ES2640013T3 - Inmunoconjugados con una unión escindible intracelularmente - Google Patents
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- ES2640013T3 ES2640013T3 ES09840166.4T ES09840166T ES2640013T3 ES 2640013 T3 ES2640013 T3 ES 2640013T3 ES 09840166 T ES09840166 T ES 09840166T ES 2640013 T3 ES2640013 T3 ES 2640013T3
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Abstract
Un conjugado que tiene una fórmula estructural de MAb-CL2A-SN-38, con una estructura representada por:**Fórmula**
Description
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En otro ejemplo, la parte escindible intracelularmente es un carbonato que comprende un grupo hidroxilo activado de la parte quimioterapéutica y una parte etanolamina sustituida, y la última, mediante su grupo amino, está unida a un L-aminoácido o un polipéptido que comprende hasta cuatro partes de L-aminoácido; donde el término N está unido a un enlazador cruzado que termina en el grupo que se une a la parte direccionadora; y donde la parte etanolamina sustituida deriva opcionalmente de un L-aminoácido, donde el grupo de ácido carboxílico del último se reemplaza con una parte de hidroximetilo.
En otro ejemplo, la parte escindible intracelularmente es un carbonato que comprende un grupo hidroxilo activado de la parte quimioterapéutica y un alcohol 4-aminobencílico o alcohol 4-aminobencílico sustituido, sustituido con un grupo alquilo C1-C10 en la posición bencílica, y el último, mediante su grupo amino, se une a un L-aminoácido o un polipéptido que comprende hasta cuatro partes de L-aminoácido; donde el término N se une a un enlazador cruzado que termina en el grupo que se une a la parte direccionadora.
En ciertos ejemplos, un grupo amino de una parte quimioterapéutica se acopla al grupo hidroxilo activado de una parte de etanolamina sustituida y protegida con amina, o un alcohol 4-aminobencílico, y el último está unido, mediante su grupo amino, a un L-aminoácido o un polipéptido que comprende hasta cuatro partes de L-aminoácido; donde el término N se une a un enlazador cruzado que termina en el grupo que se une a la parte direccionadora; cuando dicha parte etanolamina sustituida deriva opcionalmente de un L-aminoácido, donde el grupo de ácido carboxílico de la última se reemplaza con una parte de hidroximetilo; y donde el alcohol 4-aminobencílico está sustituido opcionalmente con un grupo alquilo C1-C10 en la posición bencílica. El derivado farmacológico bifuncional se conjuga después con una parte direccionadora para obtener un inmunoconjugado como se debatió anteriormente. Al dirigirse al sitio de la enfermedad con el inmunoconjugado, el inmunoconjugado se endocitosa y se cataboliza para liberar la parte fármaco-enlazador; donde el grupo amino libre de la parte etanolamina sustituida facilita la liberación del fármaco libre por el ataque nucleofílico en el grupo carbonilo de la parte de carbamato.
Breve descripción de las figuras
Figura 1. Terapia preclínica in vivo de ratones atímicos sin pelo, portadores de un carcinoma pancreático humano Capan 1, con conjugados MAb-CL2A-SN-38.
Figura 2. Terapia preclínica in vivo de ratones atímicos sin pelo, portadores de un carcinoma pancreático humano BxPC3, con conjugados MAb-CL2A-SN-38.
Figura 3. Terapia preclínica in vivo de ratones atímicos sin pelo, portadores de un carcinoma de colon humano LS174T, con el conjugado hMN-14CL2A-SN-38.
Descripción detallada de la invención
Definiciones
En la descripción que sigue, se emplean varios términos y expresiones, y las definiciones expuestas a continuación se brindan para facilitar la comprensión del tema central reivindicado. Aquellos términos que no estén expresamente definidos aquí se emplean según sus significados simples y comunes.
Salvo que se indique lo contrario, uno/a o unas/unos se refiere a “uno o más elementos”.
Las expresiones aproximadamente/alrededor de se usa en este documento para hacer referencia a más o menos el diez por ciento (10 %) de un valor. Por ejemplo, “aproximadamente/alrededor de 100” se refiere a cualquier número entre 90 y 110.
La expresión parte direccionadora, tal y como se usa en la presente se refiere a una molécula, un complejo o agregado, que se une específica o selectivamente a una molécula, una célula, una partícula, un tejido o un agregado diana u objetivo. El experto comprenderá que la unión específica se refiere a la unión a un objetivo particular sin reactividad cruzada con otros objetivos, en tanto que unión selectiva se refiere a la unión preferencial a un objetivo particular. En realizaciones preferidas, una parte direccionadora es un anticuerpo, un fragmento de anticuerpo, un anticuerpo biespecífico u otra molécula u otro compuesto basado en un anticuerpo. Sin embargo, otros ejemplos de partes direccionadoras son conocidos en la técnica y se pueden utilizar, tales como aptámeros, avímeros, ligandos de unión al receptor, ácidos nucleicos, pares de unión biotina-avidina, péptidos o proteínas de unión, etc. Las expresiones “parte direccionadora” y “parte de unión” se utilizan como sinónimos en la presente.
Un anticuerpo, tal y como se usa en la presente, se refiere a una molécula de inmunoglobulina de extensión completa (es decir, naturales o formadas por procedimientos de recombinación de genes de inmunoglobulina normal) (por ejemplo, un anticuerpo de IgG) o una porción de unión al antígeno de una molécula de inmunoglobulina, tales como un fragmento de anticuerpo. Un anticuerpo o fragmento de anticuerpo puede estar conjugado u obtenerse de otro modo dentro del alcance del tema central reivindicado. Estos anticuerpos incluyen, aunque no taxativamente, IgG1, IgG2a, IgG3, IgG4 (y las subformas IgG4), así como también los isotipos IgA.
Un fragmento de anticuerpo es una porción de un anticuerpo, tales como F(ab’)2, F(ab) 2, Fab’, Fab, Fv, scFv (Fv de
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comprender, adicionalmente, un agente terapéutico.
Un inmunomodulador es un agente terapéutico que cuando está presente, altera, elimina o estimula el sistema inmunológico del organismo. Por lo general, un inmunomodulador para usar estimula las células inmunes para proliferar o activarse en una cascada de respuestas inmunitarias, tales como macrófagos, células dendríticas, células B y/o células T. Sin embargo, en ciertos casos un inmunomodulador puede suprimir la proliferación o activación de células inmunes, como en el tratamiento terapéutico de una enfermedad autoinmunitaria. Un ejemplo de un inmunomodulador como el que aquí se describe es una citocina, que es una pequeña proteína soluble de aproximadamente 5-20 kDa, que es liberada por una población celular (por ejemplo, linfocitos T cebados) en contacto con antígenos específicos, y que actúa como un mediador intercelular entre las células. Como lo comprenderá el experto, los ejemplos de citocinas incluyen linfocinas, monocinas, interleucinas y varias moléculas de señalización relacionadas, tales como factor de necrosis tumoral (TNF) e interferones. Las quimiocinas son un subconjunto de citocinas. Ciertas interleucinas e interferones son ejemplos de citocinas que estimulan la proliferación de células T u otras células inmunes.
