RU2504553C2 - Антитела к her - Google Patents

Антитела к her Download PDF

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RU2504553C2
RU2504553C2 RU2011142281/10A RU2011142281A RU2504553C2 RU 2504553 C2 RU2504553 C2 RU 2504553C2 RU 2011142281/10 A RU2011142281/10 A RU 2011142281/10A RU 2011142281 A RU2011142281 A RU 2011142281A RU 2504553 C2 RU2504553 C2 RU 2504553C2
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cancer
seq
antibody
her3
egfr
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RU2011142281A (ru
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Жермен Фу
Габриэле ШЕФЕР
Лорик АБЕР
Марк К. СЛИВКОВСКИ
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Дженентек, Инк.
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    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • 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
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Изобретение относится к области биотехнологии и иммунологии. Представлены варианты биспецифичных антител, специфически связывающихся с EGFR и HER3, которые содержат аминокислотные последовательности вариабельных областей тяжелой и легкой цепей, соответственно, SEQ ID NO:30 и 29; или SEQ ID NO:28 и 27; или SEQ ID NO:28 и 29; или содержат комплементарные регионы CDR тяжелой и легкой цепей из указанных последовательностей вариабельных областей. Описаны нуклеиновая кислота, кодирующая вариантное антитело, и клетка-хозяин, содержащая указанную нуклеиновую кислоту и используемая для экспрессии антитела. Представлен иммуноконъюгат, содержащий вариант антитела и цитотоксический агент, применяемый при лечении рака, содержащего клетки, экспрессирующие EGFR и HER3. Раскрыт способ получения биспецифичного антитела, включающий культивирование клетки-хозяина таким образом, что производится антитело. Описана фармацевтическая композиция для лечения рака, включающего клетки, экспрессирующие EGFR и HER3, содержащая эффективное количество биспецифичного антитела и фармацевтически приемлемый носитель. Предложены: способ лечения рака, включающего клетки, экспрессирующие EGFR и HER3, и способ ингибирования биологической активности EGFR и/или HER3 у субъекта, включающие введение эффективного количества биспецифичного антитела. Описано применение указанного антитела в производстве лекарства для лечения рака, клетки которого экспрессируют EGFR и HER3. Изобретение позволяет получить биспецифичные антитела, связывающие EGFR и HER3, которые не являются конъюгатами двух антител. 14 н. и 8 з.п. ф-лы, 33 ил., 4 табл., 19 пр.

Description

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Claims (22)

