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RU2018131636A - Новые конъюгаты аманитина - Google Patents

Новые конъюгаты аманитина Download PDF

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RU2018131636A
RU2018131636A RU2018131636A RU2018131636A RU2018131636A RU 2018131636 A RU2018131636 A RU 2018131636A RU 2018131636 A RU2018131636 A RU 2018131636A RU 2018131636 A RU2018131636 A RU 2018131636A RU 2018131636 A RU2018131636 A RU 2018131636A
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cancer
binding fragment
target binding
amatoxin
amino acid
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RU2018131636A
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RU2753416C2 (ru
RU2018131636A3 (ru
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Кристиан ЛУТЦ
Ян АНДЕРЛЬ
Кристоф МЮЛЛЕР
Вернер Зимон
Сюзанне ВЕРНЕР-ЗИМОН
Торстен ХЕХЛЕР
Михаэль КУЛЬКЕ
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Хайдельберг Фарма Рисеч Гмбх
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817Toxins
    • A61K47/6831Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/54Medicinal 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 compound
    • A61K47/549Sugars, nucleosides, nucleotides or nucleic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/62Medicinal 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 a protein, peptide or polyamino acid
    • A61K47/64Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6835Medicinal 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
    • A61K47/6851Medicinal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30Immunoglobulins [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

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

Claims (19)

1. Конъюгат, включающий в себя (а) аматоксин, включающий (i) аминокислоту 4 с 6'-дезокси-положением и (ii) аминокислоту 8 с S-дезокси-положением, (b) мишень-связывающий фрагмент и (с) расщепляемый линкер, связывающий указанный аматоксин и указанный мишень-связывающий фрагмент.
2. Конъюгат по п. 1, имеющий структуру I
Figure 00000001
в которой:
R2 представляет собой S;
R3 выбран из -NHR5, -NH-OR5, и -OR5;
R4 представляет собой Н; и
в которой один из R5 представляет собой -Ln-X, в котором L - расщепляемый линкер, n выбран из 0 и 1, и X представляет собой мишень-связывающий фрагмент, и в котором остальные R5 представляют собой Н.
3. Конъюгат, включающий в себя (а) аматоксин, включающий (i) аминокислоту 4 с 6'-дезокси-положением и (ii) аминокислоту 8 с S-дезокси-положением, (b) мишень-связывающий фрагмент и (с) необязательно линкер, связывающий указанный аматоксин и указанный мишень-связывающий фрагмент.
4. Конъюгат по п. 3, имеющий структуру I
Figure 00000002
в которой:
R2 представляет собой S;
R3 выбран из -NHR5, -NH-OR5, и -OR5;
R4 представляет собой Н; и
в которой один из R5 представляет собой -Ln-X, в котором L - линкер, n выбран из 0 и 1, и X представляет собой мишень-связывающий фрагмент, и в котором остальные R5 представляют собой Н.
5. Фармацевтическая композиция, содержащая конъюгат по любому из пп. 1-4.
6. Конъюгат по любому из пп. 1-4 для применения в лечении рака у пациента, в частности, в котором рак выбран из группы, состоящей из рака молочной железы, рака поджелудочной железы, холангиокарциномы, колоректального рака, рака легких, рака предстательной железы, рака яичников, рака желудка, рака почек, злокачественной меланомы, лейкемии и злокачественной лимфомы.
7. Конструкт, включающий в себя (а) аматоксин, включающий (i) аминокислоту 4 с 6'-дезокси-положением и (ii) аминокислоту 8 с S-дезокси-положением, и (с) фрагмент расщепляемого линкера, несущий реакционноспособную группу Y для связывания указанного аматоксина с мишень-связывающим фрагментом.
RU2018131636A 2016-03-03 2017-03-02 Новые конъюгаты аманитина RU2753416C2 (ru)

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EP16000511.2 2016-03-03
EP16000511.2A EP3222292A1 (en) 2016-03-03 2016-03-03 Amanitin conjugates
PCT/EP2017/054911 WO2017149077A1 (en) 2016-03-03 2017-03-02 Amanitin conjugates

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AU2017228020A1 (en) 2018-09-06
SG10201913942SA (en) 2020-03-30
EP3423104A1 (en) 2019-01-09
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HUE059360T2 (hu) 2022-11-28
MX2018010247A (es) 2018-12-19
SI3423104T1 (sl) 2022-09-30
EP3423104B1 (en) 2022-05-18
HRP20220948T1 (hr) 2022-10-28
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CN108778341A (zh) 2018-11-09
CN108778341B (zh) 2022-11-01
CL2018002502A1 (es) 2019-02-22
US12201693B2 (en) 2025-01-21
CY1125428T1 (el) 2025-05-09
KR20180114191A (ko) 2018-10-17
DK3423104T3 (da) 2022-08-29
CA3015138A1 (en) 2017-09-08
JP7084313B2 (ja) 2022-06-14
AU2017228020B2 (en) 2024-05-16
LT3423104T (lt) 2022-08-10
RS63451B1 (sr) 2022-08-31
RU2753416C2 (ru) 2021-08-16
JP7362714B2 (ja) 2023-10-17
NZ745508A (en) 2023-05-26
JP2019511484A (ja) 2019-04-25
EP3222292A1 (en) 2017-09-27
CO2018009533A2 (es) 2018-09-20
JP2022028756A (ja) 2022-02-16
BR112018067615A2 (en) 2018-12-26
RU2018131636A3 (ru) 2020-04-08
ZA201805336B (en) 2023-09-27

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