CPT es la abreviatura de la camptotecina, y como se usa en la presente solicitud, la CPT representa la camptotecina en sí o un análogo o derivado de la camptotecina. Las estructuras de camptotecina y ciertos de sus análogos, con la numeración indicada y los anillos rotulados con las letras A-E, se proporcionan en la fórmula 1 en el siguiente gráfico 1.
Gráfico 1
CPT: R1=R2=R3=H 10-Hidroxi-CPT: R= OH; R= R= H
1 2 3
CPT-11: R1 =
R2 = etilo; R3= H
SN-38: R= OH; R= etilo; R= H
12 3
Topotecán: R= OH; R= H; R= CH-N(CH)
1 2 3 232
Conjugados de camptotecina
Los métodos se han concebido de las siguientes maneras para la preparación de conjugados de fármacos quimioterapéuticos con partes direccionadoras (TM, targeting moieties), tales como un anticuerpo (MAb). Los métodos que se describen representan una realización preferida de la invención. (1) La solubilidad del fármaco se potencia al colocar una parte de polietilenglicol (PEG) definida (es decir, un PEG que contiene un número definido de unidades monoméricas) entre el fármaco y el vector direccionador, donde el PEG definido es un PEG de bajo peso molecular, preferiblemente que contiene de 1 a 30 unidades monoméricas, más preferiblemente, que contiene de 1 a 12 unidades monoméricas; (2) un primer enlazador conecta el fármaco en un extremo y termina con un acetileno o un grupo azida en el otro extremo; este primer enlazador comprende una parte de PEG definida con un grupo azida o acetileno en un extremo y un grupo reactivo diferente, tales como un ácido carboxílico o grupo hidroxilo, en el otro extremo y dicho PEG definido bifuncional se une al grupo amina de un alcohol amino, y el grupo hidroxilo del último se une al grupo hidroxilo en el fármaco en forma de un carbonato; de manera alternativa, la parte no azida(o acetileno) de dicho PEG definido bifuncional está unida opcionalmente al término N de un L-aminoácido o un polipéptido, con el término C unido al grupo amino del alcohol amino, y el grupo hidroxi del último se une al grupo hidroxilo del fármaco en forma de carbonato o carbamato, respectivamente; (3) un segundo enlazador, que comprende un grupo de acoplamiento a la parte direccionadora y una parte reactiva complementaria del grupo azida (o acetileno) del primer enlazador, a saber acetileno (o azida), reacciona con el conjugado de fármaco-(primer enlazador) mediante la reacción de cicloadición de acetileno-azida para proveer el producto farmacológico bifuncional final, que es de utilidad para conjugarse con las partes direccionadoras de la enfermedad, tales como los
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En otro ejemplo del conjugado de la realización preferida de la fórmula 2, m es 1 y está representado por una L-lisina derivada, A’ es L-valinol, y el fármaco se ejemplifica mediante SN-38. La estructura se muestra en la fórmula 4.
En este ejemplo, primero se forma una unión de amida entre el ácido carboxílico de un aminoácido, tal como lisina y
5 el grupo amino de valinol, usando grupos protectores ortogonales para los grupos amino de lisina. El grupo protector en el término N de lisina se elimina, manteniendo el grupo protector de la cadena lateral de lisina intacta, y el término N se acopla al grupo carboxilo en el PEG definido con azida (o acetileno) en el otro extremo. El grupo hidroxilo de valinol luego se une al derivado de 20-cloroformato de SN-38 10-hidroxi-protegido, y el intermediario se acopla al componente L2 que lleva el vector direccionador-la parte de unión, así como también el grupo acetileno
10 complementario (o azida) involucrado en la química clic de cicloadición. Finalmente, la eliminación de grupos protectores tanto de la cadena lateral de la lisina como del SN-38 brinda el producto de este ejemplo, que se muestra en la fórmula 3.
Lejos de aceptar las limitaciones de la teoría, el producto SN-38 de bajo peso molecular (MW, molecular weight), a saber carbonato de valinol-SN-38, generado después de la proteólisis intracelular, tiene la vía adicional de liberación
15 de SN-38 intacto mediante ciclización intramolecular, que implica el grupo amino de valinol y el carbonilo del carbonato.
En otro ejemplo, A’ de la fórmula general 2 es A-OH, por lo que A-OH es una parte plegable, tales como alcohol 4aminobencílico o un alcohol 4-aminobencílico sustituido, sustituido con un grupo alquilo C1-C10 en la posición bencílica, y el último, mediante su grupo amino, se une a un L-aminoácido o un polipéptido que comprende hasta
20 cuatro partes de L-aminoácido; donde el término N se une a un enlazador cruzado que termina en el grupo que se une a la parte direccionadora.
A continuación se brinda un ejemplo, en el que la realización A-OH de A’ de la fórmula general (2) deriva de un alcohol 4-aminobencílico sustituido, y ’AA’ comprende un solo L-aminoácido, donde m =1 en la fórmula general (2), y el fármaco se ejemplifica con SN-38. La estructura se representa a continuación (fórmula 5, denominada MAb-CLX
25 SN-38). El único aminoácido de AA se selecciona entre uno cualquiera de los siguientes L-aminoácidos: alanina, arginina, asparagina, ácido aspártico, cisteína, glutamina, ácido glutámico, glicina, histidina, isoleucina, leucina, lisina, metionina, fenilalanina, prolina, serina, treonina, triptófano, tirosina y valina. El sustituyente R en la parte del alcohol 4-aminobencílico (realización A-OH de A’) es hidrógeno o un grupo alquilo seleccionado de los grupos alquilo C1-C10.
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enzimática, química o genética, toda vez que los fragmentos se unan al antígeno que es reconocido por el anticuerpo intacto. Por ejemplo, los fragmentos Fv comprenden una asociación de cadenas VH y VL. Esta associación puede ser no covalente, como se describe en Inbar et al., 1972, Proc. Nat’l. Acad. Sci. USA, 69:2659. De manera alternativa, las cadenas variables pueden enlazarse mediante una unión de disulfuro intermolecular o entrecruzarse con químicos, tales como glutaraldehído. Véase Sandhu, 1992, Crit. Rev. Biotech., 12:437.
Preferiblemente, los fragmentos Fv comprenden cadenas VH y VL conectadas por un péptido enlazador. Estas proteínas que se unen al antígeno monocatenario (scFv) se preparan construyendo un gen estructural que comprende secuencias de ADN que codifican los dominios VH y VL, conectados mediante una secuencia enlazadora de oligonucleótidos. El gen estructural se inserta en un vector de expresión que posteriormente se introduce en una célula hospedadora, tales como E. coli. Las células hospedadoras recombinantes sintetizan una única cadena de polipéptido con un péptido enlazador que forma un puente entre los dos dominios V. Los métodos para producir los scFv son ampliamente conocidos en la técnica. Véase Whitlow et al., 1991, Methods: a Companion to Methods in Enzymology 2:97; Bird et al., 1988, Science, 242:423; documento de patente de los EE. UU. con el número 4,946,778; Pack et al., 1993, Bio/Technology, 11:1271, y Sandhu, 1992, Crit. Rev. Biotech., 12:437.
