RU2019117750A - Иммуноконъюгаты il2 и мутантного tnf - Google Patents

Иммуноконъюгаты il2 и мутантного tnf Download PDF

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RU2019117750A
RU2019117750A RU2019117750A RU2019117750A RU2019117750A RU 2019117750 A RU2019117750 A RU 2019117750A RU 2019117750 A RU2019117750 A RU 2019117750A RU 2019117750 A RU2019117750 A RU 2019117750A RU 2019117750 A RU2019117750 A RU 2019117750A
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seq
conjugate
scfv
amino acid
acid sequence
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RU2019117750A3 (ru
RU2758139C2 (ru
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Дарио Нери
Роберто ДЕ ЛУКА
Сара ВУЛЬХФАРД
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Филоджен С.П.А.
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
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    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/626—Diabody or triabody
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Claims (28)

1. Конъюгат, содержащий интерлейкин-2 (IL2), мутант фактора некроза опухоли (TNFα) человека и молекулу антитела, которая связывает фибронектин,
где мутант TNFα человека имеет сниженную активность относительно TNFα человека дикого типа и содержит аминокислотную последовательность TNFα дикого типа с заменой R в положении, соответствующем R32 SEQ ID NO: 15 или R52 SEQ ID NO: 17, на A, F или V;
где молекула антитела представляет собой одноцепочечный Fv (scFv) или диантитело.
2. Конъюгат по п. 1, где мутант TNFα человека имеет мутацию R на A в указанном положении.
3. Конъюгат по п. 1 или 2, где TNFα человека содержит аминокислотную последовательность SEQ ID NO: 37 или SEQ ID NO: 39.
4. Конъюгат по любому из пп. 1-3, где молекула антитела связывает экстрадомен-A (ED-A) фибронектина.
5. Конъюгат по п. 4, где
(i) молекула антитела содержит антигенсвязывающий центр, имеющий определяющие комплементарность области (CDR) антитела F8, указанные в SEQ ID NO: 6-11,
(ii) молекула антитела содержит домены VH и VL антитела F8, указанные в SEQ ID NO: 2 и 4; и/или
(iii) где молекула антитела содержит аминокислотную последовательность scFv F8, указанную в SEQ ID NO: 5.
6. Конъюгат по любому из пп. 1-3, где молекула антитела связывает экстрадомен-B (ED-B) фибронектина.
7. Конъюгат по п. 6, где
(i) молекула антитела содержит антигенсвязывающий центр, имеющий определяющие комплементарность области (CDR) антитела L19, указанные в SEQ ID NO: 18-23,
(ii) молекула антитела содержит домены VH и VL антитела L19, указанные в SEQ ID NO: 24 и 25, и/или
(iii) молекула антитела содержит аминокислотную последовательность scFv L19, указанную в SEQ ID NO: 26.
8. Конъюгат по любому из пп. 1-7, где молекула антитела представляет собой или содержит одноцепочечный Fv (scFv) и где
(i) IL2 связан с N-концом домена VH scFv через пептидный линкер и мутант TNF связан с C-концом домена VL scFv через пептидный линкер,
(ii) мутант TNF связан с N-концом домена VH scFv через пептидный линкер и IL2 связан с C-концом домена VL scFv через пептидный линкер, или
(iii) IL2 и мутант TNF связаны с C-концом домена VL scFv через пептидный линкер или IL2 и TNFα связаны с N-концом scFv через пептидный линкер.
9. Конъюгат по любому из пп. 1-5, где
(i) конъюгат содержит аминокислотную последовательность SEQ ID NO: 1 с мутацией R на A в положении 432 или аминокислотную последовательность SEQ ID NO: 16 с мутацией R на A в положении 452, или
(ii) конъюгат содержит аминокислотную последовательность SEQ ID NO: 36 или SEQ ID NO: 38.
10. Конъюгат по любому из пп. 1-3 и пп. 6-7, где
(i) конъюгат содержит аминокислотную последовательность SEQ ID NO: 70 с мутацией R на A в положении 430 или аминокислотную последовательность SEQ ID NO: 71 с мутацией R на A в положении 450, или
(ii) конъюгат содержит аминокислотную последовательность SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44 или SEQ ID NO: 45.
11. Молекула нуклеиновой кислоты, кодирующая конъюгат по любому из пп. 1-10, или экспрессирующий вектор, содержащий указанную нуклеиновую кислоту, или клетка-хозяин, содержащая указанный вектор.
12. Конъюгат по любому из пп. 1-10 для применения в способе лечения злокачественной опухоли путем нацеливания IL2 и TNF на новообразованные сосуды in vivo или для применения в способе доставки IL2 и TNF в новообразованные сосуды опухоли у пациента.
13. Конъюгат для применения по п. 10, где злокачественная опухоль представляет собой меланому, рак головы и шеи, рак почки или саркому, или опухоль является результатом меланомы, рака головы и шеи, рака почки или саркомы.
RU2019117750A 2016-11-09 2017-11-08 Иммуноконъюгаты il2 и мутантного tnf RU2758139C2 (ru)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB1618888.0 2016-11-09
GB201618888 2016-11-09
GBGB1712916.4A GB201712916D0 (en) 2017-08-11 2017-08-11 IL2 and TNF mutant immunoconjugates
GB1712916.4 2017-08-11
PCT/EP2017/078652 WO2018087172A1 (en) 2016-11-09 2017-11-08 Il2 and tnf mutant immunoconjugates

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RU2019117750A true RU2019117750A (ru) 2020-12-10
RU2019117750A3 RU2019117750A3 (ru) 2021-04-01
RU2758139C2 RU2758139C2 (ru) 2021-10-26

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AU (1) AU2017358578B2 (ru)
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