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AR129066A1 - Conjugados de ligando-fármaco con propiedades farmacocinéticas y de liberación de fármaco mejoradas - Google Patents

Conjugados de ligando-fármaco con propiedades farmacocinéticas y de liberación de fármaco mejoradas

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Publication number
AR129066A1
AR129066A1 ARP230100915A ARP230100915A AR129066A1 AR 129066 A1 AR129066 A1 AR 129066A1 AR P230100915 A ARP230100915 A AR P230100915A AR P230100915 A ARP230100915 A AR P230100915A AR 129066 A1 AR129066 A1 AR 129066A1
Authority
AR
Argentina
Prior art keywords
drug
group
reacting
containing drug
thiol
Prior art date
Application number
ARP230100915A
Other languages
English (en)
Inventor
Lo Marx
Mathilde Lucile Colette Pantin
Aurlien Simon Denis Adam
Original Assignee
Debiopharm Res & Manufacturing S A
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 Debiopharm Res & Manufacturing S A filed Critical Debiopharm Res & Manufacturing S A
Publication of AR129066A1 publication Critical patent/AR129066A1/es

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    • 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
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
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    • 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
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    • 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
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • 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
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    • 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
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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
    • 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
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    • 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
    • A61K47/6867—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 a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K47/6889—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
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
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    • 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
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic

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  • Engineering & Computer Science (AREA)
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  • Hematology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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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)

Abstract

La presente invención se refiere a conjugados de ligando-fármaco para el tratamiento de enfermedades. En particular, la presente invención se refiere a conjugados de ligando-fármaco que comprenden un sistema enlazador, que permite una administración mejorada de un fármaco a una célula diana al mismo tiempo que conserva las propiedades farmacocinéticas favorables de los anticuerpos. La presente invención también se refiere a conjugados de ligando-fármaco, que logran una alta tasa de fármaco-anticuerpo y exhiben excelentes propiedades farmacocinéticas, lo que da como resultado una eficacia significativamente mejorada. En ciertos aspectos, la presente invención también se refiere a conjugados de ligando-fármaco para la administración intracelular de fármacos citotóxicos a células tumorales o cancerosas. Reivindicación 1: Un compuesto representado por la fórmula general (1) en donde, D representa una fracción derivada de un fármaco, siendo seleccionado el fármaco entre un fármaco que contiene carboxilo como auristatina F (AF), un fármaco que contiene tiol como mertansina (DM1) o ravtansina (DM4), un fármaco que contiene amino como monometil auristatina F (MMAF) o exatecán, y un fármaco que contiene hidroxilo tal como Maaa-1181a, de preferencia de un fármaco que contiene tiol, un fármaco que contiene amino y un fármaco que contiene hidroxilo; si está presente más de un (D), cada (D) se selecciona independientemente de un fármaco que contiene carboxilo, un fármaco que contiene tiol, un fármaco que contiene amino y un fármaco que contiene hidroxilo, siendo las fracciones (D) de preferencia idénticas entre sí; X representa un grupo divalente que comprende entre uno y siete, de preferencia entre dos y seis, de mayor preferencia entre dos y cinco átomos de la cadena principal seleccionados independientemente entre C, N, O y S; estando X unido de forma covalente a (D) a través de un átomo seleccionado entre C, S, N y O derivado del grupo funcional carboxilo, tiol, amino o hidroxilo comprendido en (D); Y es un grupo divalente que comprende uno o más átomos seleccionados entre C, N, O, P y S, de preferencia un grupo divalente derivado de un compuesto seleccionado entre maleimidas, triazoles, hidrazonas, compuestos que contienen carbonilo y derivados de los mismos, de mayor preferencia un grupo divalente derivado de maleimidas y derivados de las mismas tales como maleimidas hidrolizadas abiertas, y de máxima preferencia un grupo divalente derivado de una maleimida hidrolizada abierta; L representa un enlazador capaz de ser escindido por catepsina B; T representa un grupo de ramificación (2 + n)-valente; S representa una fracción derivada de un compuesto que comprende uno o más, por ejemplo, dos, tres o cuatro grupos solubilizantes; V representa una fracción derivada de un grupo de vectores capaz de interactuar con una célula diana; n es un número entero comprendido entre 1 y 4, de preferencia 1 o 2, de mayor preferencia 1; y m es un número entero comprendido entre 1 y 12, de preferencia entre 2 y 10, de mayor preferencia entre 4 y 8. Reivindicación 30: Un compuesto representado por la fórmula general (11) en donde, D, X, L, T, S y n tienen los mismos significados que se especifican en las reivindicaciones 1, 2, 4, 5, 6, 7, 8, 9, 10, 11 o 12; Y’ representa una fracción que comprende un grupo de conjugación capaz de formar un enlace covalente con una molécula capaz de interactuar con una célula diana (V’) tal como un anticuerpo monoclonal o un fragmento de anticuerpo incorporado en una proteína de fusión Fc; siendo Y’ de preferencia una fracción que comprende un grupo de conjugación seleccionado entre: una maleimida opcionalmente sustituida, de preferencia capaz de reaccionar con uno o dos grupos tiol de (V’), una haloacetamida opcionalmente sustituida, de preferencia capaz de reaccionar con un grupo tiol de (V’), un éster, de preferencia capaz de reaccionar con la cadena lateral de un aminoácido de (V’) tal como un haluro de acilo, un éster de N-hidroxisuccinimida o un éster fenólico, un carbonato, de preferencia capaz de reaccionar con la cadena lateral de un aminoácido de (V’) tal como un haloformiato o un carbonato que comprende un grupo saliente tal como N-hidroxisuccinimida o fenol; un isocianato o isotiocianato, de preferencia capaz de reaccionar con la cadena lateral de un aminoácido de (V’); una azida, de preferencia capaz de reaccionar con un grupo alquino comprendido en (V’); un alquino, de preferencia capaz de reaccionar con un grupo azida comprendido en (V’); un grupo amino, de preferencia capaz de reaccionar con una molécula (V’) en presencia de una enzima tal como una transglutaminasa; el compuesto de preferencia tiene una estructura tal como se muestra en la reivindicación 13 o 15, con la condición de que (Y’) reemplace a (Y) y que m sea 1. Reivindicación 32: Método para la modificación de una molécula capaz de interactuar con una célula diana que comprende hacer reaccionar una molécula capaz de interactuar con una célula diana, tal como un anticuerpo monoclonal o un fragmento de anticuerpo incorporado en una proteína de fusión Fc, con un compuesto de acuerdo con la reivindicación 30.
ARP230100915A 2022-04-14 2023-04-14 Conjugados de ligando-fármaco con propiedades farmacocinéticas y de liberación de fármaco mejoradas AR129066A1 (es)

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EP2022060099 2022-04-14
EP2022084848 2022-12-07
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US (1) US20250249113A1 (es)
EP (1) EP4507734A1 (es)
JP (1) JP2025512064A (es)
KR (1) KR20250004774A (es)
CN (1) CN119255824A (es)
AR (1) AR129066A1 (es)
AU (1) AU2023253796A1 (es)
CA (1) CA3255303A1 (es)
IL (1) IL316062A (es)
MX (1) MX2024012649A (es)
TW (1) TW202345904A (es)
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