Otra forma de un fragmento de anticuerpo es un anticuerpo de dominio único (dAb, single domain antibody), denominado en ocasiones anticuerpo de cadena única. Las técnicas para producir anticuerpos de dominios únicos son ampliamente conocidas en esta área (véase, por ejemplo, Cossins et al., Protein Expression and Purification, 2007, 51:253-59; Shuntao et al., Molec Immunol 2006, 43:1912-19; Tanha et al., J. Biol. Chem. 2001, 276:24774780). Otros tipos de fragmentos de anticuerpos pueden comprender una o más regiones determinantes de la complementariedad (CDR). Los péptidos de las CDR (“unidades mínimas de reconocimiento”) pueden obtenerse construyendo genes que codifican las CDR de un anticuerpo de interés. Tales genes se preparan, por ejemplo, usando la reacción en cadena de la polimerasa para sintetizar la región variable del ARN de la células productoras de los anticuerpos. Véase Larrick et al., 1991, Methods: A Companion to Methods in Enzymology 2:106; Ritter et al. (eds.), 1995, MONOCLONAL ANTIBODIES: PRODUCTION, ENGINEERING AND CLINICAL APPLICATION, pages 166-179 (Cambridge University Press); Birch et al., (eds.), 1995, MONOCLONAL ANTIBODIES: PRINCIPLES AND APPLICATIONS, pages 137-185 (Wiley-Liss, Inc.).
Variaciones de anticuerpos
En ciertas realizaciones, las secuencias de anticuerpos, tales como las porciones Fc de los anticuerpos, pueden variarse, para optimizar las características fisiológicas de los conjugados, tales como la semivida en suero. Los métodos para sustituir secuencias de aminoácidos en las proteínas son muy conocidos en la técnica, tales como por mutagnénesis dirigida al sitio (por ejemplo Sambrook et al., Molecular Cloning, a laboratory manual, 2.ª Ed, 1989). En las realizaciones preferidas, la variación puede implicar la adición o eliminación de uno más sitios de glicosilación en la secuencia de Fc (por ejemplo, documento de patente de los EE. UU. con el número 6.254.868). En otras realizaciones preferidas, pueden hacerse sustituciones específicas de aminoácidos en la secuencia de Fc (por ejemplo, Hornick et al., 2000, J Nucl Med 41:355-62; Hinton et al., 2006, J Immunol 176:346-56; Petkova et al. 2006, Int Immunol 18:1759-69; documento de patente de los EE. UU. con el número 7.217.797).
Anticuerpos biespecíficos y multiespecíficos
Los anticuerpos biespecíficos son de utilidad en varias aplicaciones biomédicas. Por ejemplo, un anticuerpo biespecífico con sitios de unión para un antígeno de la superficie de la célula tumoral y para un receptor de la superficie de las células T puede dirigir la lisis de las células tumorales específicas por las células T. Los anticuerpos biespecíficos que reconocen los gliomas y el epítopo de la CD3 en las células T se han usado con éxito en el tratamiento de tumores cerebrales en pacientes humanos (Nitta, et al. Lancet. 1990; 355:368-371). En ciertas realizaciones, las técnicas y las composiciones para la conjugación de agentes terapéuticos explicadas en la presente memoria descriptiva pueden usarse con anticuerpos multiespecíficos o biespecíficos como partes direccionadoras.
Se conocen numerosos métodos para producir anticuerpos biespecíficos o multiespecíficos, tal como se explica, por ejemplo, en el documento de patente de los EE. UU. con el número 7.405.320. Los anticuerpos biespecíficos pueden producirse por el método del cuadroma, que implica la fusión de dos hibridomas diferentes, cada uno de los cuales produce un anticuerpo monoclonal que reconoce un sitio antigénico diferente (Milstein y Cuello, Nature, 1983; 305:537-540).
Otro método para producir anticuerpos biespecíficos emplea enlazadores cruzados heterobifuncionales para enlazarse químicamente con dos anticuerpos monoclonales diferentes (Staerz, et al. Nature. 1985; 314:628-631; Perez, et al. Nature. 1985; 316:354-356). Los anticuerpos biespecíficos también se pueden producir por reducción de cada uno de los anticuerpos monoclonales de origen para resolver las respectivas hemimoléculas, que luego se mezclan y se las deja para que vuelvan a oxidarse, a fin de obtener la estructura híbrida (Staerz y Bevan. Proc Natl Acad Sci USA. 1986; 83:1453-1457). Otra alternativa implica el entrecruzar químicamente dos o tres fragmentos Fab’ purificados por separado, usando enlazadores apropiados. (Véase, por ejemplo, la solicitud de patente europea número 0453082).
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Otros métodos incluyen mejorar la eficiencia de generar hibridomas híbridos por transferencia genética de marcadores distintivos seleccionables mediante vectores lanzadera derivados de retrovirus en los respectivos hibridomas progenitores, que posteriormente se fusionan (DeMonte, et al. Proc Natl Acad Sci USA. 1990, 87:29412945); o transfección de una línea celular del hibridoma con plásmidos de expresión que contienen genes de cadena pesada y liviana de un anticuerpo diferente.
Los dominios cognados VH y VL pueden unirse con un péptido enlazador de una composición y longitud apropiados (por lo general, consistente en más de 12 residuos de aminoácidos) para formar un Fv de cadena única (scFv, single chain Fv) con actividad de unión. Los métodos de fabricación de los scFv se describen en el documento de patente de los EE. UU. con el número 4.946.778 y en el documento de patente de los EE. UU. con el número 5.132.405. La reducción de la extensión del péptido enlazador a menos de 12 residuos de aminoácidos previene el apareamiento de los dominios VH y VL en la misma cadena y fuerza el apareamiento de los dominios VH y VL con dominios de complementariedad en otras cadenas, lo cual da como resultado la formación de multímeros funcionales. Las cadenas polipeptídicas de los dominios VH y VL que se unen con los enlazadores entre los residuos de aminoácidos 3 y 12 forman predominantemente dímeros (denominados diacuerpos). Con los enlazadores, se favorecen entre 0 y 2 residuos de aminoácidos, trímeros (denominados triacuerpos) y terámeros (denominados tetracuerpos), aunque los patrones exactos de oligomerización parecen depender de la composición, así como también, de la orientación de los dominios V (VH-enlazador-VL o VL-enlazador-VH), además de la longitud del enlazador.