1. Выделенное биспецифичное антитело, содержащее последовательность вариабельного домена тяжелой цепи SEQ ID NO: 30 и последовательность вариабельного домена легкой цепи SEQ ID NO: 29, где антитело специфически связывается с EGFR и HER3.
2. Выделенное биспецифичное антитело, включающее антигенсвязывающий домен, который специфично связывается с EGFR и HER3, где антитело включает
(a) HVR-H1, содержащий аминокислотную последовательность LSGDWIH (SEQ ID NO: 48);
(b) HVR-H2, содержащий аминокислотную последовательность VGEISAAGGYTD (SEQ ID NO: 51); и
(c) HVR-H3, содержащий аминокислотную последовательность ARESRVSFEAAMDY (SEQ ID NO: 53); и
(d) HVR-L1, содержащий аминокислотную последовательность NIATDVA (SEQ ID NO: 55);
(e) HVR-L2, содержащий аминокислотную последовательность SASF (SEQ ID NO: 56); и
(f) HVR-L3, содержащий аминокислотную последовательность SEPEPYT (SEQ ID NO: 57).
3. Выделенное биспецифичное антитело, включающее антигенсвязывающий домен, который специфично связывается с EGFR и HER3, где антитело включает
(a) HVR-H1, содержащий аминокислотную последовательность LSGDWIH (SEQ ID NO: 48);
(b) HVR-H2, содержащий аминокислотную последовательность LGEISAAGGYTD (SEQ ID NO: 50); и
(c) HVR-H3, содержащий аминокислотную последовательность ARESRVSFEAAMDY (SEQ ID NO: 53); и
(d) HVR-L1, содержащий аминокислотную последовательность DLATDVА (SEQ ID NO: 54);
(e) HVR-L2, содержащий аминокислотную последовательность SASF (SEQ ID NO: 56); и
(f) HVR-L3, содержащий аминокислотную последовательность SEPEPYT (SEQ ID NO: 57).
4. Выделенное биспецифичное антитело, включающее антигенсвязывающий домен, который специфично связывается с EGFR и HER3, где антитело включает
(a) HVR-H1, содержащий аминокислотную последовательность LSGDWIH (SEQ ID NO: 48);
(b) HVR-H2, содержащий аминокислотную последовательность LGEISAAGGYTD (SEQ ID NO: 50); и
(c) HVR-H3, содержащий аминокислотную последовательность ARESRVSFEAAMDY (SEQ ID NO: 53); и
(d) HVR-L1, содержащий аминокислотную последовательность NIATDVA (SEQ ID NO: 55);
(e) HVR-L2, содержащий аминокислотную последовательность SASF (SEQ ID NO: 56); и
(f) HVR-L3, содержащий аминокислотную последовательность SEPEPYT (SEQ ID NO: 57).
5. Выделенное биспецифичное антитело, содержащее последовательность вариабельного домена тяжелой цепи SEQ ID NO: 28 и последовательность вариабельного домена легкой цепи SEQ ID NO: 27, где антитело специфически связывается с EGFR и HER3.
6. Выделенное биспецифичное антитело, содержащее последовательность вариабельного домена тяжелой цепи SEQ ID NO: 28 и последовательность вариабельного домена легкой цепи SEQ ID NO: 29, где антитело специфически связывается с EGFR и HER3.
7. Антитело по любому из пп.1-6, где антитело представляет собой полноразмерное антитело IgG1.
8. Антитело по п.7, где антитело проявляет активность ADCC.
9. Антитело по любому из пп.1-8 для применения в качестве лекарства для лечения рака, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
10. Антитело по любому из пп.1-8 для использования при лечении рака, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
11. Антитело по п.9 или 10, где рак выбран из группы, состоящей из рака молочной железы, колоректального рака, рака поджелудочной железы, рака головы и шеи, меланомы, рака яичника, рака предстательной железы и немелкоклеточного рака легкого.
12. Выделенная нуклеиновая кислота, кодирующая антитело по любому из пп.1-8.
13. Клетка-хозяин, содержащая нуклеиновую кислоту по п.12, где клетка способна эксперессировать экзогенный генетический материал.
14. Способ получения антитела, включающий культивирование клетки-хозяина по п.13 таким образом, что производится антитело.
15. Иммуноконъюгат, содержащий антитело по любому из пп.1-8 и цитотоксический агент, для использования при лечении рака, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
16. Фармацевтическая композиция, содержащая эффективное количество антитела по любому из пп.1-8 и фармацевтически приемлемый носитель, для использования при лечении рака, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
17. Способ лечения субъекта, страдающего раком, включающий введение субъекту эффективного количества антитела по любому из пп.1-8, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
18. Способ по п.17, где рак выбран из группы, состоящей из рака молочной железы, колоректального рака, рака поджелудочной железы, рака головы и шеи, меланомы, рака яичника, рака предстательной железы и немелкоклеточного рака легкого.
19. Способ ингибирования биологической активности EGFR и/или HER3 у субъекта, включающий введение субъекту эффективного количества антитела по любому из пп.1-8 для ингибирования биологической активности EGFR и/или HER3.
20. Антитело по любому из пп.1-8 для применения в ингибировании биологической активности EGFR и/или HER3.
21. Применение антитела по любому из пп.1-8 в производстве лекарства для лечения рака, где рак включает в себя клетки, которые экспрессируют EGFR и HER3.
22. Применение по п.21, где рак выбран из группы, состоящей из рака молочной железы, колоректального рака, рака поджелудочной железы, рака головы и шеи, меланомы, рака яичника, рака предстательной железы и немелкоклеточного рака легкого.
RU2011142281/10A 2009-03-20 2010-03-19 Антитела к her RU2504553C2 (ru)

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US21056209P 2009-03-20 2009-03-20
US61/210,562 2009-03-20
PCT/US2010/028023 WO2010108127A1 (en) 2009-03-20 2010-03-19 Bispecific anti-her antibodies

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