201605602XA (en) 2016-08-30
BR112016015848A2 (pt) 2017-08-08
KR20160106693A (ko) 2016-09-12
MX368396B (es) 2019-10-01
RU2689779C2 (ru) 2019-05-29
KR102323302B1 (ko) 2021-11-09
NO3069735T3 (zh) 2018-08-11
JP6342517B2 (ja) 2018-06-13
WO2015104385A2 (en) 2015-07-16
PT2948184T (pt) 2016-07-08
US20190314513A1 (en) 2019-10-17
US20160008486A1 (en) 2016-01-14
AU2019264575B2 (en) 2020-10-29
KR102344354B1 (ko) 2021-12-28
ZA201604535B (en) 2018-11-28

Similar Documents

Publication Publication Date Title
US11382982B2 (en) Duocarmycin ADCs showing improved in vivo antitumor activity
CN105899237B (zh) 用于治疗子宫内膜癌的倍癌霉素adc
TW202415410A (zh) 抗體-藥物結合物之用途
WO2025054916A1 (en) Methods of treating cervical cancer using anti-her2 antibody-drug conjugates
WO2025038638A1 (en) Methods of treating cancer using anti-her2 antibody-drug conjugates

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: Nijmegen

Patentee after: Byodes Private Limited

Address before: Nijmegen

Patentee before: SYNTHON BIOPHARMACEUTICALS B.V.