Estas técnicas para producir anticuerpos multiespecíficos o biespecíficos denotan diversas dificultades en términos de bajos rendimientos, necesidad de recurrir a la purificación, baja estabilidad o un exigente trabajo de mano de obra de la técnica. En los últimos tiempos, se ha empleado una técnica conocida como “dock and lock” (DNL) [acople de seguridad] para producir combinaciones de virtualmente cualquiera de los anticuerpos, fragmentos de anticuerpos y otras moléculas efectoras que se desean (véanse, por ejemplo, los documentos de patente de los EE. UU. con los números 7.550.143; 7.521.056; 7.534.866; 7.527.787 y USSN 11/925.408). La técnica emplea dominios complementarios de unión a la proteína, denominados dominios de anclaje (AD, anchoring domains) y dominios de dimerización y acople (DDD, dimerization and docking domains), que se unen entre sí y permiten el ensamblaje de las estructuras del complejo, que varían entre dímeros, trímeros, tetrámeros, quintámeros y hexámeros. Estos forman complejos estables con un alto rendimiento, sin requerir una purificación exhaustiva. La técnica DNL permite el ensamblaje de anticuerpos monoespecíficos, biespecíficos o multiespecíficos. Es posible utilizar cualquiera de las técnicas conocidas en el campo de fabricar anticuerpos biespecíficos o multiespecíficos en la práctica de los métodos reivindicados en esta memoria descriptiva.
En diversas realizaciones, un conjugado tal como se explica en la presente memoria descriptiva puede ser parte de un anticuerpo multiespecífico compuesto. Tales anticuerpos pueden contener dos o más sitios de unión al antígeno que sean diferentes, con especificidades distintas. El compuesto multiespecífico puede unirse a diferentes epítopos del miso antígeno o, de manera alternativa, puede unirse a dos antígenos diferentes. Algunas de las combinaciones direccionadoras que más se prefieren son las enumeradas en la tabla 1. Esta es una lista de ejemplos de las combinaciones preferidas, pero no pretende ser exhaustiva.
Tabla 1. Algunos ejemplos de anticuerpos multiespecíficos.
- Primera diana
- Segunda diana
- MIF
- Una segunda citocina efectora proinflamatoria, especialmente HMGB-1, TNF-α, IL-1 o IL-6
- MIF
- Quimiocina efectora proinflamatoria, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- MIF
- Receptor efector proinflamatorio, especialmente IL-6R, IL-13R y IL-15R
- MIF
- Factor de coagulación, especialmente TF o trombina
- MIF
- Factor de complemento, especialmente C3, C5, C3a o C5a
- MIF
- Proteína regulatoria de complemento, especialmente CD46, CD55, CD59 y mCRP
- MIF
- Antígeno o receptor asociado con el cáncer
- HMGB-1
- Una segunda citocina efectora proinflamatoria, especialmente MIF, TNF-α, IL-1 o IL-6
- HMGB-1
- Quimiocina efectora proinflamatoria, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- HMGB-1
- Receptor efector proinflamatorio, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- HMGB-1
- Factor de coagulación, especialmente TF o trombina
- HMGB-1
- Factor de complemento, especialmente C3, C5, C3a o C5a
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- HMGB-1
- Proteína regulatoria de complemento, especialmente CD46, CD55, CD59 y mCRP
- HMGB-1
- Antígeno o receptor asociado con el cáncer
- TNF-α
- Una segunda citocina efectora proinflamatoria, especialmente MIF, HMGB-1, TNF-α, IL-1 o IL-6
- TNF-α
- Quimiocina efectora proinflamatoria, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- TNF-α
- Receptor efector proinflamatorio, especialmente IL-6R IL-13R y IL-15R
- TNF-α
- Factor de coagulación, especialmente TF o trombina
- TNF-α
- Factor de complemento, especialmente C3, C5, C3a o C5a
- TNF-α
- Proteína regulatoria de complemento, especialmente CD46, CD55, CD59 y mCRP
- TNF-α
- Antígeno o receptor asociado con el cáncer
- LPS
- Citocina efectora proinflamatoria, especialmente MIF, HMGB-1, TNF-α, IL-1 o IL-6
- LPS
- Quimiocina efectora proinflamatoria, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- LPS
- Receptor efector proinflamatorio, especialmente IL-6R IL-13R y IL-15R
- LPS
- Factor de coagulación, especialmente TF o trombina
- LPS
- Factor de complemento, especialmente C3, C5, C3a o C5a
- LPS
- Proteína regulatoria de complemento, especialmente CD46, CD55, CD59 y mCRP
- TF o trombina
- Citocina efectora proinflamatoria, especialmente MIF, HMGB=1, TNF-α, IL-1 o IL-6
- TF o trombina
- Quimiocina efectora proinflamatoria, especialmente MCP-1, RANTES, MIP-1A o MIP-1B
- TF o trombina
- Receptor efector proinflamatorio, especialmente IL-6R IL-13R y IL-15R
- TF o trombina
- Factor de complemento, especialmente C3, C5, C3a o C5a
- TF o trombina
- Proteína regulatoria de complemento, especialmente CD46, CD55, CD59 y mCRP
- TF o trombina
- Antígeno o receptor asociado con el cáncer
Otras combinaciones más, tales como las preferidas para las terapias contra el cáncer, incluyen anticuerpos CD20 +
CD22, anticuerpos CD74 + CD20, anticuerpos CD74 + CD22, anticuerpos CEACAM5 (CEA) + CEACAM6 (NCA),
factor de crecimiento del tipo insulina (ILGF, insulin-like growth factor) + anticuerpos CEACAM5, EGP-1 (por
5 ejemplo, RS-7) + anticuerpos ILGF, anticuerpos CEACAM5 + EGFR. Tales anticuerpos no solo deben usarse en
combinación, sino que se los puede combinar como proteínas de fusión de varias formas, tales como IgG, Fab, scFv,
y similares, según se describe en los documentos de patente de los EE. UU. con los números 6.083.477; 6.183.744
y 6.962.702 y en la publicación de solicitudes de patente de los EE. UU. con los números 20030124058;
20030219433; 20040001825; 20040202666; 20040219156; 20040219203; 20040235065; 20050002945; 10 20050014207; 20050025709; 20050079184; 20050169926; 20050175582; 20050249738; 20060014245 y
20060034759.
Antígenos diana y anticuerpos ejemplares
En una realización preferida, se usan anticuerpos que reconocen o se unen a los marcadores o antígenos asociados
con el tumor que se expresan en niveles elevados en las células diana y que se expresan predominantemente o solo 15 en las células enfermas y no en los tejidos normales, y anticuerpos que se internalizan rápidamente. Los anticuerpos
útiles dentro del alcance de la presente invención incluyen MAb con propiedades tales como las que se han descrito
anteriormente (y muestran propiedades distintivas de los diferentes niveles de internalización en las células y
microorganismos), y contemplan el uso, aunque no de manera taxativa, en el cáncer, de los siguientes MAbs: LL1
(anti-CD74), LL2 y RFB4 (anti-CD22), RS7 (anti-glicoproteína epitelial 1 (EGP-1, anti-epithelial glycoprotein-1)), 20 PAM4 y KC4 (ambos anti-mucina), MN14 (antígeno anti-carcinoembriónico (CEA [anti-carcinoembryonic antigen],
también conocido como CD66e), Mu-9 (antígeno-p anti-colon específico), Immu 31 (una antialfa-fetoproteína), TAG
72 (por ejemplo, CC49), Tn, J591 o HuJ591 (anti-PSMA (prostate-specific membrane antigen, antígeno de la
membrana específico de la próstata)), ABPG1-XG1-026 (anti-dímero de PSMA), D2/B (anti-PSMA), G250 (un IX
MAb anti-anhidrasa carbónica) y hL243 (anti-HLADR). Tales anticuerpos son conocidos en la técnica (por ejemplo,
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expresado en los linfomas de células B (incluso el mieloma múltiple) y las leucemias, ciertos linfomas de células T, melanomas, cánceres colónico, pulmonar y renal, glioblastomas, y ciertos otros cánceres (Ong et al., Immunology 98:296-302 (1999)), así como también, ciertas enfermedades autoinmunitarias. Hay una revisión del uso de los anticuerpos CD74 en el cáncer en Stein et al., Clin Cancer Res. 2007 Sep 15;13(18 Pt 2):5556s-5563s.
