ES2547552T3 - Metabolito de nemorrubicina y reactivos análogos, conjugados anticuerpo-fármaco y métodos - Google Patents

Metabolito de nemorrubicina y reactivos análogos, conjugados anticuerpo-fármaco y métodos Download PDF

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ES2547552T3
ES2547552T3 ES09707128.6T ES09707128T ES2547552T3 ES 2547552 T3 ES2547552 T3 ES 2547552T3 ES 09707128 T ES09707128 T ES 09707128T ES 2547552 T3 ES2547552 T3 ES 2547552T3
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pyridylmethyl
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Robert L. Cohen
Edward Hyungsuk Ha
Mark E. Reynolds
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Abstract

Compuesto de conjugado anticuerpo-fármaco representado por la estructura:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en la que: Ab es un anticuerpo; Y1 es C(O)(C(R10)2)q, (C(R10)2)q o (C(R10)2)qO(C(R10)2)q; q es 2, 3, 4, 5 o 6, Y2 es O, NR10, S, OC(O)NR10-(alquil C1-C6)-NR10; R1 y R2 son independientemente una cadena lateral de aminoácido seleccionada entre hidrógeno, metilo, isopropilo, isobutilo, sec-butilo, bencilo, p-hidroxibencilo, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, - CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(>=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, - (CH2)3NHCHO, -(CH2)4NHC(>=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, - (CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-piridilmetil-, 3-piridilmetil-, 4-piridilmetil-, fenilo, ciclohexilo y las estructuras:**Fórmula** cada R10 se selecciona independientemente entre H, alquilo C1-C8, alquenilo C2-C8, alquinilo C2-C8, carbociclilo C3-C12, heterociclilo C2-C20, arilo C6-C20 y heteroarilo C1-C20, opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, Cl, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, - CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2 y -S(O)2CH3; n es 1, 2, 3, 4, 5, 6 o 7; y p es 1, 2, 3, 4, 5, 6, 7 u 8.