Las enfermedades que se tratan preferiblemente con anticuerpos anti-CD74 incluyen, aunque no de manera taxativa: linfoma no Hodgkin, enfermedad de Hodgkin, melanoma, cáncer de pulmón, colon y renal, glioblastoma multiforme, histiocitomas, leucemias mieloides y mieloma múltiple. La expresión continua del antígeno CD74 por cortos períodos en la superficie de las células diana, seguida por la internalización del antígeno y la reexpression del antígeno, permite que el anticuerpo LL1 direccionador sea internalizado junco con cualquier parte quimioterapéutica que transporte. Esto permite que una alta concentración terapéutica del conjugado LL1-fármaco quimioterapéutico se acumule dentro de las células. Los conjugados internalizados de LL1-fármaco quimioterapéutico forman ciclos a través de los lisosomas y endosomas, y la parte quimioterapéutica se libera en una forma activa dentro de las células diana.
Dock-and-Lock (DNL, acople seguro)
En ciertas realizaciones preferidas, los anticuerpos biespecíficos o multiespecíficos pueden producirse usando la tecnología dock-and-lock (véanse, por ejemplo, los documentos de patente de los EE. UU. con los números 7.521.056; 7.550.143; 7.534.866; 7.527.787 y la solicitud de patente de los EE. UU. No. 11/925.408). El método DNL aprovecha las interacciones específicas proteína/proteína que tienen lugar entre las subunidades regulatorias (R) de la cinasa de la proteína dependiente de (PKA, cAMP-dependent protein kinase) y el dominio de anclaje (AD, anchoring domain) de las proteínas de anclaje de la A-cinasa (AKAP, A-kinase anchoring proteins) (Baillie et al., FEBS Letters. 2005; 579: 3264. Wong y Scott, Nat. Rev. Mol. Cell Biol. 2004; 5: 959). La PKA, que desempeña un rol central en una de las mejores estudiadas vías de transducción de señales, disparada por la unión de la segunda cAMP mensajera a las subunidades R, se aisló por primera vez del músculo de esqueleto del conejo en 1968 (Walsh et al., J. Biol. Chem. 1968;243:3763). La estructura de la holoenzima consiste en dos subunidades catalíticas que se mantienen en una forma inactiva por ls subunidades R (Tailor, J. Biol. Chem. 1989;264:8443). Las isozimas de la PKA se encuentran con dos tipos de subunidades R (RI y RII), y cada tipo tiene las isoformas α y β (Scott, Pharmacol. Ther. 1991;50:123). Las subunidades R se han aislado solo como dímeros estables, y se ha demostrado que el dominio de dimerización consiste en los primeros 44 residuos de terminal amino (Newlon et al., Nat. Struct. Biol. 1999; 6:222). La unión de cAMP a las subunidades R conduce a la liberación de subunidades catalíticas activas para un amplio espectro de actividades de cinasa de serina/treonina, que están orientadas hacia los sustratos seleccionados, a través de la compartamentalización de la PKA mediante su acople con las AKAP (Scott et al., J. Biol. Chem. 1990;265;21561)
Como la primera AKAP, la proteína 2 asociada al microtúbulo, se caracterizó en 1984 (Lohmann et al., Proc. Natl. Acad. Sci USA. 1984;81:6723), se han identificado más de 50 AKAP que se localizan a diversos sitios subcelulares, lo cual incluye la membrana plasmática, el citoesqueleto de la actina, el núcleo, las mitocondrias y el retículo endoplasmático, con diversas estructuras en especies que varían desde las levaduras hasta los seres humanos (Wong y Scott, Nat. Rev. Mol. Cell Biol. 2004;5:959). La AD de las AKAP para PKA es una hélice anfipática de 14-18 residuos (Carr et al., J. Biol. Chem. 1991;266:14188). Las secuencias de aminoácidos de la AD son bastante variadas entre las AKAP individuales, donde las afinidades de unión reportadas para los dímeros RII varían de 2 a 90 nM (Alto et al., Proc. Natl. Acad. Sci. USA. 2003;100:4445). Lo más interesante es que, las AKAP solo se unen a las subunidades R diméricas. Para el RIIα humano, la AD se una a una superficie hidrofóbica formada por los 23 residuos de terminal amino (Colledge y Scott, Trends Cell Biol. 1999; 6:216). Así, el dominio de dimerización y el dominio de unión de la AKAP de la RIIα humana se encuentran ambos dentro de la misma secuencia de 44 aminoácidos de terminal N (Newlon et al., Nat. Struct. Biol. 1999;6:222; Newlon et al., EMBO J. 2001;20:1651), denominado en este documento, DDD.
Hemos desarrollado una tecnología de plataforma para utilizar el DDD del RIIα humano y la AD de una cierta secuencia de aminoácidos como un par excelente de módulos enlazadores para acoplar dos entidades cualesquiera, denominadas en la presente en este documento como A y B, en un complejo no covalente, que podría acoplarse además en una estructura liada de manera estable, a través de la introducción de residuos de cisteína tanto en DDD como en AD, en posiciones estratégicas, para facilitar la formación de uniones disulfuro. La metodología general del abordaje “dock-and-lock” es la siguiente. La entidad A se construye enlazando una secuencia DDD con un precursor de A, lo cual resulta en un primer componente, denominado en adelante en la presente memoria descriptiva como a. Dado que la secuencia DDD efectuaría la formación espontánea de un dímero, A estaría compuesta entonces por a2. La entidad B se construye enlazando una secuencia AD con un precursor de B, lo cual da como resultado un segundo componente denominado en adelante en la presente memoria descriptiva como b. El motivo dimérico de DDD contenido en a2 creará un sitio de acople para unir la secuencia de AD contenida en b, facilitando de esta manera una asociación lista de a2 y b para formar un complejo trimérico binario, compuesto por a2b. Este evento de unión se torna irreversible con una posterior reacción para asegurar de un modo covalente las dos entidades, mediante puentes disulfuro, lo cual tiene lugar de un modo eficiente basándose en el principio de la concentración local eficaz, porque las interacciones iniciales de unión deberían acercar los grupos tiol reactivos ubicados tanto en DDD como AD (Chimura et al., Proc. Natl. Acad. Sci. USA. 2001;98:8480) para que se liguen específicamente de acuerdo con el sitio.