Description

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La expresión "anticuerpo monoclonal", como se usa en el presente documento, se refiere a un anticuerpo obtenido a partir de una población de anticuerpos básicamente homogénea, es decir, los anticuerpos individuales que comprende la población son idénticos excepto por posibles mutaciones de origen natural que pueden estar presentes en cantidades minoritarias. Los anticuerpos monoclonales son altamente específicos, dirigiéndose frente a un sitio antigénico individual. Además, a diferencia de las preparaciones de anticuerpo policlonal que incluyen diferentes anticuerpos dirigidos frente a diferentes determinantes (epítopos), cada anticuerpo monoclonal se dirige frente a un determinante individual en el antígeno. Además de su especificidad, los anticuerpos monoclonales son ventajosos en que se pueden sintetizar sin estar contaminados por otros anticuerpos. El modificador "monoclonal" indica que el carácter del anticuerpo se obtiene de una población de anticuerpos básicamente homogénea, y no pretende indicar que requiere una producción del anticuerpo mediante ningún método en particular. Por ejemplo, los anticuerpos monoclonales que se usan de acuerdo con la presente invención se pueden preparar mediante el método del hibridoma descrito en primer lugar por Kohler et al. (1975) Nature 256:495, o se pueden preparar mediante métodos de ADN recombinante (véase, el documento de Patente US 4816567). Los anticuerpos monoclonales también se pueden aislar a partir de librerías de anticuerpos de fagos usando las técnicas que se describen en Clackson et al. (1991) Nature, 352:624-628; Marks et al. (1991) J. Mol. Biol., 222:581-597.
En el presente documento, los anticuerpos monoclonales incluyen específicamente anticuerpos "quiméricos" en los que una parte de la cadena pesada y/o ligera es idéntica u homóloga a las secuencias correspondientes de anticuerpos derivados de una especie particular o pertenecen a una clase o subclase de anticuerpo particular, mientras que el resto de la cadena o cadenas son idénticas u homólogas a las secuencias correspondientes de anticuerpos derivados de otras especies o pertenecen a otra clase o subclase de anticuerpo, así como fragmentos de tales anticuerpos, de modo que exhiben la actividad biológica deseada (documento de Patente US 4816567; y Morrison et al. (1984) Proc. Natl. Acad. Sci. USA, 81:6851-6855). Los anticuerpos quiméricos incluyen anticuerpos "primatizados" que comprenden secuencias de unión a antígeno de dominio variable derivadas de un primate no humano (por ejemplo, mono o simio del viejo mundo) y secuencias de región constante humanas.
En el presente documento, un "anticuerpo intacto" es el que comprende los dominios VL y VH, así como un dominio constante de cadena ligera (CL) y dominios constantes de cadena pesada, CH1, CH2 y CH3. Los dominios constantes pueden ser dominios constantes de secuencia nativa (por ejemplo, dominios constantes de secuencia nativa humana) o una variante de la secuencia de aminoácidos de los mismos. El anticuerpo intacto puede tener una
o más "funciones efectoras" que se refieren a las actividades biológicas atribuibles a la región Fc (una región Fc de secuencia nativa o una región Fc de variante de secuencia de aminoácidos) de un anticuerpo. Algunos ejemplos de funciones efectoras de anticuerpo incluyen unión a C1q; citotoxicidad dependiente de complemento; unión a receptor Fc; citotoxicidad mediada por células dependiente de anticuerpos (ADCC); fagocitosis; y regulación negativa de receptores de la superficie celular tales como el receptor de linfocitos B y BCR.
Dependiendo de la secuencia de aminoácidos del dominio constante de sus cadenas pesadas, los anticuerpos intactos se pueden asignar a diferentes "clases". Existen cinco clases principales de anticuerpos intactos: IgA, IgD, IgE, IgG, e IgM, y varias de estas se pueden dividir además en "subclases" (isotipos), por ejemplo, IgG1, IgG2, IgG3, IgG4, IgA, e IgA2. Los dominios constantes de cadena pesada que corresponden a las diferentes clases de anticuerpos se denominan α, δ, ε, γ y µ, respectivamente. Se conocen bien las estructuras y las configuraciones tridimensionales de las subunidades de las diferentes clases de inmunoglobulinas.
Un "receptor ErbB" es una proteína tirosina quinasa receptora que pertenece a la familia de receptores ErbB que son importantes mediadores del crecimiento, diferenciación y supervivencia celular. La familia de receptores ErbB incluye cuatro miembros distintos que incluyen el receptor del factor de crecimiento epidérmico (EGFR, ErbB1, HER1), HER2 (ErbB2 o p185neu), HER3 (ErbB3) y HER4 (ErbB4 o tyro2). El receptor ErbB comprende generalmente un dominio extracelular, que se puede unir a un ligando ErbB; un dominio transmembrana lipofílico; un dominio de tirosina quinasa intracelular conservado; y un dominio de señalización carboxilo terminal que aloja varios restos de tirosina que se pueden fosfororila. El receptor ErbB puede ser un receptor ErbB de "secuencia nativa" o una "variante de secuencia de aminoácidos" del mismo. El receptor ErbB puede ser un receptor ErbB humano de secuencia nativa. Por lo tanto, un "miembro de la familia de receptores ErbB" es EGFR (ErbB1), ErbB2, ErbB3, ErbB4 o cualquier otro receptor ErbB conocido en la actualidad o que se identifique en el futuro. El análisis sistemático de identificación de secuencia ha dado como resultado la identificación de otros dos miembros de la familia de receptores ErbB; ErbB3 (documentos de Patente US 5183884; US 5480968; Kraus et al. (1989) PNAS (USA) 86:9193-9197) y ErbB4 (documento de Patente EP 599274; Plowman et al. (1993) Proc. Natl. Acad. Sci. USA, 90:1746-1750; y Plowman et al. (1993) Nature 366:473-475). Estos dos receptores presentan un aumento de expresión en al menos algunas líneas de células de cáncer de mama. Se han caracterizado anticuerpos anti-ErbB2 (documentos de Patente US 5677171; US 5821337; US 6054297; US 6165464; US 6407213; US 6719971; US 6800738; Fendly et al. (1990) Cancer Research 50:1550-1558; Kotts et al. (1990) In Vitro 26(3):59A; Sarup et al. (1991) Growth Regulation 1:72-82; Shepard et al. J. (1991) Clin. Immunol. 11(3): 117-127; Kumar et al. (1991) Mol. Cell. Biol. 11(2):979-986; Lewis et al. (1993) Cancer Immunol. Immunother. 37:255-263; Pietras et al. (1994) Oncogene 9:1829-1838; Vitetta et al. (1994) Cancer Research 54:5301-5309; Sliwkowski et al. (1994) J. Biol. Chem. 269(20): 14661-14665; Scott et al. (1991) J. Biol. Chem. 266:14300-5; D’souza et al. Proc. Natl. Acad. Sci. (1994) 91:7202-7206; Lewis et al. (1996) Cancer Research 56:1457-1465; y Schaefer et al. (1997) Oncogene 15:1385-1394.
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REACTIVOS FÁRMACO-CONECTOR Los reactivos de fármaco-conector tienen generalmente la estructura:
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10 enlaqueYesN-X6,S,uO;y uno de X1, X2, X3, X4, X5, o X6 comprende un conector y un grupo funcional reactivo seleccionado entre un grupo maleimida, un grupo tiol, un grupo carboxilo, y un éster NHS.
Por lo tanto, los reactivos de fármaco-conector incluyen la estructura: 15
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Claims (1)

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ES09707128.6T 2008-02-01 2009-01-16 Metabolito de nemorrubicina y reactivos análogos, conjugados anticuerpo-fármaco y métodos Active ES2547552T3 (es)

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PCT/US2009/031199 WO2009099741A1 (en) 2008-02-01 2009-01-16 Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods

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