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Al unir DDD y AD alejados de los grupos funcionales de los dos precursores, también es de esperar que tales ligaduras específicas del sitio conserven las actividades originales de los dos precursores. Este abordaje es modular en la naturaleza y potencialmente puede aplicarse para enlazar, específicamente según el sitio y de manera covalente, una amplia variedad de sustancias, incluso los péptidos, las proteínas, los anticuerpos, los fragmentos de anticuerpos y otras partes efectoras con una amplia variedad de actividades. Utilizando el método de proteínas de fusión para construir efectores conjugados de AD y DDD, virtualmente cualquier proteína o péptido puede incorporarse en un constructo DNL. Sin embargo, la técnica no es limitativa y es posible utilizar otros métodos de conjugación.
Se conoce una variedad de métodos para fabricar proteínas de fusión, incluso la síntesis de ácido nucleico, la hibridización y/o la amplificación para producir un ácido nucleico bicatenario sintético, que codifica una proteína de fusión de interés. Dichos ácidos nucleicos bicaternarios pueden insertarse en vectores de expresión para la producción de proteínas de fusión por técnicas estándar de biología molecular (véase, por ejemplo, Sambrook et al., Molecular Cloning, a laboratory manual, 2.ª Ed, 1989). En tales realizaciones preferidas, la parte AD y/o DDD puede unirse ya sea al extremo de terminal N o terminal C de una proteína o de un péptido efector, tales como un anticuerpo o fragmento. Sin embargo, el experto advertirá que el sitio de unión de una parte AD o DDD a una parte efectora puede variar, dependiendo de la naturaleza química de la parte efectora y la o las porciones de la parte efectora involucradas en su actividad fisiológica. La unión específica del sitio de un una variedad de partes efectoras puede llevarse a cabo usando técnicas conocidas en este campo, tales como el uso de reactivos de entrecruzamiento bivalentes y/o otras técnicas de conjugación químicas.
En una realización preferida, las proteínas de fusión se ensamblan mediante las técnicas dock and lock (DNL) que se explican, por ejemplo, en Rossi EA, et al.,Proc Natl Acad Sci USA 2006; 103:6841-6846; en los documentos de patente de los EE. UU. con los números 7.521.056; 7.550.143; 7.534.866; 7.527.787 y en la solicitud de patente de los EE. UU. No. 11/925.408. Las secuencias ejemplares de DDD y AD que se pueden utilizar en el método DNL para formar complejos sintéticos se describen a continuación.
DDD1
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (ID. DE SEC. N.º: 1)
DDD2
CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (ID. DE SEC. N.º: 2)
AD1 QIEILAKQIVDNAIQQA (ID. DE SEC. N.º: 3)
AD2
CGQIEILAKQIVDNAIQQAGC (ID. DE SEC. N.º: 4)
Variantes de secuencia de DNL
0125] En realizaciones alternativas, las variantes de secuencias de las partes AD y/o DDD pueden utilizarse en la construcción de los complejos DNL. Las relaciones estructura-función de los dominios AD y DDD han sido tema de investigación. (Véase, por ejemplo, Burns-Hamuro et al., 2005, Protein Sci 14:2982-92; Carr et al., 2001, J Biol Chem 276:17332-38; Alto et al., 2003, Proc Natl Acad Sci USA 100:4445-50; Hundsrucker et al., 2006, Biochem J 396:297306; Stokka et al., 2006, Biochem J 400:493-99; Gold et al., 2006, Mol Cell 24:383-95; Kinderman et al., 2006, Mol Cell 24:397-408.)
Por ejemplo, Kinderman et al. (2006) examinaron la estructura cristalina de la interacción de unión de AD-DDD y llegaron a la conclusión de que la secuencia DDD humana contenía una serie de residuos de aminoácidos conservados que eran importantes ya sea en la formación del dímero o en la unión de AKAP, subrayado en la ID. DE SEC. N.º: 1 presentada más abajo. (Véase la figura 1 de Kinderman et al., 2006.) El experto advertirá que al designar las variantes de secuencias de la secuencia de DDD, uno evitaría convenientemente cambiar cualquiera de los residuos subrayados, en tanto que podrían hacerse sustituciones de aminoácidos conservadores para los residuos que son menos críticos para la dimerización y la unión de AKAP.
Secuencia de DDD humana a partir de la cinasa A de la proteína
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (ID. DE SEC. N.º: 1)
Alto et al. (2003) llevaron a cabo un análisis bioinformático de la secuencia AD de diversas proteínas AKAP ara diseñar una secuencia AD selectiva de RII llamada AKAP-IS (ID. DE SEC. N.º: 5), con una constante de unión para DDD de 0,4 nM. La secuencia AKAPIS se diseñó como un antagonista peptídico de AKAP que se une a PKA. Los residuos en la secuencia AKAP-IS donde las sustituciones tendían a reducir la unión a DDD están subrayados en la ID. DE SEC. N.º: 3.
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SECUENCIA AKAP-IS
QIEILAKQIVDNAIQQA (ID. DE SEC. N.º: 3)
De manera similar, Gold (2006) utilizó cristalografía y tamizado de péptidos para desarrollar una secuencia SuperAKAP-IS (ID. DE SEC. N.º: 5), que exhibe una selectividad que es cinco órdenes de magnitud mayor para la 5 isoforma de RII de PKA, en comparación con la isoforma de RI. Los residuos subrayados indican las posiciones de las substituciones de los aminoácidos, con relación a la secuencia de AKAP-IS, que aumentaron la unión a la parte DDD de RIIα. En esta secuencia, el residuo Q de terminal N está numerado como el número de residuo 4 y un residuo de terminal Cu es un residuo número 20. Los residuos en los que podrían hacerse sustituciones para afectar la afinidad para RIIα fueron los residuos 8, 11, 15, 16, 18, 19 y 20 (Gold et al., 2006). Se contempla que en ciertas 10 realizaciones alternativas, la secuencia SuperAKAP-IS puede estar sustituida para la secuencia de la parte AD de AKAP-IS a fin de preparar los constructos de DNL. Otras secuencias alternativas que podrían sustituirse para la secuencia AD de AKAP-IS se muestran en las ID. DE SEC. N.º: 6-8. Las sustituciones relativas a la secuencia AKAP-IS se han subrayado. Se prevé que, al igual que con la secuencia AKAP-IS (ID. DE SEC. N.º: 3), la parte de AD también puede incluir los residuos cisteína y glicina adicionales con terminal N y los residuos glicina y cisteína
15 con terminal C, como se muestra en la ID. DE SEC. N.º: 4.
SuperAKAP-IS
QIEYVAKQIVDYAIHQA (ID. DE SEC. N.º: 5)
Secuencias de AKAP alternativas
QIEYKAKQIVDHAIHQA (ID. DE SEC. N.º: 6)
QIEYVAKQIVDHAIHQA (ID. DE SEC. N.º: 8)
Stokka et al. (2006) también desarrollaron competidores peptídicos de la unión de AKAP a PKA, lo cual se muestra en la ID. DE SEC. N.º: 9-11. Los antagonistas peptídicos se designaron como Ht31 (ID. DE SEC. N.º: 9), RIAD (ID. DE SEC. N.º: 10) y PV-38 (ID. DE SEC. N.º: 11). El péptido Ht-31 exhibió una mayor afinidad para la isoforma RII de
25 PKA, en tanto que RIAD y PV-38 demostraron una mayor afinidad para RI.
Ht31
DLIEEAASRIVDAVIEQVKAAGAY (ID. DE SEC. N.º: 9)
RIAD
LEQYANQLADQIIKEATE (ID. DE SEC. N.º: 10)
30 PV-38
FEELAWKIAKMIWSDVFQQC (ID. DE SEC. N.º: 11)
Hundsrucker et al. (2006) desarrollaron otros competidores peptídicos más para la unión de AKAP a PKA, con una constante de unión tan baja como de 0.4 nM a DDD de la forma RII de PKA. Las secuencias de diversos péptidos antagonísticos de AKAP se proveen en la tabla 1 de Hundsrucker et al. Los residuos que estaban altamente
35 conservados entre los dominios de AD de diferentes proteínas de AKAP se indican abajo subrayados, con referencia a la secuencia AKAP IS. Los residuos son los mismos que los observados por Alto et al. (2003), con la adición del residió de alanina de terminal C. (Véase la figura 4 de Hundsrucker et al. (2006)). Las secuencias de antagonistas de péptidos con afinidades particularmente altas para la secuencia de DDD de RII se muestra en la ID. DE SEC. N.º: 12-14.
40 AKAP-IS
QIEILAKQIVDNAIQQA (ID. DE SEC. N.º: 3)
AKAP7δ-wt-pep
PEDAELVRLSKRLVENAVLKAVQQY (ID. DE SEC. N.º: 12)
AKAP7δ-L304T-pep
AKAP7δ-L308D-pep
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PEDAELVRLSKRDVENAVLKAVQQY (ID. DE SEC. N.º: 14)
Carr et al. (2001) examinaron el grado de homología de secuencia entre diferentes secuencias de DDD de unión a AKAP provenientes de proteínas humanas y no humanas e identificaron los residuos en las secuencias de DDD que parecieron ser las más altamente conservadas entre las diferentes partes de DDD. Estas se indican a continuación, subrayadas, con referencia a la secuencia de DDD de RIIα de PKA humana de la ID. DE SEC. N.º: 1. Los residuos que estaban particularmente conservados se indican en cursiva. Los residuos se superponen con los sugeridos por Kinderman et al. (2006) pero no son idénticos a ellos, para que sean importantes para unirse a las proteínas de AKAP.
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (ID. DE SEC. N.º: 1)
El experto advertirá en general, que aquellos residuos de aminoácidos que son altamente conservados en las secuencias DDD y AD de las diferentes proteínas son los que pueden preferirse que permanezcan constantes para hacer las sustituciones de aminoácidos, en tanto que los residuos que son menos altamente conservados pueden ser más proclives de variaciones para producir variantes de secuencias de las secuencias AD y/o DDD que se describen en el presente documento.
Sustituciones de aminoácidos
En realizaciones alternativas, los métodos y las composiciones descritos pueden involucrar la producción y el uso de proteínas o péptidos con uno o más residuos de aminoácidos sustituidos. Por ejemplo, las secuencias DDD y/o AD empleadas para hacer los constructos DNL pueden modificarse como se describió anteriormente.
El experto será consciente de que, en general, las sustituciones de aminoácidos típicamente implican el reemplazo de un aminoácido con otro aminoácido de propiedades relativamente similares (es decir, sustituciones conservadoras de aminoácidos). Las propiedades de los diversos aminoácidos y el efecto de la sustitución de los aminoácidos en la estructura y función de la proteína han sido objeto de un exhaustivo estudio y conocimiento en la técnica.
Por ejemplo, puede considerarse el índice hidropático de los aminoácidos (Kyte & Doolittle, 1982, J. Mol. Biol., 157:105-132). El carácter hidropático relativo del aminoácido contribuye a la estructura secundaria de la proteína resultante, que a su vez, define la interacción de la proteína con otras moléculas. A cada aminoácido se le ha asignado un índice hidropático, basándose en su hidrofobicidad y en las características de carga (Kyte & Doolittle, 1982), estos son: isoleucina (+4,5); valine (+4,2); leucina (+3,8); fenilalanina (+2,8); cisteína/istina (+2,5); metionina (+1,9); alanina (+1,8); glicina (-0,4); treonina (-0,7); serina (-0,8); triptófano (-0,9); tirosina (-1,3); prolina (-1,6); histidina (-3,2); glutamato (-3,5); glutamina (-3,5); aspartato (-3,5); asparagina (-3,5); lisina (-3,9); y arginina (-4,5). Al hacer las sustituciones conservadoras, se prefiere el uso de aminoácidos cuyos índices hidropáticos están dentro de ± 2, se prefiere más si está dentro de ± 1, y más todavía si está dentro de ± 0,5.
La sustitución de aminoácidos también puede tomar en cuenta la hidrofilicidad del residuo del aminoácido (por ejemplo, documento de patente de los EE, UU, con el número 4.554.101). Se han asignado valores de hidrofilicidad a los residuos de aminoácidos: arginina (+3,0); lisina (+3,0); aspartato (+3,0); glutamato (+3,0); serina (+0,3); asparagina (+0,2); glutamina (+0,2); glicina (0); treonina (-0,4); prolina (-0,5 ,+-,1); alanina (-0,5); histidina (-0,5); cisteína (-1,0); metionina (-1,3); valine (-1,5); leucina (-1,8); isoleucina (-1,8); tirosina (-2,3); fenilalanina (-2,5); triptófano (-3,4). Se prefiere el reemplazo de aminoácidos con otros de similar hidrofilicidad.
Otras consideraciones incluyen el tamaño de la cadena lateral del aminoácido. Por ejemplo, por lo general, no sería preferible reemplazar un aminoácido con una cadena lateral compacta, tales como la glicina o la serina, con un aminoácido con una cadena lateral voluminosa, por ejemplo, un triptófano o una tirosina. El efecto de diversos residuos de aminoácidos sobre la estructura secundaria de la proteína es también un tema de consideración. Mediante el estudio empírico, se ha determinado el efecto de diferentes residuos de aminoácidos sobre la tendencia de los dominios de la proteína para adoptar una estructura secundaria alfa-helicoidal, de lámina beta o de giro inverso y es conocida en la técnica (véase, por ejemplo, Chou & Fasman, 1974, Biochemistry, 13:222-245; 1978, Ann. Rev. Biochem., 47: 251-276; 1979, Biophys. J., 26:367-384).
Basándose en tales consideraciones y en estudios empíricos exhaustivos, se han construido tablas de sustituciones conservadoras de aminoácidos y son conocidas en la técnica. Por ejemplo: arginina y lisina; glutamato y aspartato; serina y treonina; glutamina y asparagina; y valina, leucina e isoleucina. De manera alternativa: Ala (A) leu, ile, val; Arg (R) gln, asn, lys; Asn (N) his, asp, lys, arg, gln; Asp (D) asn, glu; Cys (C) ala, ser; Gln (Q) glu, asn; Glu (E) gln, asp; Gly (G) ala; His (H) asn, gln, lys, arg; Ile (I) val, met, ala, phe, leu; Leu (L) val, met, ala, phe, ile; Lys (K) gln, asn, arg; Met (M) phe, ile, leu; Phe (F) leu, val, ile, ala, tyr; Pro (P) ala; Ser (S), thr; Thr (T) ser; Trp (W) phe, tyr; Tyr (Y) trp, phe, thr, ser; Val (V) ile, leu, met, phe, ala.
Otras consideraciones para las sustituciones de aminoácidos incluyen si el residuo está o no ubicado en el interior de una proteína o si está expuesto al disolvente. Para los residuos interiores, las sustituciones conservadoras incluirían: Asp y Asn; Ser y Thr; Ser y Ala; Thr y Ala; Ala y Gly; Ile y Val; Val y Leu; Leu y Ile; Leu y Met; Phe y Tyr; Tyr y Trp. (Véase, por ejemplo, el sitio web de PROWL en rockefeller.edu) Para los residuos expuestos al disolvente,
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cromatografía por exclusión de tamaños y/o diafiltración, y se intercambió con tampón en un tampón adecuado a un pH de 6,5. El contenido de tiol se determinó por ensayo de Ellman, y se ubicó en el intervalo de 6,5 a 8,5 SH/IgG. De manera alternativa, los anticuerpos se redujeron con Tris (2-carboxietil) fosfina (TCEP) en tampón de fosfina, a un pH en el intervalo de 5-7, seguido por conjugación in situ. El MAb reducido se hizo reaccionar con un exceso molar de ∼10 a 15 veces de ’CL6-SN-38’ del ejemplo 1, o ’CL7-SN-38’ del ejemplo 2, o ’CL6SN-38-10-O-CO2Et’ del ejemplo 3, o ’CL7-SN-38-10-O-CO2Et’ del ejemplo 4, CL2A-SN-38 del ejemplo 10, o CL2ESN-38 del ejemplo 11, usando DMSO al 7-15 % v/v como cosolvente e incubando durante 20 minutos a temperatura ambiente. El conjugado se purificó por SEC centrifugado, pasaje por una columna hidrofóbica y finalmente, por ultrafiltracióndiafiltración. El producto se sometió a ensayo para SN-38 por absorbancia a 366 nm y se correlacionó con valores estándar, mientras la concentración de la proteína se dedujo de la absorbancia a 280 nm, se corrigió para subsanar el derrame de absorbancia de SN-38 en esta longitud de onda. De este modo, se determinaron las relaciones de sustitución de SN-38/MAb. Los conjugados purificados almacenados como formulaciones liofilizadas en viales de vidrio, se taparon al vacío y se almacenaron en un congelador a -20 °C. Las relaciones de sustitución molar (MSR, molar substitution ratios) de SN-38 obtenidas para algunos de estos conjugados, que típicamente estuvieron en el intervalo de 5 a 7, se muestran en la tabla 2.
Tabla 2: relaciones de sustitución molar (MSR) de SN-38/MAb en ciertos conjugados
- MAb
- Conjugado MSR
- hMN-14-[CL2A-SN-38], utilizando el enlazador farmacológico del ejemplo 10
- 6,1
- hMN-14-[CL6-SN-38], utilizando el enlazador farmacológico del ejemplo 1
- 6,8
- hMN-14
- hMN-14-[CL7-SN-38], utilizando el enlazador farmacológico del ejemplo 2 5,9
- hMN-14-[CL7-SN-38-10-O-CO2Et], utilizando el enlazador farmacológico del ejemplo 4
- 5,8
- hMN-14-[CL2E-SN-38], utilizando el enlazador farmacológico del ejemplo 11
- 5,9
- hRS7-CL2A-SN-38 utilizando el enlazador farmacológico del ejemplo 10
- 5,8
- hRS7
- hRS7-CL7-SN-38 utilizando el enlazador farmacológico del ejemplo 2 5,9
- hRS7-CL7-SN-38 (Et) utilizando el enlazador farmacológico del ejemplo 4
- 6,1
- hA20
- hA20-CL2A-SN-38 utilizando el enlazador farmacológico del ejemplo 10 5,8
- hLL2
- hLL2-CL2A-SN-38 utilizando el enlazador farmacológico del ejemplo 10 5,7
- hPAM4
- hPAM4-CL2A-SN-38 utilizando el enlazador farmacológico del ejemplo 10 5,9
Ejemplo 15 [SIC]: eficacias terapéuticas in vivo en modelos preclínicos del carcinoma pancreático o de colon humano
Se trataron unas ratonas atímicas sin pelo inmunocomprometidas, portadoras de xenoinjertos subcutáneos de tumor pancreático o de colon humano con conjugado CL2A-SN-38 específico o con conjugado de control, o se dejaron sin tratar. Se observaron las eficacias terapéuticas de los conjugados específicos. La figura 1 muestra un modelo de tumor pancreático Capan 1, donde los conjugados CL2A-SN-38 específicos de los anticuerpos hRS7 (anti-EGP-1), hPAM4 (anti-mucina), y hMN-14 (anti-CEACAM5) demostraron mejores eficacias que el conjugado hA20-CL2A-SN38 (anti-CD20) de control y el control no tratado. De un modo similar en un modelo BXPC3 de cáncer pancreático humano, el hRS7-CL2A-SN-38 específico demostró una mejor eficacia terapéutica que los tratamientos de control (figura 2). Del mismo modo, en un modelo LS174T agresivo de carcinoma de colon humano, el tratamiento con hMN14-CL2A-SN-38 específica fue más eficaz que no implementar tratamiento (figura 3).
Ejemplo 16: eliminación de la infección por VIH mediante el tratamiento con un conjugado de SN-38 de un MAb antigp120
Un MAb dirigido al anticuerpo anti-gp120 de la proteína gp120 de la envuelta del VIH, tal como P4/D10, se reduce usando las condiciones descritas en el ejemplo 7, y el MAb reducido se hace reaccionar con un exceso molar de 20 veces del enlazador del fármaco CL7SN-38, que es tal como se describe en el ejemplo 2. Se obtiene un conjugado anti-gp120-SN-38 con una sustitución de ∼8 moléculas de fármaco por anticuerpo. Un ensayo de inhibición de VIH in vitro con dicho conjugado se lleva a cabo usando diversas mezclas de células Jurkat-T no infectadas y células Jurkat-T totalmente infectadas (en las relaciones de 99,8:0,2 a 95:5), y tratando con diluciones en serie del
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